Publications

Nielsen, T.O. Leung, S.C. Rimm, D.L. Dodson, A. Acs, B. Badve, S. Denkert, C. Ellis, M.J. Fineberg, S. Flowers, M. Kreipe, H.H. Laenkholm, A.-. Pan, H. Penault-Llorca, F.M. Polley, M.-. Salgado, R. Smith, I.E. Sugie, T. Bartlett, J.M. McShane, L.M. Dowsett, M. Hayes, D.F. (2021). Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. Jnci: journal of the national cancer institute, Vol.113 (7), pp. 808-819. show abstract

Parry, S. Dowsett, M. Dodson, A. (2021). UK NEQAS ICC & ISH Ki-67 Data Reveal Differences in Performance of Primary Antibody Clones. Applied immunohistochemistry & molecular morphology, Vol.29 (2), pp. 86-94.

Richman, J. Ring, A. Dowsett, M. Sestak, I. (2021). Clinical validity of clinical treatment score 5 (CTS5) for estimating risk of late recurrence in unselected, non-trial patients with early oestrogen receptor-positive breast cancer. Breast cancer research and treatment, Vol.186 (1), pp. 115-123. show abstract

Abstract Purpose Clinical Treatment Score at 5 years (CTS5) is a prognostic tool to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with oestrogen receptor-positive (ER-positive) breast cancer. Methods The validity of CTS5 was tested in a retrospective cohort of patients diagnosed with early ER-positive breast cancer. The primary endpoint was DR in years 5–10. The primary analysis cohort consisted of postmenopausal women, with premenopausal women as a secondary analysis cohort. Cox regression models were used to determine the prognostic value of CTS5 and Kaplan–Meier curves were used with associated 10-year DR risks (%). Results 2428 women were included with a median follow-up of 13.4 years. The CTS5 was significantly prognostic in both postmenopausal (N = 1662, HR = 2.18 95% CI (1.78–2.67)) and premenopausal women (N = 766, HR = 1.84 95% CI (1.32–2.56)). The 10-year DR risks were 2.9% (1.9–4.5), 7.2% (5.3–9.9), and 12.9% (10.0–16.7) for low, intermediate and high risk in postmenopausal women and 3.8% (2.2–6.7), 6.9% (4.4–10.8), and 11.1% (7.4–16.5) in premenopausal women, respectively. The number of observed DRs was significantly greater than expected in those predicted to be at high risk by CTS5 but this discordance was lost when those receiving more than 60 months of endocrine therapy were excluded. Conclusions The CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected postmenopausal patients but less so in premenopausal patients. Calibration of the CTS5 was good in patients who did not receive extended endocrine therapy. The CTS5 low-risk cohort has risk of DR so low as to not warrant extended endocrine therapy. .

Alataki, A. Zabaglo, L. Tovey, H. Dodson, A. Dowsett, M. (2021). A simple digital image analysis system for automated Ki67 assessment in primary breast cancer. Histopathology, Vol.79 (2), pp. 200-209.

Buus, R. Sestak, I. Kronenwett, R. Ferree, S. Schnabel, C.A. Baehner, F.L. Mallon, E.A. Cuzick, J. Dowsett, M. (2021). Molecular Drivers of Oncotype DX, Prosigna, EndoPredict, and the Breast Cancer Index: A TransATAC Study. Journal of clinical oncology, Vol.39 (2), pp. 126-135. show abstract

PURPOSE The Onco type DX Recurrence Score (RS), Prosigna Prediction Analysis of Microarray 50 (PAM50) Risk of Recurrence (ROR), EndoPredict (EP), and Breast Cancer Index (BCI) are used clinically for estimating risk of distant recurrence for patients receiving endocrine therapy. Discordances in estimates occur between them. We aimed to identify the molecular features that drive the tests and lead to these differences. PATIENTS AND METHODS Analyses for RS, ROR, EP, and BCI were conducted by the manufacturers in the TransATAC sample collection that consisted of the tamoxifen or anastrozole arms of the ATAC trial. Estrogen receptor–positive/human epidermal growth factor receptor 2 (HER2)–negative cases without chemotherapy treatment were included in which all four tests were available (n = 785). Clinicopathologic features included in some tests were excluded from the comparisons. Estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of variance tests were applied. RESULTS There were moderate to strong correlations among the four molecular scores (ρ = 0.63-0.74) except for RS versus ROR (ρ = 0.32) and RS versus BCI (ρ = 0.35). RS had strong negative correlation with its estrogen module (ρ = −0.79) and moderate positive correlation with its proliferation module (ρ = 0.36). RS’s proliferation module explained 72.5% of ROR’s variance, while the estrogen module explained only 0.6%. Most of EP’s and BCI’s variation was accounted for by the proliferation module (50.0% and 54.3%, respectively) and much less by the estrogen module (20.2% and 2.7%, respectively). CONCLUSION In contrast to common understanding, RSs are determined more strongly by estrogen-related features and only weakly by proliferation markers. However, the EP, BCI, and particularly ROR scores are determined largely by proliferative features. These relationships help to explain the differences in the prognostic performance of the tests. .

Doran, S.J. Kumar, S. Orton, M. d’Arcy, J. Kwaks, F. O’Flynn, E. Ahmed, Z. Downey, K. Dowsett, M. Turner, N. Messiou, C. Koh, D.-. (2021). “Real-world” radiomics from multi-vendor MRI: an original retrospective study on the prediction of nodal status and disease survival in breast cancer, as an exemplar to promote discussion of the wider issues. Cancer imaging, Vol.21 (1). show abstract

Abstract Background Most MRI radiomics studies to date, even multi-centre ones, have used “pure” datasets deliberately accrued from single-vendor, single-field-strength scanners. This does not reflect aspirations for the ultimate generalisability of AI models. We therefore investigated the development of a radiomics signature from heterogeneous data originating on six different imaging platforms, for a breast cancer exemplar, in order to provide input into future discussions of the viability of radiomics in “real-world” scenarios where image data are not controlled by specific trial protocols but reflective of routine clinical practice. Methods One hundred fifty-six patients with pathologically proven breast cancer underwent multi-contrast MRI prior to neoadjuvant chemotherapy and/or surgery. From these, 92 patients were identified for whom T2-weighted, diffusion-weighted and contrast-enhanced T1-weighted sequences were available, as well as key clinicopathological variables. Regions-of-interest were drawn on the above image types and, from these, semantic and calculated radiomics features were derived. Classification models using a variety of methods, both with and without recursive feature elimination, were developed to predict pathological nodal status. Separately, we applied the same methods to analyse the information carried by the radiomic features regarding the originating scanner type and field strength. Repeated, ten-fold cross-validation was employed to verify the results. In parallel work, survival modelling was performed using random survival forests. Results Prediction of nodal status yielded mean cross-validated AUC values of 0.735 ± 0.15 (SD) for clinical variables alone, 0.673 ± 0.16 (SD) for radiomic features only, and 0.764 ± 0.16 (SD) for radiomics and clinical features together. Prediction of scanner platform from the radiomics features yielded extremely high values of AUC between 0.91 and 1 for the different classes examined indicating the presence of confounding features for the nodal status classification task. Survival analysis, gave out-of-bag prediction errors of 19.3% (clinical features only), 36.9–51.8% (radiomic features from different combinations of image contrasts), and 26.7–35.6% (clinical plus radiomics features). Conclusions Radiomic classification models whose predictive ability was consistent with previous single-vendor, single-field strength studies have been obtained from multi-vendor, multi-field-strength data, despite clear confounding information being present. However, our sample size was too small to obtain useful survival modelling results. .

Narayanan, P.L. Raza, S.E. Hall, A.H. Marks, J.R. King, L. West, R.B. Hernandez, L. Guppy, N. Dowsett, M. Gusterson, B. Maley, C. Hwang, E.S. Yuan, Y. (2021). Unmasking the immune microecology of ductal carcinoma in situ with deep learning. Npj breast cancer, Vol.7 (1). show abstract

Pearson, A. Proszek, P. Pascual, J. Fribbens, C. Shamsher, M.K. Kingston, B. O'Leary, B. Herrera-Abreu, M.T. Cutts, R.J. Garcia-Murillas, I. Bye, H. Walker, B.A. Gonzalez De Castro, D. Yuan, L. Jamal, S. Hubank, M. Lopez-Knowles, E. Schuster, E.F. Dowsett, M. Osin, P. Nerurkar, A. Parton, M. Okines, A.F. Johnston, S.R. Ring, A. Turner, N.C. (2020). Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance. Clinical cancer research, Vol.26 (3), pp. 608-622.

Buus, R. Sestak, I. Barron, S. Loughman, T. Fender, B. Ruiz, C.L. Dynoodt, P. Wang, C.-. O'Leary, D. Gallagher, W.M. Dowsett, M. Cuzick, J. (2020). Validation of the OncoMasTR Risk Score in Estrogen Receptor–Positive/HER2-Negative Patients: A TransATAC study. Clinical cancer research, Vol.26 (3), pp. 623-631.

Cuzick, J. Sestak, I. Forbes, J.F. Dowsett, M. Cawthorn, S. Mansel, R.E. Loibl, S. Bonanni, B. Evans, D.G. Howell, A. (2020). Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. The lancet, Vol.395 (10218), pp. 117-122.

Sestak, I. Filipits, M. Buus, R. Rudas, M. Balic, M. Knauer, M. Kronenwett, R. Fitzal, F. Cuzick, J. Gnant, M. Greil, R. Dowsett, M. Dubsky, P. (2020). Prognostic Value of EndoPredict in Women with Hormone Receptor–Positive, HER2-Negative Invasive Lobular Breast Cancer. Clinical cancer research, Vol.26 (17), pp. 4682-4687.

Turner, N.C. Swift, C. Kilburn, L. Fribbens, C. Beaney, M. Garcia-Murillas, I. Budzar, A.U. Robertson, J.F. Gradishar, W. Piccart, M. Schiavon, G. Bliss, J.M. Dowsett, M. Johnston, S.R. Chia, S.K. (2020). ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials. Clinical cancer research, Vol.26 (19), pp. 5172-5177.

Banerjee, S. Tovey, H. Bowen, R. Folkerd, E. Kilburn, L. McLachlan, J. Hall, M. Tunariu, N. Attygalle, A. Lima, J.P. Perry, S. Chatfield, P. Hills, M. Kaye, S. Attard, G. Dowsett, M. Bliss, J.M. (2020). Abiraterone in patients with recurrent epithelial ovarian cancer: principal results of the phase II Cancer of the Ovary Abiraterone (CORAL) trial (CRUK – A16037). Therapeutic advances in medical oncology, Vol.12, pp. 175883592097535-175883592097535. show abstract

Smith, I. Robertson, J. Kilburn, L. Wilcox, M. Evans, A. Holcombe, C. Horgan, K. Kirwan, C. Mallon, E. Sibbering, M. Skene, A. Vidya, R. Cheang, M. Banerji, J. Morden, J. Sidhu, K. Dodson, A. Bliss, J.M. Dowsett, M. (2020). Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. The lancet oncology, Vol.21 (11), pp. 1443-1454.

Chopra, N. Tovey, H. Pearson, A. Cutts, R. Toms, C. Proszek, P. Hubank, M. Dowsett, M. Dodson, A. Daley, F. Kriplani, D. Gevensleben, H. Davies, H.R. Degasperi, A. Roylance, R. Chan, S. Tutt, A. Skene, A. Evans, A. Bliss, J.M. Nik-Zainal, S. Turner, N.C. (2020). Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer. Nature communications, Vol.11 (1). show abstract

Dowsett, M. Ellis, M.J. Dixon, J.M. Gluz, O. Robertson, J. Kates, R. Suman, V.J. Turnbull, A.K. Nitz, U. Christgen, M. Kreipe, H. Kuemmel, S. Bliss, J.M. Barry, P. Johnston, S.R. Jacobs, S.A. Ma, C.X. Smith, I.E. Harbeck, N. (2020). Evidence-based guidelines for managing patients with primary ER+ HER2− breast cancer deferred from surgery due to the COVID-19 pandemic. Npj breast cancer, Vol.6 (1). show abstract

Woolf, D.K. Li, S.P. Detre, S. Liu, A. Gogbashian, A. Simcock, I.C. Stirling, J. Kosmin, M. Cook, G.J. Siddique, M. Dowsett, M. Makris, A. Goh, V. (2019). Assessment of the Spatial Heterogeneity of Breast Cancers: Associations Between Computed Tomography and Immunohistochemistry. Biomarkers in cancer, Vol.11, pp. 1179299X1985151-1179299X1985151. show abstract

Rimm, D.L. Leung, S.C. McShane, L.M. Bai, Y. Bane, A.L. Bartlett, J.M. Bayani, J. Chang, M.C. Dean, M. Denkert, C. Enwere, E.K. Galderisi, C. Gholap, A. Hugh, J.C. Jadhav, A. Kornaga, E.N. Laurinavicius, A. Levenson, R. Lima, J. Miller, K. Pantanowitz, L. Piper, T. Ruan, J. Srinivasan, M. Virk, S. Wu, Y. Yang, H. Hayes, D.F. Nielsen, T.O. Dowsett, M. (2019). An international multicenter study to evaluate reproducibility of automated scoring for assessment of Ki67 in breast cancer. Modern pathology, Vol.32 (1), pp. 59-69.

Willis, S. Polydoropoulou, V. Sun, Y. Young, B. Tsourti, Z. Karlis, D. Long, B. Lin, X. Theel, S. Carlson, J. Győrffy, B. Williams, C. Abramovitz, M. Dafni, U. Dowsett, M. Leyland-Jones, B. (2019). Exploratory Analysis of Single-Gene Predictive Biomarkers in HERA DASL Cohort Reveals That C8A mRNA Expression Is Prognostic of Outcome and Predictive of Benefit of Trastuzumab. Jco precision oncology, (2), pp. 1-12.

SONNENBLICK, A. BAILEY, A. UZIELY, B. UNTCH, M. SMITH, I.A. GIANNI, L. BASELGA, J. JACKISCH, C. CAMERON, D. BELL, R. ZARDAVAS, D. AL-SAKAFF, N. GELBER, R.D. DOWSETT, M. LEYLAND-JONES, B. PICCART-GEBHART, M.J. DE AZAMBUJA, E. (2019). Autoimmunity and Benefit from Trastuzumab Treatment in Breast Cancer: Results from the HERA Trial. Anticancer research, Vol.39 (2), pp. 797-802.

Dowsett, M. (2019). Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions. Jnci cancer spectrum, .

Richman, J. Dowsett, M. (2019). Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat rev clin oncol, Vol.16 (5), pp. 296-311. show abstract

Leal, M.F. Haynes, B.P. MacNeill, F.A. Dodson, A. Dowsett, M. (2019). Comparison of protein expression between formalin-fixed core-cut biopsies and surgical excision specimens using a novel multiplex approach. Breast cancer research and treatment, Vol.175 (2), pp. 317-326.

Boddington, C. Bradley, R. Braybrooke, J. Burrett, J. Clarke, M. Davies, C. Davies, L. Dodwell, D. Duane, F. Evans, V. Gettins, L. Godwin, J. Gray, R. Hills, R. James, S. Liu, H. Liu, Z. MacKinnon, E. Mannu, G. McGale, P. McHugh, T. Morris, P. Pan, H. Peto, R. Read, S. Taylor, C. Wang, Y. Wang, Z. Bradley, R. Braybrooke, J. Gray, R. Bergh, J. Peto, R. Gray, R. Bradley, R. Braybrooke, J. Liu, Z. Peto, R. Davies, L. Dodwell, D. McGale, P. Pan, H. Taylor, C. Barlow, W. Bliss, J. Bruzzi, P. Cameron, D. Fountzilas, G. Loibl, S. Mackey, J. Martin, M. Del Mastro, L. Moebus, V. Nekljudova, V. De Placido, S. Swain, S. Untch, M. Pritchard, K.I. Bergh, J. Norton, L. Fasching, P. Harbeck, N. Untch, M. Piedbois, P. Gnant, M. Steger, G. Di Leo, A. Dolci, S. Francis, P. Larsimont, D. Nogaret, J.M. Philippson, C. Piccart-Gebhart, M.J. Linn, S. Peer, P. Tjan-Heijnen, V. Vliek, S. Mackey, J. Martin, M. Slamon, D. Bartlett, J.M. Bramwell, V.H. Chen, B.E. Chia, S.K. Gelmon, K. Goss, P.E. Levine, M.N. Parulekar, W. Pater, J.L. Pritchard, K.I. Rakovitch, E. Shepherd, L.E. Tu, D. Whelan, T. Berry, D. Broadwater, G. Cirrincione, C. Muss, H. Norton, L. Weiss, R.B. Shan, Y. Shao, Y.F. Wang, X. Xu, B. Zhao, D.B. Bartelink, H. Bijker, N. Bogaerts, J. Cardoso, F. Cufer, T. Julien, J.P. Poortmans, P.M. Rutgers, E. van de Velde, C.J. Carrasco, E. Martin, M. Segui, M.A. Blohmer, J.U. Costa, S.D. Gerber, B. Jackisch, C. Loibl, S. Nekljudova, V. von Minckwitz, G. Bruzzi, P. Giuliano, M. De laurentiis, M. De Placido, S. Del Mastro, L. Bamia, C. Fountzilas, G. Koliou, G.-. Mavroudis, D. A'Hern, R. Bliss, J. Cameron, D. Ellis, P. Kilburn, L. Morden, J. Yarnold, J.R. Sadoon, M. Tulusan, A.H. Anderson, S. Bass, G. Costantino, J. Dignam, J. Fisher, B. Geyer, C. Mamounas, E.P. Paik, S. Redmond, C. Swain, S. Wickerham, L. Wolmark, N. Del Mastro, L. Venturini, M. Bighin, C. Bruzzi, P. Del Mastro, L. Pastorino, S. Pronzato, P. Sertoli, M.R. Barlow, W. Bergh, J. Foukakis, T. Pritchard, K.I. Swain, S. Cameron, D. Albain, K. Anderson, S. Arriagada, R. Barlow, W. Bartlett, J. Bergsten-Nordstrom, E. Bliss, J. Boccardo, F. Bradley, R. Brain, E. Braybrooke, J. Carey, L. Clarke, M. Coates, A. Coleman, R. Correa, C. Costantino, J. Cuzick, J. Davidson, N. Davies, C. Davies, L. Di Leo, A. Dodwell, D. Dowsett, M. Duane, F. Ewertz, M. Forbes, J. Francis, P. Gelber, R. Gnant, M. Goldhirsch, A. Goodwin, P. Gray, R. Hayes, D. Hill, C. Ingle, J. Jagsi, R. Janni, W. Liu, Z. Loibl, S. MacKinnon, E. Mannu, G. Martin, M. McGale, P. Mukai, H. Nekljudova, V. Norton, L. Ohashi, Y. Paik, S. Pan, H. Peto, R. Piccart, M. Pierce, L. Poortmans, P. Raina, V. Ravdin, P. Rea, D. Regan, M. Robertson, J. Rutgers, E. Slamon, D. Sparano, J. Steger, G. Taylor, C. Tutt, A. Viale, G. Wang, X. Whelan, T. Wilcken, N. Wolmark, N. Wood, W. Zambetti, M. EBCTCG, (2019). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37298 women with early breast cancer in 26 randomised trials. Lancet, Vol.393 (10179), pp. 1440-1452.

Abubakar, M. Figueroa, J. Ali, H.R. Blows, F. Lissowska, J. Caldas, C. Easton, D.F. Sherman, M.E. Garcia-Closas, M. Dowsett, M. Pharoah, P.D. (2019). Combined quantitative measures of ER, PR, HER2, and KI67 provide more prognostic information than categorical combinations in luminal breast cancer. Modern pathology, Vol.32 (9), pp. 1244-1256.

Cocce, K.J. Jasper, J.S. Desautels, T.K. Everett, L. Wardell, S. Westerling, T. Baldi, R. Wright, T.M. Tavares, K. Yllanes, A. Bae, Y. Blitzer, J.T. Logsdon, C. Rakiec, D.P. Ruddy, D.A. Jiang, T. Broadwater, G. Hyslop, T. Hall, A. Laine, M. Phung, L. Greene, G.L. Martin, L.-. Pancholi, S. Dowsett, M. Detre, S. Marks, J.R. Crawford, G.E. Brown, M. Norris, J.D. Chang, C.-. McDonnell, D.P. (2019). The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer. Cell reports, Vol.29 (4), pp. 889-903.e10.

Haynes, B.P. Ginsburg, O. Gao, Q. Folkerd, E. Afentakis, M. Buus, R. Quang, L.H. Thi Han, P. Khoa, P.H. Dinh, N.V. To, T.V. Clemons, M. Holcombe, C. Osborne, C. Evans, A. Skene, A. Sibbering, M. Rogers, C. Laws, S. Noor, L. Smith, I.E. Dowsett, M. (2019). Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer. Npj breast cancer, Vol.5 (1). show abstract

AbstractThe major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27–35 and 1–6; low oestradiol and low progesterone), W2 (days 7–16; high oestradiol and low progesterone) and W3 (days 17–26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of PGR, GREB1, TFF1 and PDZK1) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including GREB1, PGR and TFF1, and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3–2.4-fold; FDR 0.016–0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer..

Dowsett, M. Turner, N. (2019). Estimating Risk of Recurrence for Early Breast Cancer: Integrating Clinical and Genomic Risk. J clin oncol, Vol.37 (9), pp. 689-692.

Asselain, B. Barlow, W. Bartlett, J. Bergh, J. Bergsten-Nordström, E. Bliss, J. Boccardo, F. Boddington, C. Bogaerts, J. Bonadonna, G. Bradley, R. Brain, E. Braybrooke, J. Broet, P. Bryant, J. Burrett, J. Cameron, D. Clarke, M. Coates, A. Coleman, R. Coombes, R.C. Correa, C. Costantino, J. Cuzick, J. Danforth, D. Davidson, N. Davies, C. Davies, L. Di Leo, A. Dodwell, D. Dowsett, M. Duane, F. Evans, V. Ewertz, M. Fisher, B. Forbes, J. Ford, L. Gazet, J.-. Gelber, R. Gettins, L. Gianni, L. Gnant, M. Godwin, J. Goldhirsch, A. Goodwin, P. Gray, R. Hayes, D. Hill, C. Ingle, J. Jagsi, R. Jakesz, R. James, S. Janni, W. Liu, H. Liu, Z. Lohrisch, C. Loibl, S. MacKinnon, L. Makris, A. Mamounas, E. Mannu, G. Martín, M. Mathoulin, S. Mauriac, L. McGale, P. McHugh, T. Morris, P. Mukai, H. Norton, L. Ohashi, Y. Olivotto, I. Paik, S. Pan, H. Peto, R. Piccart, M. Pierce, L. Poortmans, P. Powles, T. Pritchard, K. Ragaz, J. Raina, V. Ravdin, P. Read, S. Regan, M. Robertson, J. Rutgers, E. Scholl, S. Slamon, D. Sölkner, L. Sparano, J. Steinberg, S. Sutcliffe, R. Swain, S. Taylor, C. Tutt, A. Valagussa, P. van de Velde, C. van der Hage, J. Viale, G. von Minckwitz, G. Wang, Y. Wang, Z. Wang, X. Whelan, T. Wilcken, N. Winer, E. Wolmark, N. Wood, W. Zambetti, M. Zujewski, J.A. (2018). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. The lancet oncology, Vol.19 (1), pp. 27-39.

Filipits, M. Dafni, U. Gnant, M. Polydoropoulou, V. Hills, M. Kiermaier, A. de Azambuja, E. Larsimont, D. Rojo, F. Viale, G. Toi, M. Harbeck, N. Prichard, K.I. Gelber, R.D. Dinh, P. Zardavas, D. Leyland-Jones, B. Piccart-Gebhart, M.J. Dowsett, M. (2018). Association of p27 and Cyclin D1 Expression and Benefit from Adjuvant Trastuzumab Treatment in HER2-Positive Early Breast Cancer: A TransHERA Study. Clinical cancer research, Vol.24 (13), pp. 3079-3086.

Heindl, A. Sestak, I. Naidoo, K. Cuzick, J. Dowsett, M. Yuan, Y. (2018). Relevance of spatial heterogeneity of immune infiltration for predicting risk of recurrence after endocrine therapy of ER+ breast cancer. Journal of the national cancer institute, Vol.110 (2), pp. 166-175.

Tutt, A. Tovey, H. Cheang, M.C. Kernaghan, S. Kilburn, L. Gazinska, P. Owen, J. Abraham, J. Barrett, S. Barrett-Lee, P. Brown, R. Chan, S. Dowsett, M. Flanagan, J.M. Fox, L. Grigoriadis, A. Gutin, A. Harper-Wynne, C. Hatton, M.Q. Hoadley, K.A. Parikh, J. Parker, P. Perou, C.M. Roylance, R. Shah, V. Shaw, A. Smith, I.E. Timms, K.M. Wardley, A.M. Wilson, G. Gillett, C. Lanchbury, J.S. Ashworth, A. Rahman, N. Harries, M. Ellis, P. Pinder, S.E. Bliss, J.M. (2018). Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat med, Vol.24 (5), pp. 628-637. show abstract

Xiao, T. Li, W. Wang, X. Xu, H. Yang, J. Wu, Q. Huang, Y. Geradts, J. Jiang, P. Fei, T. Chi, D. Zang, C. Liao, Q. Rennhack, J. Andrechek, E. Li, N. Detre, S. Dowsett, M. Jeselsohn, R.M. Liu, X.S. Brown, M. (2018). Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy. Proc natl acad sci u s a, . show abstract

Dodson, A. Parry, S. Ibrahim, M. Bartlett, J.M. Pinder, S. Dowsett, M. Miller, K. (2018). Breast cancer biomarkers in clinical testing: analysis of a UK national external quality assessment scheme for immunocytochemistry and in situ hybridisation database containing results from 199 300 patients. The journal of pathology: clinical research, Vol.4 (4), pp. 262-273.

Sestak, I. Buus, R. Cuzick, J. Dubsky, P. Kronenwett, R. Denkert, C. Ferree, S. Sgroi, D. Schnabel, C. Baehner, F.L. Mallon, E. Dowsett, M. (2018). Comparison of the Performance of 6 Prognostic Signatures for Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. Jama oncol, . show abstract

Importance: Multiple molecular signatures are available for managing estrogen receptor (ER)-positive breast cancer but with little direct comparative information to guide the patient's choice. Objective: To conduct a within-patient comparison of the prognostic value of 6 multigene signatures in women with early ER-positive breast cancer who received endocrine therapy for 5 years. Design, Setting, and Participants: This retrospective biomarker analysis included 774 postmenopausal women with ER-positive ERBB2 (formerly HER2)-negative breast cancer. This analysis was performed as a preplanned secondary study of data from the Anastrozole or Tamoxifen Alone or Combined randomized clinical trial comparing 5-year treatment with anastrozole vs tamoxifen with 10-year follow-up data. The signatures included the Oncotype Dx recurrence score, PAM50-based Prosigna risk of recurrence (ROR), Breast Cancer Index (BCI), EndoPredict (EPclin), Clinical Treatment Score, and 4-marker immunohistochemical score. Data were collected from January 2009, through April 2015. Main Outcomes and Measures: The primary objective was to compare the prognostic value of these signatures in addition to the Clinical Treatment Score (nodal status, tumor size, grade, age, and endocrine treatment) for distant recurrence for 0 to 10 years and 5 to 10 years after diagnosis. Likelihood ratio (LR) statistics were used with the χ2 test and C indexes to assess the prognostic value of each signature. Results: In this study of 774 postmenopausal women with ER-positive, ERBB2-negative disease (mean [SD] age, 64.1 [8.1] years), 591 (mean [SD] age, 63.4 [7.9] years) had node-negative disease. The signatures providing the most prognostic information were the ROR (hazard ratio [HR], 2.56; 95% CI, 1.96-3.35), followed by the BCI (HR, 2.46; 95% CI, 1.88-3.23) and EPclin (HR, 2.14; 95% CI, 1.71-2.68). Each provided significantly more information than the Clinical Treatment Score (HR, 1.99; 95% CI, 1.58-2.50), the recurrence score (HR, 1.69; 95% CI, 1.40-2.03), and the 4-marker immunohistochemical score (HR, 1.95; 95% CI, 1.55-2.45). Substantially less information was provided by all 6 molecular tests for the 183 patients with 1 to 3 positive nodes, but the BCI (ΔLR χ2 = 9.2) and EPclin (ΔLR χ2 = 7.4) provided more additional prognostic information than the other signatures. Conclusions and Relevance: For women with node-negative disease, the ROR, BCI, and EPclin were significantly more prognostic for overall and late distant recurrence. For women with 1 to 3 positive nodes, limited independent information was available from any test. These data might help oncologists and patients to choose the most appropriate test when considering chemotherapy use and/or extended endocrine therapy. Trial Registration: isrctn.com Identifier: ISRCTN18233230..

Wolff, A.C. Hammond, M.E. Allison, K.H. Harvey, B.E. McShane, L.M. Dowsett, M. (2018). HER2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update Summary. J oncol pract, , pp. JOP1800206-JOP1800206.

Dowsett, M. Sestak, I. Regan, M.M. Dodson, A. Viale, G. Thürlimann, B. Colleoni, M. Cuzick, J. (2018). Integration of Clinical Variables for the Prediction of Late Distant Recurrence in Patients With Estrogen Receptor-Positive Breast Cancer Treated With 5 Years of Endocrine Therapy: CTS5. J clin oncol, , pp. JCO2017764258-JCO2017764258. show abstract

Gao, Q. López-Knowles, E. Chon U Cheang, M. Ribas, R. Sidhu, K. Evans, D. Martins, V. Dodson, A. Bliss, J.M. Smith, I. Martin, L.-. Dowsett, M. (2018). Major Impact of Sampling Methodology on Gene Expression in Estrogen Receptor–Positive Breast Cancer. Jnci cancer spectrum, . show abstract

Vlachogiannis, G. Hedayat, S. Vatsiou, A. Jamin, Y. Fernández-Mateos, J. Khan, K. Lampis, A. Eason, K. Huntingford, I. Burke, R. Rata, M. Koh, D.-. Tunariu, N. Collins, D. Hulkki-Wilson, S. Ragulan, C. Spiteri, I. Moorcraft, S.Y. Chau, I. Rao, S. Watkins, D. Fotiadis, N. Bali, M. Darvish-Damavandi, M. Lote, H. Eltahir, Z. Smyth, E.C. Begum, R. Clarke, P.A. Hahne, J.C. Dowsett, M. de Bono, J. Workman, P. Sadanandam, A. Fassan, M. Sansom, O.J. Eccles, S. Starling, N. Braconi, C. Sottoriva, A. Robinson, S.P. Cunningham, D. Valeri, N. (2018). Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science, Vol.359, pp. 920-926. show abstract

Wolff, A.C. Hammond, M.E. Allison, K.H. Harvey, B.E. Mangu, P.B. Bartlett, J.M. Bilous, M. Ellis, I.O. Fitzgibbons, P. Hanna, W. Jenkins, R.B. Press, M.F. Spears, P.A. Vance, G.H. Viale, G. McShane, L.M. Dowsett, M. (2018). Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J clin oncol, , pp. JCO2018778738-JCO2018778738. show abstract

Purpose To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. Methods Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in > 10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended work-up for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥ 2.0; average HER2 copy number < 4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 4.0 and < 6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results. Find additional information at www.asco.org/breast-cancer-guidelines ..

Wolff, A.C. Hammond, M.E. Allison, K.H. Harvey, B.E. Mangu, P.B. Bartlett, J.M. Bilous, M. Ellis, I.O. Fitzgibbons, P. Hanna, W. Jenkins, R.B. Press, M.F. Spears, P.A. Vance, G.H. Viale, G. McShane, L.M. Dowsett, M. (2018). Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch pathol lab med, . show abstract

Smith, I. Yardley, D. Burris, H. De Boer, R. Amadori, D. McIntyre, K. Ejlertsen, B. Gnant, M. Jonat, W. Pritchard, K.I. Dowsett, M. Hart, L. Poggio, S. Comarella, L. Salomon, H. Wamil, B. O'Shaughnessy, J. (2017). Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial. J clin oncol, Vol.35 (10), pp. 1041-1048. show abstract

Ellis, M.J. Suman, V.J. Hoog, J. Goncalves, R. Sanati, S. Creighton, C.J. DeSchryver, K. Crouch, E. Brink, A. Watson, M. Luo, J. Tao, Y. Barnes, M. Dowsett, M. Budd, G.T. Winer, E. Silverman, P. Esserman, L. Carey, L. Ma, C.X. Unzeitig, G. Pluard, T. Whitworth, P. Babiera, G. Guenther, J.M. Dayao, Z. Ota, D. Leitch, M. Olson, J.A. Allred, D.C. Hunt, K. (2017). Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J clin oncol, Vol.35 (10), pp. 1061-1069. show abstract

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588)..

Cuzick, J. Brentnall, A.R. Segal, C. Byers, H. Reuter, C. Detre, S. Lopez-Knowles, E. Sestak, I. Howell, A. Powles, T.J. Newman, W.G. Dowsett, M. (2017). Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials. J clin oncol, Vol.35 (7), pp. 743-750. show abstract

Cameron, D. Piccart-Gebhart, M.J. Gelber, R.D. Procter, M. Goldhirsch, A. de Azambuja, E. Castro, G. Untch, M. Smith, I. Gianni, L. Baselga, J. Al-Sakaff, N. Lauer, S. McFadden, E. Leyland-Jones, B. Bell, R. Dowsett, M. Jackisch, C. (2017). 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. The lancet, Vol.389 (10075), pp. 1195-1205.

Bartlett, J.M. Ahmed, I. Regan, M.M. Sestak, I. Mallon, E.A. Dell'Orto, P. Thurlimann, B. Seynaeve, C. Putter, H. Van de Velde, C.J. Brookes, C.L. Forbes, J.F. Viale, G. Cuzick, J. Dowsett, M. Rea, D.W. Inhibitor, T.A. (2017). HER2 status predicts for upfront AI benefit: A TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1-98 and TEAM with centrally determined HER2. European journal of cancer, Vol.79, pp. 129-138.

Sheri, A. Smith, I.E. Hills, M. Jones, R.L. Johnston, S.R. Dowsett, M. (2017). Relationship between IHC4 score and response to neo-adjuvant chemotherapy in estrogen receptor-positive breast cancer. Breast cancer research and treatment, Vol.164 (2), pp. 395-400.

Loibl, S. Turner, N.C. Ro, J. Cristofanilli, M. Iwata, H. Im, S. Masuda, N. Loi, S. André, F. Harbeck, N. Verma, S. Folkerd, E. Puyana Theall, K. Hoffman, J. Zhang, K. Bartlett, C.H. Dowsett, M. (2017). Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA‐3 Results. The oncologist, Vol.22 (9), pp. 1028-1038.

Farland, L.V. Mu, F. Eliassen, A.H. Hankinson, S.E. Tworoger, S.S. Barbieri, R.L. Dowsett, M. Pollak, M.N. Missmer, S.A. (2017). Menstrual cycle characteristics and steroid hormone, prolactin, and growth factor levels in premenopausal women. Cancer causes & control, Vol.28 (12), pp. 1441-1452.

Haynes, B.P. Ginsburg, O. Gao, Q. Folkerd, E. Afentakis, M. Quang, L.H. Han, P.T. Khoa, P.H. Dinh, N.V. To, T.V. Clemons, M. Smith, I.E. Dowsett, M. (2017). Molecular changes in premenopausal oestrogen receptor-positive primary breast cancer in Vietnamese women after oophorectomy. Npj breast cancer, Vol.3 (1).

Bianchini, G. Kiermaier, A. Bianchi, G.V. Im, Y.-. Pienkowski, T. Liu, M.-. Tseng, L.-. Dowsett, M. Zabaglo, L. Kirk, S. Szado, T. Eng-Wong, J. Amler, L.C. Valagussa, P. Gianni, L. (2017). Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer. Breast cancer research, Vol.19 (1).

Prat, A. Lluch, A. Turnbull, A.K. Dunbier, A.K. Calvo, L. Albanell, J. de la Haba-Rodríguez, J. Arcusa, A. Chacón, J.I. Sánchez-Rovira, P. Plazaola, A. Muñoz, M. Paré, L. Parker, J.S. Ribelles, N. Jimenez, B. Bin Aiderus, A.A. Caballero, R. Adamo, B. Dowsett, M. Carrasco, E. Martín, M. Dixon, J.M. Perou, C.M. Alba, E. (2017). A PAM50-Based Chemoendocrine Score for Hormone Receptor–Positive Breast Cancer with an Intermediate Risk of Relapse. Clinical cancer research, Vol.23 (12), pp. 3035-3044.

Schoemaker, M.J. Jones, M.E. Allen, S. Hoare, J. Ashworth, A. Dowsett, M. Swerdlow, A.J. (2017). Childhood body size and pubertal timing in relation to adult mammographic density phenotype. Breast cancer res, Vol.19, p. 13. show abstract

Fribbens, C. O'Leary, B. Kilburn, L. Hrebien, S. Garcia-Murillas, I. Beaney, M. Cristofanilli, M. Andre, F. Loi, S. Loibl, S. Jiang, J. Bartlett, C.H. Koehler, M. Dowsett, M. Bliss, J.M. Johnston, S.R. Turner, N.C. (2016). Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. J clin oncol, Vol.34 (25), pp. 2961-2968. show abstract

PURPOSE: ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor-positive advanced breast cancer. MATERIALS AND METHODS: In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. RESULTS: In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). CONCLUSION: ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required..

Dowsett, M. (2016). Intrinsic Subgroups or Individual Biomarkers for Predicting Outcome of Metastatic Breast Cancer?. Jama oncol, Vol.2 (10), pp. 1269-1271.

Loi, S. Dafni, U. Karlis, D. Polydoropoulou, V. Young, B.M. Willis, S. Long, B. de Azambuja, E. Sotiriou, C. Viale, G. Rüschoff, J. Piccart, M.J. Dowsett, M. Michiels, S. Leyland-Jones, B. (2016). Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial. Jama oncol, Vol.2 (8), pp. 1040-1047. show abstract

IMPORTANCE: A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. OBJECTIVE: To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. DESIGN, SETTING, AND PARTICIPANTS: The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2). INTERVENTIONS: Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines. MAIN OUTCOMES AND MEASURES: Disease-free survival (DFS) and overall survival (OS) were the primary and secondary end points in the intent-to-treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models. RESULTS: Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (≥2 to <5) group (DFS: 3-way ITT Pvalue for interaction = .07; censored = .02; IPW = .03; OS ITT Pvalue for interaction = .007; censored = .04; IPW = .03). In cohort 2, consistent with cohort 1, a significant predictive effect of the ESR1 gene for both end points was also observed (DFS Pvalue for interaction = .06; OS = .02), indicating that breast cancers with higher ESR1 levels also derive less benefit from trastuzumab. CONCLUSIONS AND RELEVANCE: Patients with HER2-positive breast cancers that are ER-positive by IHC analyses with low FISH ratio (≥2 to <5), or with higher ESR1 levels derive significantly less benefit from adjuvant trastuzumab after chemotherapy. These data may explain heterogeneity in response to anti-HER2 agents in HER2-positive, ER-positive breast cancers as some may be more luminal-like than HER2 driven. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00045032..

Thompson, D.J. O'Mara, T.A. Glubb, D.M. Painter, J.N. Cheng, T. Folkerd, E. Doody, D. Dennis, J. Webb, P.M. _, _. Gorman, M. Martin, L. Hodgson, S. _, _. Michailidou, K. Tyrer, J.P. Maranian, M.J. Hall, P. Czene, K. Darabi, H. Li, J. Fasching, P.A. Hein, A. Beckmann, M.W. Ekici, A.B. Dörk, T. Hillemanns, P. Dürst, M. Runnebaum, I. Zhao, H. Depreeuw, J. Schrauwen, S. Amant, F. Goode, E.L. Fridley, B.L. Dowdy, S.C. Winham, S.J. Salvesen, H.B. Trovik, J. Njolstad, T.S. Werner, H.M. Ashton, K. Proietto, T. Otton, G. Carvajal-Carmona, L. Tham, E. Liu, T. Mints, M. _, _. Scott, R.J. McEvoy, M. Attia, J. Holliday, E.G. Montgomery, G.W. Martin, N.G. Nyholt, D.R. Henders, A.K. Hopper, J.L. Traficante, N. _, _. Ruebner, M. Swerdlow, A.J. Burwinkel, B. Brenner, H. Meindl, A. Brauch, H. Lindblom, A. Lambrechts, D. Chang-Claude, J. Couch, F.J. Giles, G.G. Kristensen, V.N. Cox, A. Bolla, M.K. Wang, Q. Bojesen, S.E. Shah, M. Luben, R. Khaw, K.-. Pharoah, P.D. Dunning, A.M. Tomlinson, I. Dowsett, M. Easton, D.F. Spurdle, A.B. (2016). CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer. Endocrine-related cancer, Vol.23 (2), pp. 77-91. show abstract

Dodson, A. Zabaglo, L. Yeo, B. Miller, K. Smith, I. Dowsett, M. (2016). Risk of recurrence estimates with IHC4+C are tolerant of variations in staining and scoring: an analytical validity study. Journal of clinical pathology, Vol.69 (2), pp. 128-135.

Dunning, A.M. Michailidou, K. Kuchenbaecker, K.B. Thompson, D. French, J.D. Beesley, J. Healey, C.S. Kar, S. Pooley, K.A. Lopez-Knowles, E. Dicks, E. Barrowdale, D. Sinnott-Armstrong, N.A. Sallari, R.C. Hillman, K.M. Kaufmann, S. Sivakumaran, H. Marjaneh, M.M. Lee, J.S. Hills, M. Jarosz, M. Drury, S. Canisius, S. Bolla, M.K. Dennis, J. Wang, Q. Hopper, J.L. Southey, M.C. Broeks, A. Schmidt, M.K. Lophatananon, A. Muir, K. Beckmann, M.W. Fasching, P.A. dos-Santos-Silva, I. Peto, J. Sawyer, E.J. Tomlinson, I. Burwinkel, B. Marme, F. Guénel, P. Truong, T. Bojesen, S.E. Flyger, H. González-Neira, A. Perez, J.I. Anton-Culver, H. Eunjung, L. Arndt, V. Brenner, H. Meindl, A. Schmutzler, R.K. Brauch, H. Hamann, U. Aittomäki, K. Blomqvist, C. Ito, H. Matsuo, K. Bogdanova, N. Dörk, T. Lindblom, A. Margolin, S. Kosma, V.-. Mannermaa, A. Tseng, C.-. Wu, A.H. Lambrechts, D. Wildiers, H. Chang-Claude, J. Rudolph, A. Peterlongo, P. Radice, P. Olson, J.E. Giles, G.G. Milne, R.L. Haiman, C.A. Henderson, B.E. Goldberg, M.S. Teo, S.H. Yip, C.H. Nord, S. Borresen-Dale, A.-. Kristensen, V. Long, J. Zheng, W. Pylkäs, K. Winqvist, R. Andrulis, I.L. Knight, J.A. Devilee, P. Seynaeve, C. Figueroa, J. Sherman, M.E. Czene, K. Darabi, H. Hollestelle, A. van den Ouweland, A.M. Humphreys, K. Gao, Y.-. Shu, X.-. Cox, A. Cross, S.S. Blot, W. Cai, Q. Ghoussaini, M. Perkins, B.J. Shah, M. Choi, J.-. Kang, D. Lee, S.C. Hartman, M. Kabisch, M. Torres, D. Jakubowska, A. Lubinski, J. Brennan, P. Sangrajrang, S. Ambrosone, C.B. Toland, A.E. Shen, C.-. Wu, P.-. Orr, N. Swerdlow, A. McGuffog, L. Healey, S. Lee, A. Kapuscinski, M. John, E.M. Terry, M.B. Daly, M.B. Goldgar, D.E. Buys, S.S. Janavicius, R. Tihomirova, L. Tung, N. Dorfling, C.M. van Rensburg, E.J. Neuhausen, S.L. Ejlertsen, B. Hansen, T.V. Osorio, A. Benitez, J. Rando, R. Weitzel, J.N. Bonanni, B. Peissel, B. Manoukian, S. Papi, L. Ottini, L. Konstantopoulou, I. Apostolou, P. Garber, J. Rashid, M.U. Frost, D. Izatt, L. Ellis, S. Godwin, A.K. Arnold, N. Niederacher, D. Rhiem, K. Bogdanova-Markov, N. Sagne, C. Stoppa-Lyonnet, D. Damiola, F. Sinilnikova, O.M. Mazoyer, S. Isaacs, C. Claes, K.B. De Leeneer, K. de la Hoya, M. Caldes, T. Nevanlinna, H. Khan, S. Mensenkamp, A.R. Hooning, M.J. Rookus, M.A. Kwong, A. Olah, E. Diez, O. Brunet, J. Pujana, M.A. Gronwald, J. Huzarski, T. Barkardottir, R.B. Laframboise, R. Soucy, P. Montagna, M. Agata, S. Teixeira, M.R. Park, S.K. Lindor, N. Couch, F.J. Tischkowitz, M. Foretova, L. Vijai, J. Offit, K. Singer, C.F. Rappaport, C. Phelan, C.M. Greene, M.H. Mai, P.L. Rennert, G. Imyanitov, E.N. Hulick, P.J. Phillips, K.-. Piedmonte, M. Mulligan, A.M. Glendon, G. Bojesen, A. Thomassen, M. Caligo, M.A. Yoon, S.-. Friedman, E. Laitman, Y. Borg, A. von Wachenfeldt, A. Ehrencrona, H. Rantala, J. Olopade, O.I. Ganz, P.A. Nussbaum, R.L. Gayther, S.A. Nathanson, K.L. Domchek, S.M. Arun, B.K. Mitchell, G. Karlan, B.Y. Lester, J. Maskarinec, G. Woolcott, C. Scott, C. Stone, J. Apicella, C. Tamimi, R. Luben, R. Khaw, K.-. Helland, Å. Haakensen, V. Dowsett, M. Pharoah, P.D. Simard, J. Hall, P. García-Closas, M. Vachon, C. Chenevix-Trench, G. Antoniou, A.C. Easton, D.F. Edwards, S.L. (2016). Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nature genetics, Vol.48 (4), pp. 374-386.

Sestak, I. Dowsett, M. Ferree, S. Baehner, F.L. Cuzick, J. (2016). Retrospective analysis of molecular scores for the prediction of distant recurrence according to baseline risk factors. Breast cancer research and treatment, Vol.159 (1), pp. 71-78.

Brentnall, A.R. Cuzick, J. Byers, H. Segal, C. Reuter, C. Detre, S. Sestak, I. Howell, A. Powles, T.J. Newman, W.G. Dowsett, M. (2016). Relationship of ZNF423 and CTSO with breast cancer risk in two randomised tamoxifen prevention trials. Breast cancer research and treatment, Vol.158 (3), pp. 591-596.

Nielsen, T.O. Leung, S.C. Zabaglo, L.A. Arun, I. Badve, S.S. Bane, A.L. Bartlet, J.M. Borgquist, S. Chang, M.C. Dodson, A. Ehinger, A. Fineberg, S. Focke, C.M. Gao, D. Gown, A.M. Gutierrez, C. Hugh, J.C. Kos, Z. Laenkholm, A.-. Mastropasqua, M.G. Moriya, T. Nofech-Mozes, S. Osborne, C.K. Penault-Llorca, F.M. Piper, T. Sakatani, T. Salgado, R. Starczynski, J. Sugie, T. van der Vegt, B. Viale, G. Hayes, D.F. McShane, L.M. Dowsett, M. (2016). Analytical validation of a standardized scoring protocol for Ki67 assessed on breast excision whole sections: An international multicenter collaboration. Cancer research, Vol.78 (4).

Dowsett, M. Lønning, P.E. Davidson, N.E. (2016). Incomplete Estrogen Suppression With Gonadotropin-Releasing Hormone Agonists May Reduce Clinical Efficacy in Premenopausal Women With Early Breast Cancer. Journal of clinical oncology, Vol.34 (14), pp. 1580-1583.

Buus, R. Sestak, I. Kronenwett, R. Denkert, C. Dubsky, P. Krappmann, K. Scheer, M. Petry, C. Cuzick, J. Dowsett, M. (2016). Comparison of EndoPredict and EPclin With Oncotype DX Recurrence Score for Prediction of Risk of Distant Recurrence After Endocrine Therapy. Journal of the national cancer institute, Vol.108 (11), pp. djw149-djw149.

López-Knowles, E. Gao, Q. Cheang, M.C. Morden, J. Parker, J. Martin, L.-. Pinhel, I. McNeill, F. Hills, M. Detre, S. Afentakis, M. Zabaglo, L. Dodson, A. Skene, A. Holcombe, C. Robertson, J. Smith, I. Bliss, J.M. Dowsett, M. (2016). Heterogeneity in global gene expression profiles between biopsy specimens taken peri-surgically from primary ER-positive breast carcinomas. Breast cancer research, Vol.18 (1).

Simigdala, N. Gao, Q. Pancholi, S. Roberg-Larsen, H. Zvelebil, M. Ribas, R. Folkerd, E. Thompson, A. Bhamra, A. Dowsett, M. Martin, L.-. (2016). Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. Breast cancer research, Vol.18 (1).

Busana, M.C. Eng, A. Denholm, R. Dowsett, M. Vinnicombe, S. Allen, S. dos-Santos-Silva, I. (2016). Impact of type of full-field digital image on mammographic density assessment and breast cancer risk estimation: a case-control study. Breast cancer research, Vol.18 (1).

Bacci, M. Giannoni, E. Fearns, A. Ribas, R. Gao, Q. Taddei, M.L. Pintus, G. Dowsett, M. Isacke, C.M. Martin, L.-. Chiarugi, P. Morandi, A. (2016). miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors. Cancer research, Vol.76 (6), pp. 1615-1626.

Herrera-Abreu, M.T. Palafox, M. Asghar, U. Rivas, M.A. Cutts, R.J. Garcia-Murillas, I. Pearson, A. Guzman, M. Rodriguez, O. Grueso, J. Bellet, M. Cortés, J. Elliott, R. Pancholi, S. Lord, C.J. Baselga, J. Dowsett, M. Martin, L.-. Turner, N.C. Serra, V. (2016). Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer. Cancer research, Vol.76 (8), pp. 2301-2313.

Sestak, I. Zhang, Y. Schroeder, B.E. Schnabel, C.A. Dowsett, M. Cuzick, J. Sgroi, D. (2016). Cross-Stratification and Differential Risk by Breast Cancer Index and Recurrence Score in Women with Hormone Receptor–Positive Lymph Node–Negative Early-Stage Breast Cancer. Clinical cancer research, Vol.22 (20), pp. 5043-5048.

Klintman, M. Buus, R. Cheang, M.C. Sheri, A. Smith, I.E. Dowsett, M. (2016). Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease. Clinical cancer research, Vol.22 (10), pp. 2405-2416.

Abubakar, M. Howat, W.J. Daley, F. Zabaglo, L. McDuffus, L.A. Blows, F. Coulson, P. Raza Ali, H. Benitez, J. Milne, R. Brenner, H. Stegmaier, C. Mannermaa, A. Chang-Claude, J. Rudolph, A. Sinn, P. Couch, F.J. Tollenaar, R.A. Devilee, P. Figueroa, J. Sherman, M.E. Lissowska, J. Hewitt, S. Eccles, D. Hooning, M.J. Hollestelle, A. Wm Martens, J. Hm van Deurzen, C. Investigators, K. Bolla, M.K. Wang, Q. Jones, M. Schoemaker, M. Broeks, A. van Leeuwen, F.E. Van't Veer, L. Swerdlow, A.J. Orr, N. Dowsett, M. Easton, D. Schmidt, M.K. Pharoah, P.D. Garcia-Closas, M. (2016). High-throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium. J pathol clin res, Vol.2, pp. 138-153. show abstract

Automated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in studies from the Breast Cancer Association Consortium. We utilized 166 TMAs containing 16,953 tumour cores representing 9,059 breast cancer cases, from 13 studies, with information on other clinical and pathological characteristics. TMAs were stained for Ki67 using standard immunohistochemical procedures, and scanned and digitized using the Ariol system. An automated algorithm was developed for the scoring of Ki67, and scores were compared to computer assisted visual (CAV) scores in a subset of 15 TMAs in a training set. We also assessed the correlation between automated Ki67 scores and other clinical and pathological characteristics. Overall, we observed good discriminatory accuracy (AUC = 85%) and good agreement (kappa = 0.64) between the automated and CAV scoring methods in the training set. The performance of the automated method varied by TMA (kappa range= 0.37-0.87) and study (kappa range = 0.39-0.69). The automated method performed better in satisfactory cores (kappa = 0.68) than suboptimal (kappa = 0.51) cores (p-value for comparison = 0.005); and among cores with higher total nuclei counted by the machine (4,000-4,500 cells: kappa = 0.78) than those with lower counts (50-500 cells: kappa = 0.41; p-value = 0.010). Among the 9,059 cases in this study, the correlations between automated Ki67 and clinical and pathological characteristics were found to be in the expected directions. Our findings indicate that automated scoring of Ki67 can be an efficient method to obtain good quality data across large numbers of TMAs from multicentre studies. However, robust algorithm development and rigorous pre- and post-analytical quality control procedures are necessary in order to ensure satisfactory performance..

Abubakar, M. Orr, N. Daley, F. Coulson, P. Ali, H.R. Blows, F. Benitez, J. Milne, R. Brenner, H. Stegmaier, C. Mannermaa, A. Chang-Claude, J. Rudolph, A. Sinn, P. Couch, F.J. Devilee, P. Tollenaar, R.A. Seynaeve, C. Figueroa, J. Sherman, M.E. Lissowska, J. Hewitt, S. Eccles, D. Hooning, M.J. Hollestelle, A. Martens, J.W. van Deurzen, C.H. Investigators, K. Bolla, M.K. Wang, Q. Jones, M. Schoemaker, M. Wesseling, J. van Leeuwen, F.E. Van 't Veer, L. Easton, D. Swerdlow, A.J. Dowsett, M. Pharoah, P.D. Schmidt, M.K. Garcia-Closas, M. (2016). Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups. Breast cancer res, Vol.18, p. 104. show abstract

BACKGROUND: The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists' visual scores available in a subset of patients. METHODS: We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors. RESULTS: Patients in the highest quartile of KI67 (>12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31-2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86-1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16-5.27)) and node-positive (1.74 (1.05-2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02-2.84)). Model fit parameters were similar for visual and automated measures of KI67 in a subset of 2440 patients with information from both sources. CONCLUSIONS: Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment..

Sheri, A. Smith, I.E. Johnston, S.R. A'Hern, R. Nerurkar, A. Jones, R.L. Hills, M. Detre, S. Pinder, S.E. Symmans, W.F. Dowsett, M. (2015). Residual proliferative cancer burden to predict long-term outcome following neoadjuvant chemotherapy. Ann oncol, Vol.26 (1), pp. 75-80. show abstract

Leary, A. Evans, A. Johnston, S.R. A'Hern, R. Bliss, J.M. Sahoo, R. Detre, S. Haynes, B.P. Hills, M. Harper-Wynne, C. Bundred, N. Coombes, G. Smith, I. Dowsett, M. (2015). Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039). Clin cancer res, Vol.21 (13), pp. 2932-2940. show abstract

Dowsett, M. Folkerd, E. (2015). Reduced progesterone levels explain the reduced risk of breast cancer in obese premenopausal women: a new hypothesis. Breast cancer res treat, Vol.149 (1), pp. 1-4. show abstract

Amoroso, V. Generali, D. Buchholz, T. Cristofanilli, M. Pedersini, R. Curigliano, G. Daidone, M.G. Di Cosimo, S. Dowsett, M. Fox, S. Harris, A.L. Makris, A. Vassalli, L. Ravelli, A. Cappelletti, M.R. Hatzis, C. Hudis, C.A. Pedrazzoli, P. Sapino, A. Semiglazov, V. Von Minckwitz, G. Simoncini, E.L. Jacobs, M.A. Barry, P. Kuhn, T. Darby, S. Hermelink, K. Symmans, F. Gennari, A. Schiavon, G. Dogliotti, L. Berruti, A. Bottini, A. (2015). International Expert Consensus on Primary Systemic Therapy in the Management of Early Breast Cancer: Highlights of the Fifth Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer, Cremona, Italy (2013). Jnci monographs, Vol.2015 (51), pp. 90-96.

Klintman, M. Dowsett, M. (2015). Early Surrogate Markers of Treatment Activity: Where Are We Now?. Jnci monographs, Vol.2015 (51), pp. 24-28.

Haynes, B.P. Viale, G. Galimberti, V. Rotmensz, N. Gibelli, B. Smith, I.E. Dowsett, M. (2015). Erratum to: Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer. Breast cancer res treat, Vol.149 (1), p. 311.

Mote, P.A. Gompel, A. Howe, C. Hilton, H.N. Sestak, I. Cuzick, J. Dowsett, M. Hugol, D. Forgez, P. Byth, K. Graham, J.D. Clarke, C.L. (2015). Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial. Breast cancer research and treatment, Vol.151 (2), pp. 309-318.

Polley, M.-. Leung, S.C. Gao, D. Mastropasqua, M.G. Zabaglo, L.A. Bartlett, J.M. McShane, L.M. Enos, R.A. Badve, S.S. Bane, A.L. Borgquist, S. Fineberg, S. Lin, M.-. Gown, A.M. Grabau, D. Gutierrez, C. Hugh, J.C. Moriya, T. Ohi, Y. Osborne, C.K. Penault-Llorca, F.M. Piper, T. Porter, P.L. Sakatani, T. Salgado, R. Starczynski, J. Lænkholm, A.-. Viale, G. Dowsett, M. Hayes, D.F. Nielsen, T.O. (2015). An international study to increase concordance in Ki67 scoring. Mod pathol, Vol.28 (6), pp. 778-786. show abstract

Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes. .

Yeo, B. Zabaglo, L. Hills, M. Dodson, A. Smith, I. Dowsett, M. (2015). Clinical utility of the IHC4+C score in oestrogen receptor-positive early breast cancer: a prospective decision impact study. British journal of cancer, Vol.113 (3), pp. 390-395.

Gnant, M. Sestak, I. Filipits, M. Dowsett, M. Balic, M. Lopez-Knowles, E. Greil, R. Dubsky, P. Stoeger, H. Rudas, M. Jakesz, R. Ferree, S. Cowens, J.W. Nielsen, T. Schaper, C. Fesl, C. Cuzick, J. (2015). Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype. Annals of oncology, Vol.26 (8), pp. 1685-1691.

Ribas, R. Pancholi, S. Guest, S.K. Marangoni, E. Gao, Q. Thuleau, A. Simigdala, N. Polanska, U.M. Campbell, H. Rani, A. Liccardi, G. Johnston, S. Davies, B.R. Dowsett, M. Martin, L.-. (2015). AKT Antagonist AZD5363 Influences Estrogen Receptor Function in Endocrine-Resistant Breast Cancer and Synergizes with Fulvestrant (ICI182780) In Vivo. Molecular cancer therapeutics, Vol.14 (9), pp. 2035-2048.

Sestak, I. Cuzick, J. Dowsett, M. Lopez-Knowles, E. Filipits, M. Dubsky, P. Cowens, J.W. Ferree, S. Schaper, C. Fesl, C. Gnant, M. (2015). Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J clin oncol, Vol.33 (8), pp. 916-922. show abstract

(2015). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. The lancet, Vol.386 (10001), pp. 1341-1352.

(2015). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. The lancet, Vol.386 (10001), pp. 1353-1361.

Turnbull, A.K. Arthur, L.M. Renshaw, L. Larionov, A.A. Kay, C. Dunbier, A.K. Thomas, J.S. Dowsett, M. Sims, A.H. Dixon, J.M. (2015). Accurate Prediction and Validation of Response to Endocrine Therapy in Breast Cancer. Journal of clinical oncology, Vol.33 (20), pp. 2270-2278. show abstract

Wolff, A.C. Hammond, M.E. Hicks, D.G. Allison, K.H. Bartlett, J.M. Bilous, M. Fitzgibbons, P. Hanna, W. Jenkins, R.B. Mangu, P.B. Paik, S. Perez, E.A. Press, M.F. Spears, P.A. Vance, G.H. Viale, G. Dowsett, M. McShane, L.M. Hayes, D.F. (2015). Reply to E A Rakha et al. Journal of clinical oncology, Vol.33 (11), pp. 1302-1304.

Schiavon, G. Hrebien, S. Garcia-Murillas, I. Cutts, R.J. Pearson, A. Tarazona, N. Fenwick, K. Kozarewa, I. Lopez-Knowles, E. Ribas, R. Nerurkar, A. Osin, P. Chandarlapaty, S. Martin, L.-. Dowsett, M. Smith, I.E. Turner, N.C. (2015). Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Science translational medicine, Vol.7 (313), pp. 313ra182-313ra182.

Yeo, B. Dowsett, M. (2015). Neoadjuvant endocrine therapy: Patient selection, treatment duration and surrogate endpoints. Breast, Vol.24, pp. S78-S83.

Yeo, B. Dowsett, M. (2015). Neoadjuvant endocrine therapy: Patient selection, treatment duration and surrogate endpoints. The breast, Vol.24, pp. S78-S83.

Engelberg, J.A. Retallack, H. Balassanian, R. Dowsett, M. Zabaglo, L. Ram, A.A. Apple, S.K. Bishop, J.W. Borowsky, A.D. Carpenter, P.M. Chen, Y.-. Datnow, B. Elson, S. Hasteh, F. Lin, F. Moatamed, N.A. Zhang, Y. Cardiff, R.D. (2015). “Score the Core” Web-based pathologist training tool improves the accuracy of breast cancer IHC4 scoring. Human pathology, Vol.46 (11), pp. 1694-1704.

López-Knowles, E. Wilkerson, P.M. Ribas, R. Anderson, H. Mackay, A. Ghazoui, Z. Rani, A. Osin, P. Nerurkar, A. Renshaw, L. Larionov, A. Miller, W.R. Dixon, J.M. Reis-Filho, J.S. Dunbier, A.K. Martin, L.-. Dowsett, M. (2015). Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer. Breast cancer research, Vol.17 (1).

Dowsett, M. Sestak, I. Buus, R. Lopez-Knowles, E. Mallon, E. Howell, A. Forbes, J.F. Buzdar, A. Cuzick, J. (2015). Estrogen Receptor Expression in 21-Gene Recurrence Score Predicts Increased Late Recurrence for Estrogen-Positive/HER2-Negative Breast Cancer. Clinical cancer research, Vol.21 (12), pp. 2763-2770.

Garcia-Murillas, I. Schiavon, G. Weigelt, B. Ng, C. Hrebien, S. Cutts, R.J. Cheang, M. Osin, P. Nerurkar, A. Kozarewa, I. Garrido, J.A. Dowsett, M. Reis-Filho, J.S. Smith, I.E. Turner, N.C. (2015). Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Science translational medicine, Vol.7 (302), pp. 302ra133-302ra133.

Gao, Q. Patani, N. Dunbier, A.K. Ghazoui, Z. Zvelebil, M. Martin, L.-. Dowsett, M. (2014). Effect of aromatase inhibition on functional gene modules in estrogen receptor-positive breast cancer and their relationship with antiproliferative response. Clin cancer res, Vol.20 (9), pp. 2485-2494. show abstract

Patani, N. Dunbier, A.K. Anderson, H. Ghazoui, Z. Ribas, R. Anderson, E. Gao, Q. A'hern, R. Mackay, A. Lindemann, J. Wellings, R. Walker, J. Kuter, I. Martin, L.-. Dowsett, M. (2014). Differences in the transcriptional response to fulvestrant and estrogen deprivation in ER-positive breast cancer. Clin cancer res, Vol.20 (15), pp. 3962-3973. show abstract

PURPOSE: Endocrine therapies include aromatase inhibitors and the selective estrogen receptor (ER) downregulator fulvestrant. This study aimed to determine whether the reported efficacy of fulvestrant over anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses. EXPERIMENTAL DESIGN: Global gene expression profiles from ERα-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 22) or anastrozole (n = 81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and estrogen deprivation were identified and integrated using Gene Ontology, pathway and network analyses to evaluate their potential significance. RESULTS: The overall transcriptional response to fulvestrant and estrogen deprivation was correlated (r = 0.61 in presurgical studies, r = 0.87 in vitro), involving downregulation of estrogen-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than estrogen deprivation (slope = 0.62 in presurgical studies, slope = 0.63 in vitro). Comparative analyses identified 28 genes and 40 Gene Ontology categories affected differentially by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, associated with ERα, androgen receptor (AR), and TP53, in a network regulating cell cycle, death, survival, and tumor morphology. Eighteen genes responding differently to fulvestrant specifically predicted antiproliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio = 0.29). CONCLUSIONS: The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ERα activity and involvement of AR signaling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens..

Jones, M.E. Schoemaker, M.J. Rae, M. Folkerd, E.J. Dowsett, M. Ashworth, A. Swerdlow, A.J. (2014). Reproducibility of estradiol and testosterone levels in postmenopausal women over 5 years: results from the breakthrough generations study. Am j epidemiol, Vol.179 (9), pp. 1128-1133. show abstract

Segal, C.V. Dowsett, M. (2014). Estrogen receptor mutations in breast cancer--new focus on an old target. Clin cancer res, Vol.20 (7), pp. 1724-1726. show abstract

Hanna, W.M. Rüschoff, J. Bilous, M. Coudry, R.A. Dowsett, M. Osamura, R.Y. Penault-Llorca, F. van de Vijver, M. Viale, G. (2014). HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity. Mod pathol, Vol.27 (1), pp. 4-18. show abstract

Trastuzumab-containing therapy is a standard of care for patients with HER2+ breast cancer. HER2 status is routinely assigned using in situ hybridization to assess HER2 gene amplification, but interpretation of in situ hybridization results may be challenging in tumors with chromosome 17 polysomy or intratumoral genetic heterogeneity. Apparent chromosome 17 polysomy, defined by increased chromosome enumeration probe 17 (CEP17) signal number, is a common genetic aberration in breast cancer and represents an alternative mechanism for increasing HER2 copy number. Some studies have linked elevated CEP17 count ('polysomy') with adverse clinicopathologic features and HER2 overexpression, although there are numerous discrepancies in the literature. There is evidence that elevated CEP17 ('polysomy') count might account for trastuzumab response in tumors with normal HER2:CEP17 ratios. Nonetheless, recent studies establish that apparent 'polysomy' (CEP17 increase) is usually related to focal pericentromeric gains rather than true polysomy. Assigning HER2 status may also be complex where multiple cell subclones with distinct HER2 amplification characteristics coexist within the same tumor. Such genetic heterogeneity affects up to 40% of breast cancers when assessed according to a College of American Pathologists guideline, although other definitions have been proposed. Recent data have associated heterogeneity with unfavorable clinicopathologic variables and poor prognosis. Genetically heterogeneous tumors harboring HER2-amplified subclones have the potential to benefit from trastuzumab, but this has yet to be evaluated in clinical studies. In this review, we discuss the implications of apparent polysomy 17 and genetic heterogeneity for assigning HER2 status in clinical practice. Among our recommendations, we support the use of mean HER2 copy number rather than HER2:CEP17 ratio to define HER2 positivity in cases where coamplification of the centromere might mask HER2 amplification. We also highlight a need to harmonize in situ hybridization scoring methodology to support accurate HER2 status determination, particularly where there is evidence of heterogeneity. .

Schoemaker, M.J. Folkerd, E.J. Jones, M.E. Rae, M. Allen, S. Ashworth, A. Dowsett, M. Swerdlow, A.J. (2014). Combined effects of endogenous sex hormone levels and mammographic density on postmenopausal breast cancer risk: results from the Breakthrough Generations Study. Br j cancer, Vol.110 (7), pp. 1898-1907. show abstract

Wolff, A.C. Hammond, M.E. Hicks, D.G. Dowsett, M. McShane, L.M. Allison, K.H. Allred, D.C. Bartlett, J.M. Bilous, M. Fitzgibbons, P. Hanna, W. Jenkins, R.B. Mangu, P.B. Paik, S. Perez, E.A. Press, M.F. Spears, P.A. Vance, G.H. Viale, G. Hayes, D.F. American Society of Clinical Oncology, College of American Pathologists, (2014). Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch pathol lab med, Vol.138 (2), pp. 241-256. show abstract

Irshad, S. Gillett, C. Pinder, S.E. A'hern, R.P. Dowsett, M. Ellis, I.O. Bartlett, J.M. Bliss, J.M. Hanby, A. Johnston, S. Barrett-Lee, P. Ellis, P. Tutt, A. (2014). Assessment of microtubule-associated protein (MAP)-Tau expression as a predictive and prognostic marker in TACT; a trial assessing substitution of sequential docetaxel for FEC as adjuvant chemotherapy for early breast cancer. Breast cancer res treat, Vol.144 (2), pp. 331-341. show abstract

The TACT trial is the largest study assessing the benefit of taxanes as part of adjuvant therapy for early breast cancer. The goal of this translational study was to clarify the predictive and prognostic value of Tau within the TACT trial. Tissue microarrays (TMA) were available from 3,610 patients. ER, PR, HER2 from the TACT trial and Tau protein expression was determined by immunohistochemistry on duplicate TMAs. Two parallel scoring systems were generated for Tau expression ('dichotomised' vs. 'combined' score). The positivity rate of Tau expression was 50 % in the trial population (n = 2,483). Tau expression correlated positively with ER (p < 0.001) and PR status (p < 0.001); but negatively with histological grade (p < 0.001) and HER2 status (p < 0.001). Analyses with either scoring systems for Tau expression demonstrated no significant interaction between Tau expression and efficacy of docetaxel. Contrary to the hypothesis that taxane benefit would be enriched in Tau negative/low patients, the only groups with a suggestion of a reduced event rate in the taxane group were the HER2-positive, Tau positive subgroups. Tau expression was seen to be a prognostic factor on univariate analysis associated with an improved DFS, independent of the treatment group (p < 0.001). It had no prognostic value in ER-negative tumours and the weak prognostic effect of Tau in ER-positive tumours (p = 0.02) diminished, when considering ER as an ordinal variable. On multivariable analyses, Tau had no prognostic value in either group. In addition, no significant interaction between Tau expression and benefit from docetaxel in patients within the PR-positive and negative subsets was seen. This is now the second large adjuvant study, and the first with quantitative analysis of ER and Tau expression, failing to show an association between Tau and taxane benefit with limited utility as a prognostic marker for Tau in ER-positive early breast cancer patients..

Lønning, P.E. Haynes, B.P. Dowsett, M. (2014). Relationship of body mass index with aromatisation and plasma and tissue oestrogen levels in postmenopausal breast cancer patients treated with aromatase inhibitors. Eur j cancer, Vol.50 (6), pp. 1055-1064. show abstract

Yeo, B.J. Dowsett, M. Smith, I.E. Zabaglo, L. (2014). 5p * the clinical impact of using the ihc4 score: our mdt experience in a prospective series of postmenopausal women with er positive early breast cancer. Ann oncol, Vol.25 Suppl 1, p. i2.

López-Knowles, E. Segal, C.V. Gao, Q. Garcia-Murillas, I. Turner, N.C. Smith, I. Martin, L.-. Dowsett, M. (2014). Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition. Breast cancer research, Vol.16 (3).

Folkerd, E.J. Lønning, P.E. Dowsett, M. (2014). Interpreting plasma estrogen levels in breast cancer: caution needed. J clin oncol, Vol.32 (14), pp. 1396-1400.

Woolf, D.K. Beresford, M. Li, S.P. Dowsett, M. Sanghera, B. Wong, W.L. Sonoda, L. Detre, S. Amin, V. Ah-See, M.-. Miles, D. Makris, A. (2014). Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer. Br j cancer, Vol.110 (12), pp. 2847-2854. show abstract

de Azambuja, E. Procter, M.J. van Veldhuisen, D.J. Agbor-Tarh, D. Metzger-Filho, O. Steinseifer, J. Untch, M. Smith, I.E. Gianni, L. Baselga, J. Jackisch, C. Cameron, D.A. Bell, R. Leyland-Jones, B. Dowsett, M. Gelber, R.D. Piccart-Gebhart, M.J. Suter, T.M. (2014). Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). J clin oncol, Vol.32 (20), pp. 2159-2165. show abstract

Wolff, A.C. Hammond, M.E. Hicks, D.G. Dowsett, M. Hayes, D.F. McShane, L.M. (2014). Reply to R Bhargava et al and K Lambein et al. J clin oncol, Vol.32 (17), pp. 1857-1859.

Haynes, B.P. Viale, G. Galimberti, V. Rotmensz, N. Gibelli, B. Smith, I.E. Dowsett, M. (2014). Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer. Breast cancer res treat, Vol.148 (2), pp. 327-335. show abstract

Sestak, I. Singh, S. Cuzick, J. Blake, G.M. Patel, R. Gossiel, F. Coleman, R. Dowsett, M. Forbes, J.F. Howell, A. Eastell, R. (2014). Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial. Lancet oncol, Vol.15 (13), pp. 1460-1468. show abstract

BACKGROUND: Aromatase inhibitors prevent breast cancer in postmenopausal women at high risk of the disease but are associated with accelerated bone loss. We assessed effectiveness of oral risedronate for prevention of reduction in bone mineral density (BMD) after 3 years of follow-up in a subset of patients in the IBIS-II trial. METHODS: The double-blind IBIS-II trial recruited 3864 healthy, postmenopausal women at increased risk of breast cancer and randomly allocated them oral anastrozole (1 mg/day) or matched placebo. 1410 (36%) postmenopausal women were then enrolled in a bone substudy and stratified at baseline according to their lowest baseline T score at spine or femoral neck (stratum I: T score at least -1·0; stratum II: T score at least -2·5 but less than -1·0; stratum III: T score less than -2·5 but greater than -4·0). Women in stratum I were monitored only; women in stratum III were all given risedronate (35 mg/week). Women in stratum II were randomly assigned (1:1) to risedronate (35 mg/week) or matched placebo by use of a block randomisation schedule via a web-based programme. The primary outcome of this per-protocol analysis (done with all women with a baseline and 3 year DXA assessment) was the effect of risedronate versus placebo for osteopenic women in stratum II randomly allocated to anastrozole (1 mg/day). Secondary outcomes included effect of anastrozole (1 mg/day) on BMD in women not receiving risedronate (strata I and II) and in osteoporotic women who were all treated with risedronate (stratum III). The trial is ongoing, but no longer recruiting. This trial is registered, number ISRCTN31488319. FINDINGS: Between Feb 2, 2003, and Sept 30, 2010, 150 (58%) of 260 women in stratum II who had been randomly allocated to anastrozole and either risedronate or placebo had baseline and 3 year assessments. At the lumbar spine, 3 year mean BMD change for the 77 women receiving anastrozole/risedronate was 1·1% (95% CI 0·2 to 2·1) versus -2·6% (-4·0 to -1·3) for the 73 women receiving anastrozole/placebo (p<0·0001). For the total hip, 3 year mean BMD change for women receiving anastrozole/risedronate was -0·7% (-1·6 to 0·2) versus -3·5% (-4·6 to -2·3) for women receiving anastrozole/placebo (p=0·0001). 652 (65%) of 1008 women in strata I and II who were not randomly allocated to risedronate had both baseline and 3 year assessments. Women not receiving risedronate in stratum I and II who received anastrozole (310 women) had a significant BMD decrease after 3 years of follow-up compared with women who received placebo (342 women) at the lumbar spine (-4·0% [-4·5 to -3·4] vs -1·2% [-1·7 to -0·7], p<0·0001) and total hip (-4·0% [-4·4 to -3·6] vs -1·8% [-2·1 to -1·4], p<0·0001). 106 (79%) of 149 women in stratum III had a baseline and a 3 year assessment. The 46 women allocated to anastrozole had a modest BMD increase of 1·2% (-0·1 to 2·6) at the spine compared with a 3·9% (2·6 to 5·2) increase for the 60 women allocated to placebo (p=0·006). For the total hip, a small 0·3% (-0·9 to 1·5) increase was noted for women allocated anastrozole compared with a 1·5% (0·5 to 2·5) increase for women allocated placebo, but the difference was not significant (p=0·12). The most common adverse event reported was arthralgia (stratum I: 94 placebo and 114 anastrozole; stratum II: 39 placebo/placebo, 25 placebo/risedronate, 34 anastrozole/placebo, and 34 anastrozole/risedronate; stratum III: 21 placebo/risedronate, 17 anastrozole/risedronate). Other adverse events included hot flushes, alopecia, abdominal pain, and back pain. INTERPRETATION: Risedronate counterbalances the effect of anastrozole-induced bone loss in osteopenic and osteoporotic women and might be offered in combination with anastrozole treatment to provide an improved risk-benefit profile. FUNDING: Cancer Research UK (C569/A5032), National Health and Medical Research Council Australia (GNT300755, GNT569213), Sanofi-Aventis, and AstraZeneca..

Almendro, V. Cheng, Y.-. Randles, A. Itzkovitz, S. Marusyk, A. Ametller, E. Gonzalez-Farre, X. Muñoz, M. Russnes, H.G. Helland, A. Rye, I.H. Borresen-Dale, A.-. Maruyama, R. van Oudenaarden, A. Dowsett, M. Jones, R.L. Reis-Filho, J. Gascon, P. Gönen, M. Michor, F. Polyak, K. (2014). Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell rep, Vol.6 (3), pp. 514-527. show abstract

Cuzick, J. Sestak, I. Forbes, J.F. Dowsett, M. Knox, J. Cawthorn, S. Saunders, C. Roche, N. Mansel, R.E. von Minckwitz, G. Bonanni, B. Palva, T. Howell, A. IBIS-II investigators, (2014). Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet, Vol.383 (9922), pp. 1041-1048. show abstract

BACKGROUND: Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease. METHODS: Between Feb 2, 2003, and Jan 31, 2012, we recruited postmenopausal women aged 40-70 years from 18 countries into an international, double-blind, randomised placebo-controlled trial. To be eligible, women had to be at increased risk of breast cancer (judged on the basis of specific criteria). Eligible women were randomly assigned (1:1) by central computer allocation to receive 1 mg oral anastrozole or matching placebo every day for 5 years. Randomisation was stratified by country and was done with blocks (size six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation; only the trial statistician was unmasked. The primary endpoint was histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat. This trial is registered, number ISRCTN31488319. FINDINGS: 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of 5·0 years (IQR 3·0-7·1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0·47, 95% CI 0·32-0·68, p<0·0001). The predicted cumulative incidence of all breast cancers after 7 years was 5·6% in the placebo group and 2·8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p=0·836). INTERPRETATION: Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer. FUNDING: Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca..

Ribas, R. Ghazoui, Z. Gao, Q. Pancholi, S. Rani, A. Dunbier, A. Dowsett, M. Martin, L.-. (2014). Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor-positive breast cancers. Breast cancer research, Vol.16 (5).

Johnson, N. Dudbridge, F. Orr, N. Gibson, L. Jones, M.E. Schoemaker, M.J. Folkerd, E.J. Haynes, B.P. Hopper, J.L. Southey, M.C. Dite, G.S. Apicella, C. Schmidt, M.K. Broeks, A. Van't Veer, L.J. Atsma, F. Muir, K. Lophatananon, A. Fasching, P.A. Beckmann, M.W. Ekici, A.B. Renner, S.P. Sawyer, E. Tomlinson, I. Kerin, M. Miller, N. Burwinkel, B. Marme, F. Schneeweiss, A. Sohn, C. Guenel, P. Truong, T. Cordina, E. Menegaux, F. Bojesen, S.E. Nordestgaard, B.G. Flyger, H. Milne, R. Zamora, M.P. Arias Perez, J.I. Benitez, J. Bernstein, L. Anton-Culver, H. Ziogas, A. Clarke Dur, C. Brenner, H. Muller, H. Arndt, V. Dieffenbach, A.K. Meindl, A. Heil, J. Bartram, C.R. Schmutzler, R.K. Brauch, H. Justenhoven, C. Ko, Y.D. Network, G. Nevanlinna, H. Muranen, T.A. Aittomaki, K. Blomqvist, C. Matsuo, K. Dork, T. Bogdanova, N.V. Antonenkova, N.N. Lindblom, A. Mannermaa, A. Kataja, V. Kosma, V.M. Hartikainen, J.M. Chenevix-Trench, G. Beesley, J. kConFab, I. Australian Ovarian Cancer Study, G. Wu, A.H. Van den Berg, D. Tseng, C.C. Lambrechts, D. Smeets, D. Neven, P. Wildiers, H. Chang-Claude, J. Rudolph, A. Nickels, S. Flesch-Janys, D. Radice, P. Peterlongo, P. Bonanni, B. Pensotti, V. Couch, F.J. Olson, J.E. Wang, X. Fredericksen, Z. Pankratz, V.S. Giles, G.G. Severi, G. Baglietto, L. Haiman, C. Simard, J. Goldberg, M.S. Labreche, F. Dumont, M. Soucy, P. Teo, S. Yip, C.H. Phuah, S.Y. Cornes, B.K. Kristensen, V.N. Grenaker Alnaes, G. Borresen-Dale, A.L. Zheng, W. Winqvist, R. Pylkas, K. Jukkola-Vuorinen, A. Grip, M. Andrulis, I.L. Knight, J.A. Glendon, G. Mulligan, A.M. Devillee, P. Figueroa, J. Chanock, S.J. Lissowska, J. Sherman, M.E. Hall, P. Schoof, N. Hooning, M. Hollestelle, A. Oldenburg, R.A. Tilanus-Linthorst, M. Liu, J. Cox, A. Brock, I.W. Reed, M.W. Cross, S.S. Blot, W. Signorello, L.B. Pharoah, P.D. Dunning, A.M. Shah, M. Kang, D. Noh, D.Y. Park, S.K. Choi, J.Y. Hartman, M. Miao, H. Lim, W.Y. Tang, A. Hamann, U. Forsti, A. Rudiger, T. Ulmer, H.U. Jakubowska, A. Lubinski, J. Jaworska-Bieniek, K. Durda, K. Sangrajrang, S. Gaborieau, V. Brennan, P. McKay, J. Slager, S. Toland, A.E. Vachon, C. Yannoukakos, D. Shen, C.Y. Yu, J.C. Huang, C.S. Hou, M.F. Gonzalez-Neira, A. Tessier, D.C. Vincent, D. Bacot, F. Luccarini, C. Dennis, J. Michailidou, K. Bolla, M.K. Wang, J. Easton, D.F. Garcia-Closas, M. Dowsett, M. Ashworth, A. Swerdlow, A.J. Peto, J. dos Santos Silva, I. Fletcher, O. (2014). Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study. Breast cancer res, Vol.16, p. R51. show abstract

Eng, A. Gallant, Z. Shepherd, J. McCormack, V. Li, J. Dowsett, M. Vinnicombe, S. Allen, S. dos-Santos-Silva, I. (2014). Digital mammographic density and breast cancer risk: a case-control study of six alternative density assessment methods. Breast cancer research, Vol.16 (5).

Weigel, M.T. Banerjee, S. Arnedos, M. Salter, J. A'Hern, R. Dowsett, M. Martin, L.A. (2013). Enhanced expression of the PDGFR/Abl signaling pathway in aromatase inhibitor-resistant breast cancer. Ann oncol, Vol.24 (1), pp. 126-133. show abstract

Dowsett, M. Sestak, I. Lopez-Knowles, E. Sidhu, K. Dunbier, A.K. Cowens, J.W. Ferree, S. Storhoff, J. Schaper, C. Cuzick, J. (2013). Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J clin oncol, Vol.31 (22), pp. 2783-2790. show abstract

Folkerd, E.J. Dixon, J.M. A'Hern, R.P. Dowsett, M. (2013). Reply to S Pauwels et al. Journal of clinical oncology, Vol.31 (4), pp. 509-510.

Wolff, A.C. Hammond, M.E. Hicks, D.G. Dowsett, M. McShane, L.M. Allison, K.H. Allred, D.C. Bartlett, J.M. Bilous, M. Fitzgibbons, P. Hanna, W. Jenkins, R.B. Mangu, P.B. Paik, S. Perez, E.A. Press, M.F. Spears, P.A. Vance, G.H. Viale, G. Hayes, D.F. American Society of Clinical Oncology, College of American Pathologists, (2013). Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J clin oncol, Vol.31 (31), pp. 3997-4013. show abstract

PURPOSE: To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. METHODS: ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing. RESULTS: The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations. RECOMMENDATIONS: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to > 10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. This guideline was developed through a collaboration between the American Society of Clinical Oncology and the College of American Pathologists and has been published jointly by invitation and consent in both Journal of Clinical Oncology and the Archives of Pathology & Laboratory Medicine..

Metzger-Filho, O. Procter, M. de Azambuja, E. Leyland-Jones, B. Gelber, R.D. Dowsett, M. Loi, S. Saini, K.S. Cameron, D. Untch, M. Smith, I. Gianni, L. Baselga, J. Jackisch, C. Bell, R. Sotiriou, C. Viale, G. Piccart-Gebhart, M. (2013). Magnitude of trastuzumab benefit in patients with HER2-positive, invasive lobular breast carcinoma: results from the HERA trial. J clin oncol, Vol.31 (16), pp. 1954-1960. show abstract

Haynes, B.P. Viale, G. Galimberti, V. Rotmensz, N. Gibelli, B. A'Hern, R. Smith, I.E. Dowsett, M. (2013). Expression of key oestrogen-regulated genes differs substantially across the menstrual cycle in oestrogen receptor-positive primary breast cancer. Breast cancer res treat, Vol.138 (1), pp. 157-165. show abstract

Plasma estradiol (E2) and progesterone vary markedly through the menstrual cycle. Data on whether these differences in hormone levels affect gene expression in oestrogen receptor-positive (ER+) tumours are inconsistent. We wished to determine whether there are substantial changes in the expression of oestrogen-regulated genes (ERGs) in ER+ breast cancer through the menstrual cycle. One hundred and seventy five paraffin-embedded ER+ breast carcinomas from premenopausal patients were analysed. Timing of the ovarian cycle was confirmed using serum progesterone levels. Patients were ascribed to one of three pre-defined menstrual cycle windows: 1 (days 27-35 + 1-6), 2 (days 7-16) and 3 (days 17-26). The RNA expression of ESR1, four ERGs (PGR, GREB1, TFF1 and PDZK1), and three proliferation genes (MKI67, TOP2A and CDC20) were compared between the windows. Gene expression of the four ERGs was 53-129 % higher in window 2 than window 1 (p = 0.0013, 0.0006, 0.022 and 0.066 for PGR, GREB1, TFF1 and PDZK1, respectively) and lower (9-41 %) in window 3 compared to window 2 (p = 0.079, 0.31, 0.031 and 0.065 for PGR, GREB1, TFF1 and PDZK1, respectively). Their average expression (AvERG) was 64 % higher in window 2 than window 1 (p < 0.0001) and 21 % lower in window 3 than window 2 (p = 0.0043). There were no significant differences between the windows for ESR1 and proliferation genes. In agreement with the gene expression data, progesterone receptor protein levels measured by immunohistochemistry (IHC) were 164 and 227 % higher in windows 2 and 3, respectively, compared to window 1 (30.7 and 37.9 % cells positive vs. 11.6 %; p = 0.0003 and 0.0004, respectively), while no difference in ER IHC score was observed. In conclusion, we observed significant differences in the expression of ERGs in ER+ breast tumours across the menstrual cycle. This variability may affect the interpretation of gene expression profiles incorporating ERGs and may be exploitable as an endogenous test of endocrine responsiveness..

Bao, T. Cai, L. Giles, J.T. Gould, J. Tarpinian, K. Betts, K. Medeiros, M. Jeter, S. Tait, N. Chumsri, S. Armstrong, D.K. Tan, M. Folkerd, E. Dowsett, M. Singh, H. Tkaczuk, K. Stearns, V. (2013). A dual-center randomized controlled double blind trial assessing the effect of acupuncture in reducing musculoskeletal symptoms in breast cancer patients taking aromatase inhibitors. Breast cancer res treat, Vol.138 (1), pp. 167-174. show abstract

Sestak, I. Dowsett, M. Zabaglo, L. Lopez-Knowles, E. Ferree, S. Cowens, J.W. Cuzick, J. (2013). Factors predicting late recurrence for estrogen receptor-positive breast cancer. J natl cancer inst, Vol.105 (19), pp. 1504-1511. show abstract

Dowsett, M. (2013). SEX HORMONES AND BREAST CANCER RISK AND PROGNOSIS. Breast, Vol.22, pp. S5-S6.

Bartlett, J.M. A'hern, R. Piper, T. Ellis, I.O. Dowsett, M. Mallon, E.A. Cameron, D.A. Johnston, S. Bliss, J.M. Ellis, P. Barrett-Lee, P.J. (2013). Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer. Breast cancer res treat, Vol.138 (3), pp. 773-781. show abstract

Patani, N. Martin, L.-. Dowsett, M. (2013). Biomarkers for the clinical management of breast cancer: international perspective. Int j cancer, Vol.133 (1), pp. 1-13. show abstract

Jones, M.E. Schoemaker, M. Rae, M. Folkerd, E.J. Dowsett, M. Ashworth, A. Swerdlow, A.J. (2013). Changes in estradiol and testosterone levels in postmenopausal women after changes in body mass index. J clin endocrinol metab, Vol.98 (7), pp. 2967-2974. show abstract

Afentakis, M. Dowsett, M. Sestak, I. Salter, J. Howell, T. Buzdar, A. Forbes, J. Cuzick, J. (2013). Immunohistochemical BAG1 expression improves the estimation of residual risk by IHC4 in postmenopausal patients treated with anastrazole or tamoxifen: a TransATAC study. Breast cancer res treat, Vol.140 (2), pp. 253-262. show abstract

Martin, L.-. Dowsett, M. (2013). BCL-2: a new therapeutic target in estrogen receptor-positive breast cancer?. Cancer cell, Vol.24 (1), pp. 7-9. show abstract

Folkerd, E. Dowsett, M. (2013). Sex hormones and breast cancer risk and prognosis. Breast, Vol.22 Suppl 2, pp. S38-S43. show abstract

The study of large prospective collections of plasma samples from women prior to the development of breast cancer has firmly established certain sex steroids as being significantly associated with risk. The strongest associations have been found in postmenopausal women in whom the within person variability of most hormones is markedly reduced but some positive associations have also been seen in premenopausal women. Plasma estrogens show the strongest correlations with risk and these are strengthened by measurement or calculation of the proportion of estradiol that circulates free of sex hormone binding globulin (SHBG), consistent with this being the most active fraction. The relationships have been reported to potentially explain virtually all of the association of breast cancer with body mass index in postmenopausal women; this is likely to be due to non-ovarian estrogen synthesis being prominent in subcutaneous fat. These strong relationships have led to plasma and urine estrogen levels being used as intermediate end-points in the search for genes that affect breast cancer risk via their role in steroid disposition. Plasma androgen levels also show a relationship with breast cancer risk that is weakened but not eliminated by 'correction' for estrogen levels. This has been argued to be evidence of the local production of estrogens being important in the etiology of breast cancer. Given that plasma steroid levels do not correlate closely with mammographic density, which is strongly associated with risk, the opportunity exists to combine the two factors in assessing breast cancer risk but the low availability of suitable estrogen assays is a major impediment to this. In established breast cancer, plasma estrogens have been found to correlate with gene expression of estrogen dependent genes and the expression of these varies across the menstrual cycle of premenopausal women. There is infrequently a need for routine measurement of plasma estrogen levels but it has been important in the comparative pharmacology and dose-related effectiveness of aromatase inhibitors. Measurement may be needed to identify residual ovarian function in women who have amenorrhea subsequent to cytotoxic chemotherapy indicating their unsuitability for aromatase inhibitor treatment. Use of highly sensitive assays has also revealed that the association between BMI and plasma estrogen levels persists in patients on 3rd generation aromatase inhibitors and that measurable increments in plasma estrogen levels occur with some vaginal estrogen preparations that are of concern in relation to treatment efficacy. .

Johnston, S.R. Kilburn, L.S. Ellis, P. Dodwell, D. Cameron, D. Hayward, L. Im, Y.-. Braybrooke, J.P. Brunt, A.M. Cheung, K.-. Jyothirmayi, R. Robinson, A. Wardley, A.M. Wheatley, D. Howell, A. Coombes, G. Sergenson, N. Sin, H.-. Folkerd, E. Dowsett, M. Bliss, J.M. SoFEA investigators, (2013). Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet oncol, Vol.14 (10), pp. 989-998. show abstract

BACKGROUND: The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation. METHODS: In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea). FINDINGS: Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4-5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6-5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0-4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83-1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79-1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3-4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight). INTERPRETATION: After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane..

Key, T.J. Appleby, P.N. Reeves, G.K. Travis, R.C. Alberg, A.J. Barricarte, A. Berrino, F. Krogh, V. Sieri, S. Brinton, L.A. Dorgan, J.F. Dossus, L. Dowsett, M. Eliassen, A.H. Fortner, R.T. Hankinson, S.E. Helzlsouer, K.J. Hoffman-Bolton, J. Comstock, G.W. Kaaks, R. Kahle, L.L. Koenig, K. Zeleniuch-Jacquotte, A. Muti, P. Overvad, K. Peeters, P.H. Riboli, E. Rinaldi, S. Rollison, D.E. Stanczyk, F.Z. Trichopoulos, D. Tworoger, S.S. Tworoger, S.S. Vineis, P. (2013). Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet oncology, Vol.14 (10), pp. 1009-1019.

Sgroi, D.C. Sestak, I. Cuzick, J. Zhang, Y. Schnabel, C.A. Schroeder, B. Erlander, M.G. Dunbier, A. Sidhu, K. Lopez-Knowles, E. Goss, P.E. Dowsett, M. (2013). Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet oncology, Vol.14 (11), pp. 1067-1076.

Dowsett, M. (2013). Pathology challenges for biology-driven trials: The Ki67 experience. European journal of cancer, Vol.49, pp. S1-S2.

Zabaglo, L. Stoss, O. Rüschoff, J. Zielinski, D. Salter, J. Arfi, M. Bradbury, I. Dafni, U. Piccart-Gebhart, M. Procter, M. Dowsett, M. HERA Trial Study Team, (2013). HER2 staining intensity in HER2-positive disease: relationship with FISH amplification and clinical outcome in the HERA trial of adjuvant trastuzumab. Ann oncol, Vol.24 (11), pp. 2761-2766. show abstract

Dunbier, A.K. Ghazoui, Z. Anderson, H. Salter, J. Nerurkar, A. Osin, P. A'hern, R. Miller, W.R. Smith, I.E. Dowsett, M. (2013). Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance. Clin cancer res, Vol.19 (10), pp. 2775-2786. show abstract

PURPOSE: Estrogen withdrawal by treatment with aromatase inhibitors is the most effective form of endocrine therapy for postmenopausal estrogen receptor-positive (ER+) breast cancer. However, response to therapy varies markedly and understanding of the precise molecular effects of aromatase inhibitors and causes of resistance is limited. We aimed to identify in clinical breast cancer those genes and pathways most associated with resistance to aromatase inhibitors by examining the global transcriptional effects of AI treatment. EXPERIMENTAL DESIGN: Baseline and 2-week posttreatment biopsies were obtained from 112 postmenopausal women with ER+ breast cancer receiving neoadjuvant anastrozole. Gene expression data were obtained from 81 baseline and 2-week paired samples. Pathway analysis identified (i) the most prevalent changes in expression and (ii) the pretreatment genes/pathways most related to poor antiproliferative response. RESULTS: A total of 1,327 genes were differentially expressed after 2-week treatment (false discovery rate < 0.01). Proliferation-associated genes and classical estrogen-dependent genes were strongly downregulated whereas collagens and chemokines were upregulated. Pretreatment expression of an inflammatory signature correlated with antiproliferative response to anastrozole and this observation was validated in an independent study. Higher expression of immune-related genes such as SLAMF8 and TNF as well as lymphocytic infiltration were associated with poorer response (P < 0.001) and validated in an independent cohort. CONCLUSIONS: The molecular response to aromatase inhibitor treatment varies greatly between patients consistent with the variable clinical benefit from aromatase inhibitor treatment. Higher baseline expression of an inflammatory signature is associated with poor antiproliferative response and should be assessed further as a novel biomarker and potential target for aromatase inhibitor-treated patients..

Sheri, A. Smith, I.E. A'Hern, R. Jones, R. Parton, M. Johnston, S.R. Dowsett, M. (2013). Abstract P1-08-03: Prediction of response to neoadjuvant chemotherapy in estrogen receptor positive (ER+) breast cancer by IHC4 or Ki67 alone. Poster session abstracts, .

Woolf, D.K. Beresford, M. Li, S.P. Sanghera, B. Wong, W.L. Amin, V. Ah-See, M.-. Miles, D. Sonoda, L. Detre, S. Dowsett, M. Makris, A. (2013). Abstract P4-01-07: Evaluation of FLT PET-CT as an imaging biomarker of proliferation in primary breast cancer. Poster session abstracts, .

Turnbull, A.K. Arthur, L. Webber, V. Larionov, A.A. Renshaw, L. Kay, C. Dunbier, A. Dowsett, M. Sims, A.H. Dixon, J.M. (2013). Abstract PD3-2: Accurate and robust prediction of clinical response to aromatase inhibitors by two weeks of neoadjuvant breast cancer treatment. Poster discussion abstracts, .

Sestak, I. Cuzick, J. Dowsett, M. Filipits, M. Dubsky, P. Cowens, W. Ferree, S. Schaper, C. Fesl, C. Gnant, M. (2013). Abstract S6-04: Prediction of late distant recurrence after 5 years of endocrine treatment: A combined analysis of 2485 patients from the ABCSG-8 and transATAC studies using the PAM50 risk of recurrence (ROR) score. General session abstracts, .

Polley, M.-. Leung, S.C. McShane, L.M. Gao, D. Hugh, J.C. Mastropasqua, M.G. Viale, G. Zabaglo, L.A. Penault-Llorca, F. Bartlett, J.M. Gown, A.M. Symmans, W.F. Piper, T. Mehl, E. Enos, R.A. Hayes, D.F. Dowsett, M. Nielsen, T.O. International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group, (2013). An international Ki67 reproducibility study. J natl cancer inst, Vol.105 (24), pp. 1897-1906. show abstract

BACKGROUND: In breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67's value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study. METHODS: Eight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays-one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. RESULTS: Intralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation. CONCLUSIONS: Substantial variability in Ki67 scoring was observed among some of the world's most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited..

Goldhirsch, A. Gelber, R.D. Piccart-Gebhart, M.J. de Azambuja, E. Procter, M. Suter, T.M. Jackisch, C. Cameron, D. Weber, H.A. Heinzmann, D. Dal Lago, L. McFadden, E. Dowsett, M. Untch, M. Gianni, L. Bell, R. Köhne, C.-. Vindevoghel, A. Andersson, M. Brunt, A.M. Otero-Reyes, D. Song, S. Smith, I. Leyland-Jones, B. Baselga, J. Herceptin Adjuvant (HERA) Trial Study Team, (2013). 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet, Vol.382 (9897), pp. 1021-1028. show abstract

BACKGROUND: Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial. METHODS: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0-10) is also reported. This study is registered with ClinicalTrials.gov, number NCT00045032. FINDINGS: We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio [HR] 0·99, 95% CI 0·85-1·14, p=0·86). Grade 3-4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 [20·4%] vs 275 [16·3%] grade 3-4 adverse events, and 120 [7·2%] vs 69 [4·1%] decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67-0·86, p<0·0001) for disease-free survival and 0·76 (0·65-0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy. INTERPRETATION: 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care. FUNDING: F Hoffmann-La Roche (Roche)..

Cuzick, J. Sestak, I. Bonanni, B. Costantino, J.P. Cummings, S. DeCensi, A. Dowsett, M. Forbes, J.F. Ford, L. LaCroix, A.Z. Mershon, J. Mitlak, B.H. Powles, T. Veronesi, U. Vogel, V. Wickerham, D.L. SERM, C.B. (2013). Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet, Vol.381 (9880), pp. 1827-1834.

Skippage, P. Wilkinson, L. Allen, S. Roche, N. Dowsett, M. a'Hern, R. (2013). Correlation of Age and HRT Use with Breast Density as Assessed by Quantra (TM). Breast journal, Vol.19 (1), pp. 79-86.

Patani, N. Martin, L.-. Reis-Filho, J.S. Dowsett, M. (2012). The role of caveolin-1 in human breast cancer. Breast cancer res treat, Vol.131 (1), pp. 1-15. show abstract

Patani, N. Lambros, M.B. Natrajan, R. Dedes, K.J. Geyer, F.C. Ward, E. Martin, L.-. Dowsett, M. Reis-Filho, J.S. (2012). Non-existence of caveolin-1 gene mutations in human breast cancer. Breast cancer res treat, Vol.131 (1), pp. 307-310. show abstract

Attard, G. Reid, A.H. Auchus, R.J. Hughes, B.A. Cassidy, A.M. Thompson, E. Oommen, N.B. Folkerd, E. Dowsett, M. Arlt, W. de Bono, J.S. (2012). Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J clin endocrinol metab, Vol.97 (2), pp. 507-516. show abstract

CONTEXT: Abiraterone acetate is a small-molecule cytochrome P450 17A1 (CYP17A1) inhibitor that is active in castration-resistant prostate cancer. OBJECTIVE: Our objective was to determine the impact of abiraterone with and without dexamethasone treatment on in vivo steroidogenesis. DESIGN AND METHODS: We treated 42 castrate, castration-resistant prostate cancer patients with continuous, daily abiraterone acetate and prospectively collected blood and urine before and during abiraterone treatment and after addition of dexamethasone 0.5 mg daily. RESULTS: Treatment with single-agent abiraterone acetate was associated with accumulation of steroids with mineralocorticoid properties upstream of CYP17A1. This resulted in side effects, including hypertension, hypokalemia, and fluid overload, in 38 of 42 patients that were generally treated effectively with eplerenone. Importantly, serum and urinary androgens were suppressed by more than 90% from baseline. Urinary metabolites of 17-hydroxypregnenolone and 17-hydroxyprogesterone downstream of 17α-hydroxylase remained unchanged. However, 3α5α-17-hydroxypregnanolone, which can be converted via the backdoor pathway toward 5α-dihydrotestosterone, increased significantly and correlated with levels of the major 5α-dihydrotestosterone metabolite androsterone. In contrast, urinary metabolites of 11-deoxycortisol and active glucocorticoids declined significantly. Addition of dexamethasone to abiraterone acetate significantly suppressed ACTH and endogenous steroids, including 3α5α-17-hydroxypregnanolone. CONCLUSION: CYP17A1 inhibition with abiraterone acetate is characterized by significant suppression of androgen and cortisol synthesis. The latter is associated with a rise in ACTH that causes raised mineralocorticoids, leading to side effects and incomplete 17α-hydroxylase inhibition. Concomitant inhibition of 17,20-lyase results in diversion of 17-hydroxyprogesterone metabolites toward androgen synthesis via the backdoor pathway. Addition of dexamethasone reverses toxicity and could further suppress androgens by preventing a rise in substrates of backdoor androgen synthesis..

Higgins, M.J. Prowell, T.M. Blackford, A.L. Byrne, C. Khouri, N.F. Slater, S.A. Jeter, S.C. Armstrong, D.K. Davidson, N.E. Emens, L.A. Fetting, J.H. Powers, P.P. Wolff, A.C. Green, H. Thibert, J.N. Rae, J.M. Folkerd, E. Dowsett, M. Blumenthal, R.S. Garber, J.E. Stearns, V. (2012). A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer. Breast cancer research and treatment, Vol.131 (3), pp. 915-924.

Johnson, N. Walker, K. Gibson, L.J. Orr, N. Folkerd, E. Haynes, B. Palles, C. Coupland, B. Schoemaker, M. Jones, M. Broderick, P. Sawyer, E. Kerin, M. Tomlinson, I.P. Zvelebil, M. Chilcott-Burns, S. Tomczyk, K. Simpson, G. Williamson, J. Hillier, S.G. Ross, G. Houlston, R.S. Swerdlow, A. Ashworth, A. Dowsett, M. Peto, J. Dos Santos Silva, I. Fletcher, O. (2012). CYP3A variation, premenopausal estrone levels, and breast cancer risk. J natl cancer inst, Vol.104 (9), pp. 657-669. show abstract

(2012). Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. The lancet, Vol.379 (9814), pp. 432-444.

Brand, J.S. van der Schouw, Y.T. Dowsett, M. Folkerd, E. Luben, R.N. Wareham, N.J. Khaw, K.-. (2012). Testosterone, SHBG and differential white blood cell count in middle-aged and older men. Maturitas, Vol.71 (3), pp. 274-278.

Wills, S. Ravipati, A. Venuturumilli, P. Kresge, C. Folkerd, E. Dowsett, M. Hayes, D.F. Decker, D.A. (2012). Effects of vaginal estrogens on serum estradiol levels in postmenopausal breast cancer survivors and women at risk of breast cancer taking an aromatase inhibitor or a selective estrogen receptor modulator. J oncol pract, Vol.8 (3), pp. 144-148. show abstract

Ferraldeschi, R. Arnedos, M. Hadfield, K.D. A'Hern, R. Drury, S. Wardley, A. Howell, A. Evans, D.G. Roberts, S.A. Smith, I. Newman, W.G. Dowsett, M. (2012). Polymorphisms of CYP19A1 and response to aromatase inhibitors in metastatic breast cancer patients. Breast cancer research and treatment, Vol.133 (3), pp. 1191-1198.

Balko, J.M. Cook, R.S. Vaught, D.B. Kuba, M.G. Miller, T.W. Bhola, N.E. Sanders, M.E. Granja-Ingram, N.M. Smith, J.J. Meszoely, I.M. Salter, J. Dowsett, M. Stemke-Hale, K. Gonzalez-Angulo, A.M. Mills, G.B. Pinto, J.A. Gomez, H.L. Arteaga, C.L. (2012). Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nature medicine, Vol.18 (7), pp. 1052-+.

Dowsett, M. (2012). Obesity may affect response to breast cancer treatment. British journal of hospital medicine, Vol.73 (8), pp. 428-428.

Rae, J.M. Hayes, D.F. Cuzick, J. Sestak, I. Dowsett, M. (2012). Re: CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women With Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial Response. Journal of the national cancer institute, Vol.104 (16), pp. 1267-1268.

Sheri, A. Dowsett, M. (2012). Developments in Ki67 and other biomarkers for treatment decision making in breast cancer. Ann oncol, Vol.23 Suppl 10, pp. x219-x227. show abstract

Simmons, C.E. Kuchuk, I. Freedman, O.C. Colgan, T. Dodd, A. Kulhanek, K. Sheiner, J. Dranitsaris, G. Dowsett, M. Folkerd, E. Clemons, M.J. (2012). Are Estring® and Vagifem® equally effective and safe for the treatment of urogenital atrophy in breast cancer patients on aromatase inhibitor therapy?. Clin oncol (r coll radiol), Vol.24 (8), pp. e128-e129.

Varghese, J.S. Smith, P.L. Folkerd, E. Brown, J. Leyland, J. Audley, T. Warren, R.M. Dowsett, M. Easton, D.F. Thompson, D.J. (2012). The heritability of mammographic breast density and circulating sex-hormone levels: two independent breast cancer risk factors. Cancer epidemiol biomarkers prev, Vol.21 (12), pp. 2167-2175. show abstract

Pinhel, I. Hills, M. Drury, S. Salter, J. Sumo, G. A'Hern, R. Bliss, J.M. Sestak, I. Cuzick, J. Barrett-Lee, P. Harris, A. Dowsett, M. NCRI Adjuvant Breast Cancer Trial Management Group, (2012). ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer. Breast cancer res, Vol.14 (2), p. R46. show abstract

INTRODUCTION: Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas. METHODS: ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm. Relations at the RNA level were assessed in 1,139 TransATAC tumors. RESULTS: ER and HER2 RNA levels were negatively correlated as expected in HER2+ve (IHC 3+ and/or FISH-amplified) tumors (r = -0.45; P = 0.0028). However, in HER2-ve tumors (ER+ve and ER-ve combined), a significant positive correlation was found (r = 0.43; P < 0.0001), HER2 RNA levels being 1.74-fold higher in ER+ve versus ER-ve tumors. This correlation was maintained in the ER+veHER2-ve subgroup (r = 0.24; P = 0.0023) and confirmed in this subgroup in 1,139 TransATAC tumours (r = 0.25; P < 0.0001). The positive relation extended to IHC-detected ER in ABC: mean ± 95% confidence interval (CI) H-scores were 90 ± 19 and 134 ± 19 for 0 and 1+ HER2 IHC categories, respectively (P = 0.0013). A trend toward lower relapse-free survival (RFS) was observed in patients with the lowest levels of ER and HER2 RNA levels within the ER+veHER2-ve subgroup both for ABC and TransATAC cohorts. CONCLUSIONS: ER and HER2 expression is positively correlated in HER2-ve tumors. The distinction between HER2+ve and HER2-ve is greater in ER-ve than in ER+ve tumors. These findings are important to consider in clinical trials of anti-HER2 and anti-endocrine therapy in HER2-ve disease. TRIAL REGISTRATION: Clinical trial identifier: ISRCTN31514446..

Motion, J. Ashcroft, L. Dowsett, M. Cuzick, J. Hickman, J. Evans, G. Eccles, D. Eeles, R. Greenhalgh, R. Affen, J. Bundred, S. Boggis, C. Sergeant, J. Fallowfield, L. Adams, J. Howell, A. (2012). Abstract P1-09-05: The RAZOR trial: a phase II prevention trial of screening plus goserilin and raloxifene versus screening alone in pre-menopausal women at increased risk of breast cancer. Poster session abstracts, .

Ross, G.M. Johnson, N. Orr, N. Walker, K. Gibson, L. Folkerd, E. Haynes, B. Palles, C. Coupland, B. Shoemaker, M. Jones, M. Broderick, P. Sawyer, E. Kerin, M. Tomlinson, I. Zvelebil, M. Chilcott-Burns, S. Tomczyk, K. Simpson, G. Willianson, J. Hillier, S. Houlston, R. Swerdlow, A. Ashworth, A. Dowsett, M. Peto, J. dos Santos, I. Fletcher, O. (2012). Abstract P3-08-04: Impact of CYP3A variation on estrone levels and breast cancer risk. Poster session abstracts, .

Ribas, R. Ghazoui, Z. Dowsett, M. Martin, L.-. (2012). Abstract PD01-05: Analysis of patients with ER-positive breast tumors treated with neoadjuvant aromatase inhibition identifies chemokine receptors as potential modulators of endocrine resistance. Poster discussion abstracts, .

Regan, M.M. Dafni, U. Karlis, D. Goldhirsch, A. Untch, M. Smith, I. Gianni, L. Jackisch, C. de Azambuja, E. Heinzmann, D. Cameron, D. Bell, R. Dowsett, M. Baselga, J. Leyland-Jones, B. Piccart-Gebhart, M.J. Gelber, R.D. (2012). Abstract P5-18-02: Selective Crossover in Randomized Trials of Adjuvant Trastuzumab for Breast Cancer: Coping with Success. Poster session abstracts, .

Nielsen, T.O. Polley, M.-. Leung, S.C. Mastropasqua, M.G. Zabaglo, L.A. Bartlett, J.M. Viale, G. McShane, L.M. Hayes, D.F. Dowsett, M. (2012). Abstract S4-6: An international Ki67 reproducibility study. General session abstracts, .

Goldhirsch, A. Piccart-Gebhart, M.J. Procter, M. de Azambuja, E. Weber, H.A. Untch, M. Smith, I. Gianni, L. Jackisch, C. Cameron, D. Bell, R. Dowsett, M. Gelber, R.D. Leyland-Jones, B. Baselga, J. (2012). Abstract S5-2: HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. General session abstracts, .

Sgroi, D.C. Sestak, I. Zhang, Y. Erlander, M.G. Schnabel, C.A. Goss, P.E. Cuzick, J. Dowsett, M. (2012). Abstract P2-10-15: Evaluation of Prognostic and Predictive Performance of Breast Cancer Index and Its Components in Hormonal Receptor-Positive Breast Cancer Patients: A TransATAC Study. Poster session abstracts, .

Sgroi, D.C. Sestak, I. Cuzick, J. Zhang, Y. Schnabel, C.A. Erlander, M.G. Goss, P.E. Dowsett, M. (2012). Abstract S1-9: Comparative Performance of Breast Cancer Index (BCI) vs Oncotype Dx and IHC4 in the Prediction of Late Recurrence in Hormonal Receptor-Positive Lymph Node-Negative Breast Cancer Patients: A TransATAC Study. General session abstracts, .

Canon, J.L. Bergh, J. Saura, C. Oliveira, M. Houk, B. Millham, R. Barton, J. Dowsett, M. Giorgetti, C. (2012). Phase lb/II study of an oral PI3K/mTOR inhibitor plus letrozole compared with letrozole (L) in pre-operative setting in patients with Estrogen Receptor-positive, HER2-negative early breast cancer (BC): Phase lb preliminary data. Cancer research, Vol.72.

Martin, L.-. Pancholi, S. Farmer, I. Guest, S. Ribas, R. Weigel, M.T. Thornhill, A.M. Ghazoui, Z. A'Hern, R. Evans, D.B. Lane, H.A. Johnston, S.R. Dowsett, M. (2012). Effectiveness and molecular interactions of the clinically active mTORC1 inhibitor everolimus in combination with tamoxifen or letrozole in vitro and in vivo. Breast cancer res, Vol.14 (5), p. R132. show abstract

INTRODUCTION: Strategies to improve the efficacy of endocrine agents in breast cancer (BC) therapy and to delay the onset of resistance include concomitant targeting of the estrogen receptor alpha (ER) and the mammalian target of rapamycin complex 1 (mTORC1), which regulate cell-cycle progression and are supported by recent clinical results. METHODS: BC cell lines expressing aromatase (AROM) and modeling endocrine-sensitive (MCF7-AROM1) and human epidermal growth factor receptor 2 (HER2)-dependent de novo resistant disease (BT474-AROM3) and long-term estrogen-deprived (LTED) MCF7 cells that had acquired resistance associated with HER2 overexpression were treated in vitro and as subcutaneous xenografts with everolimus (RAD001-mTORC1 inhibitor), in combination with tamoxifen or letrozole. End points included proliferation, cell-cycle arrest, cell signaling, and effects on ER-mediated transactivation. RESULTS: Everolimus caused a concentration-dependent decrease in proliferation in all cell lines, which was associated with reductions in S6 phosphorylation. Everolimus plus letrozole or tamoxifen enhanced the antiproliferative effect and G1-accumulation compared with monotherapy, as well as increased phosphorylation (Ser10) and nuclear accumulation of p27 and pronounced dephosphorylation of Rb. Sensitivity was greatest to everolimus in the LTED cells but was reduced by added estrogen. Increased pAKT occurred in all circumstances with everolimus and, in the BT474 and LTED cells, was associated with increased pHER3. Decreased ER transactivation suggested that the effectiveness of everolimus might be partly related to interrupting cross-talk between growth-factor signaling and ER. In MCF7-AROM1 xenografts, letrozole plus everolimus showed a trend toward enhanced tumor regression, versus the single agents. In BT474-AROM3 xenografts, everolimus alone was equally effective at reducing tumor volume as were the combination therapies. CONCLUSIONS: The results provide mechanistic support for recent positive clinical data on the combination of everolimus and endocrine therapy, as well as data on potential routes of escape via enhanced HER2/3 signaling. This merits investigation for further improvements in treatment efficacy..

Weigel, M.T. Ghazoui, Z. Dunbier, A. Pancholi, S. Dowsett, M. Martin, L.-. (2012). Preclinical and clinical studies of estrogen deprivation support the PDGF/Abl pathway as a novel therapeutic target for overcoming endocrine resistance in breast cancer. Breast cancer res, Vol.14 (3), p. R78. show abstract

INTRODUCTION: The majority of breast tumors at primary diagnosis are estrogen receptor positive (ER+). Estrogen (E) mediates its effects by binding to the ER. Therapies targeting the estrogenic stimulation of tumor growth reduce mortality from ER+ breast cancer. However, resistance remains a major clinical problem. METHODS: To identify molecular mechanisms associated with resistance to E-deprivation, we assessed the temporal changes in global gene expression during adaptation to long-term culture of MCF7 human breast cancer cells in the absence of estradiol (E2), long term estrogen deprived (LTED), that leads to recovery of proliferative status and models resistance to an aromatase inhibitor (AI). The expression levels of proteins were determined by western blotting. Proliferation assays were carried out using the dual platelet derived growth factor receptor (PDGFR)/Abelson tyrosine kinase (Abl) inhibitor nilotinib. Luciferase reporter assays were used to determine effects on ER-mediated transactivation. Changes in recruitment of cofactors to the gene regulated by estrogen in breast cancer 1 (GREB1) promoter were determined by chromatin immunoprecipitation (ChIP). Gene expression data were derived from 81 postmenopausal women with ER+ BC pre-treatment and at two-weeks post-treatment with single agent anastrozole in a neoadjuvant trial. RESULTS: The PDGF/Abl canonical pathway was significantly elevated as early as one week post E-deprivation (P = 1.94 E-04) and this became the top adaptive pathway at the point of proliferative recovery (P = 1.15 E-07). Both PDGFRβ and Abl protein levels were elevated in the LTED cells compared to wild type (wt)-MCF7 cells. The PDGF/Abl tyrosine kinase inhibitor nilotinib, suppressed proliferation in LTED cells in the presence or absence of E. Nilotinib also suppressed ER-mediated transcription by destabilizing the ER and reducing recruitment of amplified in breast cancer-1 (AIB1) and the CREB binding protein (CBP) to the promoter of the E-responsive gene GREB1. High PDGFRβ in primary ER+ breast cancer of 81 patients prior to neoadjuvant treatment with an AI was associated with poorer antiproliferative response. Additionally PDGFRβ expression increased after two weeks of AI therapy (1.25 fold, P = 0.003). CONCLUSIONS: These preclinical and clinical data indicate that the PDGF/Abl signaling pathway merits clinical evaluation as a therapeutic target with endocrine therapy in ER+ breast cancer..

Folkerd, E.J. Dixon, J.M. Renshaw, L. A'Hern, R.P. Dowsett, M. (2012). Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. J clin oncol, Vol.30 (24), pp. 2977-2980. show abstract

Rae, J.M. Drury, S. Hayes, D.F. Stearns, V. Thibert, J.N. Haynes, B.P. Salter, J. Sestak, I. Cuzick, J. Dowsett, M. ATAC trialists, (2012). CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J natl cancer inst, Vol.104 (6), pp. 452-460. show abstract

BACKGROUND: Adjuvant tamoxifen therapy substantially decreases the risk of recurrence and mortality in women with hormone (estrogen and/or progesterone) receptor-positive breast cancer. Previous studies have suggested that metabolic conversion of tamoxifen to endoxifen by cytochrome P450 2D6 (CYP2D6) is required for patient benefit from tamoxifen therapy. METHODS: Tumor specimens from a subset of postmenopausal patients with hormone receptor-positive early-stage (stages I, II, and IIIA) breast cancer, who were enrolled in the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial, were genotyped for variants in CYP2D6 (N = 1203 patients: anastrozole [trade name: Arimidex] group, n = 615 patients; tamoxifen group, n = 588 patients) and UDP-glucuronosyltransferase-2B7 (UGT2B7), whose gene product inactivates endoxifen (N = 1209 patients; anastrozole group, n = 606 patients; tamoxifen group, n = 603 patients). Genotyping was performed using polymerase chain reaction-based TaqMan assays. Based on the genotypes for CYP2D6, patients were classified as poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) phenotypes. We evaluated the association of CYP2D6 and UGT2B7 genotype with distant recurrence (primary endpoint) and any recurrence (secondary endpoint) by estimating the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using Cox proportional hazards models. All statistical tests were two-sided. RESULTS: After a median follow-up of 10 years, no statistically significant associations were observed between CYP2D6 genotype and recurrence in tamoxifen-treated patients (PM vs EM: HR for distant recurrence = 1.25, 95% CI = 0.55 to 3.15, P = .64; HR for any recurrence = 0.99, 95% CI = 0.48 to 2.08, P = .99). A near-null association was observed between UGT2B7 genotype and recurrence in tamoxifen-treated patients. No associations were observed between CYP2D6 and UGT2B7 genotypes and recurrence in anastrozole-treated patients. CONCLUSION: The results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients..

Barton, S. Zabaglo, L. A'Hern, R. Turner, N. Ferguson, T. O'Neill, S. Hills, M. Smith, I. Dowsett, M. (2012). Assessment of the contribution of the IHC4+C score to decision making in clinical practice in early breast cancer. Br j cancer, Vol.106 (11), pp. 1760-1765. show abstract

Prescott, J. Thompson, D.J. Kraft, P. Chanock, S.J. Audley, T. Brown, J. Leyland, J. Folkerd, E. Doody, D. Hankinson, S.E. Hunter, D.J. Jacobs, K.B. Dowsett, M. Cox, D.G. Easton, D.F. De Vivo, I. (2012). Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women. Plos one, Vol.7 (6), p. e37815. show abstract

Lundgren, K. Brown, M. Pineda, S. Cuzick, J. Salter, J. Zabaglo, L. Howell, A. Dowsett, M. Landberg, G. Investigators, T. (2012). Effects of cyclin D-1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Breast cancer research, Vol.14 (2).

Folkerd, E.J. Dowsett, M. (2011). Influence of Sex Hormones on Melanoma Reply. Journal of clinical oncology, Vol.29 (4), pp. E96-1.

Dunbier, A.K. Anderson, H. Ghazoui, Z. Lopez-Knowles, E. Pancholi, S. Ribas, R. Drury, S. Sidhu, K. Leary, A. Martin, L.-. Dowsett, M. (2011). ESR1 Is Co-Expressed with Closely Adjacent Uncharacterised Genes Spanning a Breast Cancer Susceptibility Locus at 6q25 1. Plos genetics, Vol.7 (4), p. 11.

Ghazoui, Z. Buffa, F.M. Dunbier, A.K. Anderson, H. Dexter, T. Detre, S. Salter, J. Smith, I.E. Harris, A.L. Dowsett, M. (2011). Close and Stable Relationship between Proliferation and a Hypoxia Metagene in Aromatase Inhibitor-Treated ER-Positive Breast Cancer. Clinical cancer research, Vol.17 (9), pp. 3005-8.

Tolhurst, R.S. Thomas, R.S. Kyle, F.J. Patel, H. Periyasamy, M. Photiou, A. Thiruchelvam, P.T. Lai, C.-. Al-Sabbagh, M. Fisher, R.A. Barry, S. Crnogorac-Jurcevic, T. Martin, L.-. Dowsett, M. Coombes, R.C. Kamalati, T. Ali, S. Buluwela, L. (2011). Transient over-expression of estrogen receptor-alpha in breast cancer cells promotes cell survival and estrogen-independent growth. Breast cancer research and treatment, Vol.128 (2), pp. 357-12.

Dunbier, A.K. Anderson, H. Ghazoui, Z. Salter, J. Parker, J.S. Perou, C.M. Smith, I.E. Dowsett, M. (2011). Association between breast cancer subtypes and response to neoadjuvant anastrozole. Steroids, Vol.76 (8), pp. 736-5.

Wolff, A.C. Dowsett, M. (2011). Estrogen Receptor: A Never Ending Story?. Journal of clinical oncology, Vol.29 (22), pp. 2955-5.

Lønning, P.E. Haynes, B.P. Straume, A.H. Dunbier, A. Helle, H. Knappskog, S. Dowsett, M. (2011). Exploring breast cancer estrogen disposition: the basis for endocrine manipulation. Clin cancer res, Vol.17 (15), pp. 4948-4958. show abstract

Dowsett, M. Lonning, P.E. (2011). Special Issue 10th International Aromatase Conference Proceedings, September 2010 Preface. Steroids, Vol.76 (8), pp. 729-1.

Lonning, P.E. Haynes, B.P. Straume, A.H. Dunbier, A. Helle, H. Knappskog, S. Dowsett, M. (2011). Recent data on intratumor estrogens in breast cancer. Steroids, Vol.76 (8), pp. 786-6.

Stanway, S.J. Palmieri, C. Stanczyk, F.Z. Folkerd, E.J. Dowsett, M. Ward, R. Coombes, R.C. Reed, M.J. Purohit, A. (2011). Effect of Tamoxifen or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer. Anticancer research, Vol.31 (4), pp. 1367-6.

Dowsett, M. (2011). Cytotoxic drugs: The endocrine part of the story. Breast, Vol.20, pp. S5-1.

Brand, J.S. Wareham, N.J. Dowsett, M. Folkerd, E. van der Schouw, Y.T. Luben, R.N. Khaw, K.-. (2011). Associations of endogenous testosterone and SHBG with glycated haemoglobin in middle-aged and older men. Clinical endocrinology, Vol.74 (5), pp. 572-7.

Miller, T.W. Balko, J.M. Ghazoui, Z. Dunbier, A. Anderson, H. Dowsett, M. Gonzalez-Angulo, A.M. Mills, G.B. Miller, W.R. Wu, H. Shyr, Y. Arteaga, C.L. (2011). A Gene Expression Signature from Human Breast Cancer Cells with Acquired Hormone Independence Identifies MYC as a Mediator of Antiestrogen Resistance. Clinical cancer research, Vol.17 (7), pp. 2024-11.

Cuzick, J. Sestak, I. Baum, M. Buzdar, A. Howell, A. Dowsett, M. Forbes, J.F. (2011). 10-year analysis of the ATAC trial: wrong conclusion? Reply. Lancet oncology, Vol.12 (3), pp. 217-1.

Sikora, M.J. Thibert, J.N. Salter, J. Dowsett, M. Johnson, M.D. Rae, J.M. (2011). High-efficiency genotype analysis from formalin-fixed, paraffin-embedded tumor tissues. Pharmacogenomics journal, Vol.11 (5), pp. 348-11.

Miller, T.W. Balko, J.M. Fox, E.M. Ghazoui, Z. Dunbier, A. Anderson, H. Dowsett, M. Jiang, A. Smith, R.A. Maira, S.-. Manning, H.C. Gonzalez-Angulo, A.M. Mills, G.B. Higham, C. Chanthaphaychith, S. Kuba, M.G. Miller, W.R. Shyr, Y. Arteaga, C.L. (2011). ER alpha-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer. Cancer discovery, Vol.1 (4), pp. 338-14.

Jones, R.L. Rojo, F. A'Hern, R. Villena, N. Salter, J. Corominas, J.M. Servitja, S. Smith, I.E. Rovira, A. Reis-Filho, J.S. Dowsett, M. Albanell, J. (2011). Nuclear NF-κB/p65 expression and response to neoadjuvant chemotherapy in breast cancer. J clin pathol, Vol.64 (2), pp. 130-135. show abstract

Dunbier, A.K. Martin, L.-. Dowsett, M. (2011). New and translational perspectives of oestrogen deprivation in breast cancer. Mol cell endocrinol, Vol.340 (2), pp. 137-141. show abstract

Stanway, S.J. Palmieri, C. Stanczyk, F.Z. Folkerd, E.J. Dowsett, M. Ward, R. Coombes, R.C. Reed, M.J. Purohit, A. (2011). Effect of tamoxifen or anastrozole on steroid sulfatase activity and serum androgen concentrations in postmenopausal women with breast cancer. Anticancer research, Vol.31 (4), pp. 1367-1372. show abstract

Martin, L.-. Ghazoui, Z. Weigel, M.T. Pancholi, S. Dunbier, A. Johnston, S. Dowsett, M. (2011). An in vitro model showing adaptation to long-term oestrogen deprivation highlights the clinical potential for targeting kinase pathways in combination with aromatase inhibition. Steroids, Vol.76 (8), pp. 772-776. show abstract

Dowsett, M. Salter, J. Zabaglo, L. Mallon, E. Howell, A. Buzdar, A.U. Forbes, J. Pineda, S. Cuzick, J. (2011). Predictive algorithms for adjuvant therapy: TransATAC. Steroids, Vol.76 (8), pp. 777-780. show abstract

Anderson, H. Hills, M. Zabaglo, L. A'hern, R. Leary, A.F. Haynes, B.P. Smith, I.E. Dowsett, M. (2011). Relationship between estrogen receptor, progesterone receptor, HER-2 and Ki67 expression and efficacy of aromatase inhibitors in advanced breast cancer. Ann oncol, Vol.22 (8), pp. 1770-1776. show abstract

Brand, J.S. Chan, M.-. Dowsett, M. Folkerd, E. Wareham, N.J. Luben, R.N. van der Schouw, Y.T. Khaw, K.-. (2011). Cigarette smoking and endogenous sex hormones in postmenopausal women. J clin endocrinol metab, Vol.96 (10), pp. 3184-3192. show abstract

Drury, S.C. Detre, S. Leary, A. Salter, J. Reis-Filho, J. Barbashina, V. Marchio, C. Lopez-Knowles, E. Ghazoui, Z. Habben, K. Arbogast, S. Johnston, S. Dowsett, M. (2011). Changes in breast cancer biomarkers in the IGF1R/PI3K pathway in recurrent breast cancer after tamoxifen treatment. Endocr relat cancer, Vol.18 (5), pp. 565-577. show abstract

Ring, A. Sestak, I. Baum, M. Howell, A. Buzdar, A. Dowsett, M. Forbes, J.F. Cuzick, J. (2011). Influence of comorbidities and age on risk of death without recurrence: a retrospective analysis of the Arimidex, Tamoxifen Alone or in Combination trial. J clin oncol, Vol.29 (32), pp. 4266-4272. show abstract

Cuzick, J. Dowsett, M. Pineda, S. Wale, C. Salter, J. Quinn, E. Zabaglo, L. Mallon, E. Green, A.R. Ellis, I.O. Howell, A. Buzdar, A.U. Forbes, J.F. (2011). Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J clin oncol, Vol.29 (32), pp. 4273-4278. show abstract

Sheri, A. Dowsett, M. (2011). Predicting response to cytotoxic drugs--the endocrine part of the story. Breast, Vol.20 Suppl 3, pp. S28-S30. show abstract

Prowell, T.M. Blackford, A.L. Byrne, C. Khouri, N.F. Dowsett, M. Folkerd, E. Tarpinian, K.S. Powers, P.P. Wright, L.A. Donehower, M.G. Jeter, S.C. Armstrong, D.K. Emens, L.A. Fetting, J.H. Wolff, A.C. Garrett-Mayer, E. Skaar, T.C. Davidson, N.E. Stearns, V. (2011). Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole. Cancer prev res (phila), Vol.4 (12), pp. 1993-2001. show abstract

Guest, S.K. Pancholi, S. Patani, N. Dowsett, M. Johnston, S.R. Martin, L.-. (2011). PD01-03: Src Is a Potential Therapeutic Target in Endocrine Resistant Breast Cancer Exhibiting Low Estrogen Receptor (ER)-Mediated Transactivation. Poster discussion abstracts, .

Bao, T. Tarpinian, K. Medeiros, M. Gould, J. Jeter, S. Cai, L. Tait, N. Shetty, J. Lewis, J. Gitten, L. Betts, K. Hoffman, A. Feigenberg, S. Chumsri, S. Armstronge, D.K. Bardia, A. Tan, M. Stebbing, J. Folkerd, E. Dowsett, M. Singh, H. Tkaczuk, K. Stearns, V. (2011). P4-12-13: A Multi-Center Randomized Controlled Double Blind Trial Assessing the Effect of Acupuncture in Reducing Musculoskeletal Symptoms in Breast Cancer Patients Taking Aromatase Inhibitors: First Interim Analysis. Poster session abstracts, .

Weigel, M.T. Banerjee, S. A'Hern, R. Arnedos, M. Ghazoui, Z. Dunbier, A.K. Dowsett, M. Martin, L.-. (2011). P4-01-01: Preclinical and Clinical Studies of Estrogen Deprivation Support the PDGF/Abl Pathway as a Novel Therapeutic Target for Overcoming Resistance. Poster session abstracts, .

Haynes, B.P. Viale, B. A'Hern, R. Smith, I.E. Dowsett, M. Galimberti, V. Rotmensz, N. Gibelli, B. (2011). S6-6: Expression of Key Estrogen-Regulated Genes (ERGs) Differ Substantially across the Menstrual Cycle in ER+ Breast Tumours. General session abstracts, .

Rae, J.M. Sestak, I. Henry, N.L. Drury, S. Hayes, D.F. Thibert, J.N. Lopez-Knowles, E. Salter, J. Pineda, S. Cuzick, J. Dowsett, M. (2011). P1-06-02: Correlation between Gene Variants in CYP19 (Aromatase) and TCL1A with Disease and Tolerability Endpoints in the ATAC Trial. Poster session abstracts, .

Dowsett, M. Lopez-Knowles, E. Sidhu, K. Pineda, S. Cowens, J.W. Ferree, S. Storhoff, J. Schaper, C. Cuzick, J. (2011). S4-5: Comparison of PAM50 Risk of Recurrence (ROR) Score with OncotypeDx and IHC4 for Predicting Residual Risk of RFS and Distant-(D)RFS after Endocrine Therapy: A TransATAC Study. General session abstracts, .

Metzger, O. Procter, M. de, A.E. Viale, G. Leyland-Jones, B. Dowsett, M. Gelber, R. Gresko, E. Loi, S. Sotiriou, C. Piccart, M. (2011). P2-18-01: The Magnitude of Trastuzumab Benefit in HER2−Positive (HER2+) Lobular Breast Carcinoma (BC): Results of a HERA Trial Sub-Group Analysis. Poster session abstracts, .

Balko, J.M. Cook, R.S. Kuba, M.G. Miller, T.W. Bhola, N.E. Sanders, M.E. Meszoely, I.M. Dowsett, M. Gomez, H. Arteaga, C.L. (2011). Inhibition of MEK/ERK- and JNK-Dependent Expression of Interleukin-6 and Interleukin-8 Targets Basal-Like Breast Cancer Stem Cells. Cancer research, Vol.71.

Wang, X. Saso, H. Iwamoto, T. Pusztai, L. Gong, Y. Woodward, W.A. Reuben, J.M. Hortobagyi, G.N. Ueno, N.T. (2011). P2-02-01: A Novel Inflammatory Breast Cancer-Specific Oncogene, Tazarotene-Induced Gene 1, Promotes Tumorigenicity and Invasiveness through the Receptor Tyrosine Kinase Axl. Poster session abstracts, .

Sestak, I. Cuzick, J. Dowsett, M. Salter, J. Quinn, E. Zabaglo, L. Howell, A. Buzdar, A. Forbes, J. (2011). P2-12-09: Prediction of Residual Risk of Recurrence after 5 Years of Follow-Up by Clinicopathologic Variables and 4 IHC Markers: A TransATAC Study. Poster session abstracts, .

Dowsett, M. Nielsen, T.O. A'Hern, R. Bartlett, J. Coombes, R.C. Cuzick, J. Ellis, M. Henry, N.L. Hugh, J.C. Lively, T. McShane, L. Paik, S. Penault-Llorca, F. Prudkin, L. Regan, M. Salter, J. Sotiriou, C. Smith, I.E. Viale, G. Zujewski, J.A. Hayes, D.F. International Ki-67 in Breast Cancer Working Group, (2011). Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J natl cancer inst, Vol.103 (22), pp. 1656-1664. show abstract

Marchiò, C. Dowsett, M. Reis-Filho, J.S. (2011). Revisiting the technical validation of tumour biomarker assays: how to open a Pandora's box. Bmc med, Vol.9, p. 41. show abstract

Mackay, A. Weigelt, B. Grigoriadis, A. Kreike, B. Natrajan, R. A'Hern, R. Tan, D.S. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2011). Microarray-based class discovery for molecular classification of breast cancer: analysis of interobserver agreement. J natl cancer inst, Vol.103 (8), pp. 662-673. show abstract

BACKGROUND: Breast cancers can be classified by hierarchical clustering using an "intrinsic" gene list into one of at least five molecular subtypes: basal-like, HER2, luminal A, luminal B, and normal breast-like. Five different intrinsic gene lists composed of varying numbers of genes have been used for molecular subtype identification and classification of breast cancers. The aim of this study was to determine the objectivity and interobserver reproducibility of the assignment of molecular subtype classes by hierarchical cluster analysis. METHODS: Three publicly available breast cancer datasets (n = 779) were subjected to two-way average-linkage hierarchical cluster analysis using five distinct intrinsic gene lists. We used free-marginal Kappa statistics to analyze interobserver agreement among five breast cancer researchers for the whole classification and for each molecular subtype separately according to each intrinsic gene list for each breast cancer dataset. RESULTS: None of the classification systems tested produced almost perfect agreement (Kappa ≥ 0.81) among observers. However, substantial interobserver agreement (70.8% to 76.1% of the samples and free-marginal Kappa scores from 0.635 to 0.701) was consistently observed in all datasets for four molecular subtypes (luminal, basal-like, HER2, and normal breast-like). When luminal cancers were subdivided (luminal A, B, and C), none of the classification systems produced substantial agreement (Kappa ≥ 0.61) in all the datasets analyzed. Analysis of each subtype separately revealed that only two (basal-like and HER2) could be reproducibly identified by independent observers (Kappa ≥ 0.81). CONCLUSIONS: Assignment of molecular subtype classes of breast cancer based on the analysis of dendrograms obtained with hierarchical cluster analysis is subjective and shows modest interobserver reproducibility. For the development of a molecular taxonomy, objective definitions for each molecular subtype and standardized methods for their identification are required..

Dowsett, M. Smith, I.E. (2011). Presurgical Progesterone in Early Breast Cancer: So Much for So Little?. Journal of clinical oncology, Vol.29 (21), pp. 2839-3.

Basu, B. Ang, J.E. Crawley, D. Folkerd, E. Sarker, D. Blanco-Codesido, M. Moran, K. Wan, S. Dobbs, N. Raynaud, F. Johnston, S.R. Dowsett, M. Tutt, A.N. Spicer, J.F. Swanton, C. De Bono, J.S. (2011). Phase I study of abiraterone acetate (AA) in patients (pts) with estrogen receptor-(ER) or androgen receptor (AR)-positive advanced breast carcinoma resistant to standard endocrine therapies. Journal of clinical oncology, Vol.29 (15).

Guerrero-Zotano, A. Gavila, J. Folkerd, E. Ortiz, B. Labrador, T. Martinez, F. Garcia, A. Climent, M.A. Guillem, V. Dowsett, M. Ruiz, A. (2011). Incidence and predictors of ovarian function recovery (OFR) in exemestane patients with breast cancer (BC) with chemotherapy-induced amenorrhea (CIA) using two estradiol assays. Journal of clinical oncology, Vol.29 (15).

Arnedos, M. Ferraldeschi, R. A'Hern, R. Hadfield, K. Roberts, S. Drury, S. Howell, A. Evans, D.G. Wardley, A.M. Smith, I.E. Newman, W.G. Dowsett, M. (2011). Polymorphisms of the aromatase gene (CYP19A1) and benefit of aromatase inhibitors (AIs) in metastatic breast cancer (mBC) patients. Journal of clinical oncology, Vol.29 (15).

Sestak, I. Harvie, M. Howell, A. Forbes, J.F. Dowsett, M. Cuzick, J.M. (2011). Weight change associated with anastrozole and tamoxifen treatment in postmenopausal women with breast cancer or at high risk of developing it. J clin oncol, Vol.29 (27_suppl), p. 165. show abstract

165 Background: Weight gain is commonly reported by patients with breast cancer. Aromatase inhibitors are being tested in the preventive setting in high risk women and it is important to evaluate the association between treatment and weight change as this may effect the patient's decision to continue to take the drug. METHODS: Weight change in postmenopausal women from three large clinical trials (ATAC, IBIS-I, IBIS-II) investigating endocrine treatment for the treatment and prevention of breast cancer have been analysed. The objective of this retrospective study was to assess the effects of anastrozole and tamoxifen on weight change in postmenopausal women. RESULTS: In the ATAC trial, a mean increase of 1.4 kg was observed after 12 months of follow-up and no statistically significant differences between treatment arms (anastrozole vs. tamoxifen) were found. The majority of women kept their weight stable and only 11.2% gained more than 5 kg within this time period. Significant baseline predictors for gaining more than 5 kg of weight after 12 months of follow-up were being younger than 60 years old at entry, smoking at entry, and mastectomy. Results for the two prevention studies IBIS-I and IBIS-II were quite similar. In the IBIS-II trial, the overall mean weight change after 12 months of follow-up was 0.5 kg. In the IBIS-I study women gained an average of 0.9 kg within the first 12 months of follow up. In both studies no differences between treatment and placebo (IBIS-I: tamoxifen vs. placebo; IBIS-II: anastrozole vs. placebo) were observed. Overall, women in the adjuvant setting gained more than 5 kg of weight (11.2%) after 12 months of follow up compared to those in the preventive setting (5.3% IBIS-I, 5.7% IBIS-II), but similar overall weight gain was seen after 60 months of follow up in both settings (5.7% IBIS-I vs. 6.1% ATAC). CONCLUSIONS: All three trials have demonstrated that weight gain occurs primarily within the first 12 months of active treatment and are similar to those on placebo. Weight stabilises after 12 months of follow up and major weight gain was rare in all trials, and unrelated to treatment..

Basu, B. Ang, J.E. Crawley, D. Folkerd, E. Sarker, D. Blanco-Codesido, M. Moran, K. Wan, S. Dobbs, N. Raynaud, F. Johnston, S.R. Dowsett, M. Tutt, A.N. Spicer, J.F. Swanton, C. De Bono, J.S. (2011). Phase I study of abiraterone acetate (AA) in patients (pts) with estrogen receptor- (ER) or androgen receptor (AR) -positive advanced breast carcinoma resistant to standard endocrine therapies. J clin oncol, Vol.29 (15_suppl), p. 2525. show abstract

2525 Background: Many advanced ER+ breast cancer pts show intrinsic resistance to endocrine treatment with the remainder acquiring resistance. Androgenic steroids upstream of aromatase can drive steroid receptor signaling critical to tumour growth. Evidence also exists for an ERα-/AR+ subset of breast cancers transcriptionally similar to ERα+ disease. We hypothesized that AA, a cytochrome (CYP) 17 inhibitor that irreversibly inhibits androgen and estrogen synthesis, would have anti-tumour activity in ER+ or ER-/AR+ pts. METHODS: Post-menopausal women with ER+ or ER-/AR+ advanced breast cancer resistant to >2 lines of hormone therapies were treated in 6-pt cohorts with AA at doses between 250 and 2000mg daily. RESULTS: A total of 25 pts were treated in the phase I trial with 2 pts ongoing on study. Median time on treatment was 1.8 mths (range 0.7 - 11.6 mths). There were no dose limiting toxicities. The majority of adverse events (AEs) were Common Toxicity Criteria grade 1 or 2: fatigue, nausea, anorexia, dyspnoea, palpitations, dizziness and flushes. Hypokalemia was frequent, due to secondary mineralocorticoid syndrome: grade 3/4 hypokalemia occurred in 4 pts. This was effectively managed with potassium supplementation, hydrocortisone (20 mg mane, 10 mg nocte) and eplerenone (50-200 mg) with no clinical consequences. Other grade 3 AEs were neutropenia and reduced left ventricular ejection fraction (1 pt) and exercise-induced hypotension with dizziness (1 pt). At the 2000mg dose 5/5 subjects had suppression of estradiol, testosterone, DHEA and DHEAS to below the lower limit of detection of the assay. Two pts (both ER+/AR+) continued on study beyond 11 mths, one of whom achieved a radiological partial response and 80% reduction in serum CA15.3 from baseline. Pharmacokinetic data will be presented. CONCLUSIONS: AA is well tolerated in advanced breast cancer pts with preliminary evidence of antitumour activity. The predominant AEs are mechanism-based (hypokalemia) and can be managed expectantly, although careful monitoring of potassium levels is recommended..

Balko, J.M. Cook, R.S. Miller, T.W. Bhola, N.E. Sanders, M. Granja-Ingram, N.M. Sanchez, V. Meszoely, I.M. Salter, J. Dowsett, M. Stemke-Hale, K. Gonzalez-Angulo, A.M. Mills, G.B. Arteaga, C.L. (2011). Use of gene expression patterns post neoadjuvant chemotherapy to identify a role for the MAPK phosphatase DUSP4 in therapeutic resistance and a stem-like phenotype in basal-like breast cancer (BLBC). J clin oncol, Vol.29 (15_suppl), p. 10509. show abstract

10509 Background: Neoadjuvant chemotherapy (NAC) leads to a pathological complete response in ~20% of patients with breast cancer. The remaining patients have residual disease and are more likely to develop metastasis. In post-NAC tumors, Ki67 levels, a marker of cell proliferation, have been shown to inform odds of recurrence and death. We hypothesized that post-NAC residual cancers with a high Ki67 harbor molecular alterations that are associated with drug resistance. METHODS: We utilized Nanostring digital RNA quantification to measure the expression levels of 350 cancer-related genes in 49 post-NAC breast cancers. Gene expression data were tested for associations with post-NAC Ki67. The cohort was enriched for triple-negative breast cancer (24/49 tumors). The candidate gene DUSP4 was explored in in vitro models of breast cancer. RESULTS: The post-NAC Ki67 (range 2.4 - 99%; median: 31.6%) was statistically different among the molecular subtypes of breast cancers enrolled, being highest in BLBC (p<0.0001). Gene expression signatures of KRAS activation were enriched in BLBC. Low levels of the MAPK phosphatase DUSP4 correlated with a high Ki67 in BLBCs (r=-0.54, p=8x10(-4)) and with Ras/MAPK pathway activation in human breast tumors and cell lines. Genome-wide studies identified preferential methylation of the DUSP4 promoter in BLBC. Among BLBC cell lines, low DUSP4 expression predicted for sensitivity to MEK inhibitors and resistance to docetaxel. Inhibition of MEK with AZD6244 or overexpression of DUSP4 in DUSP4-low BLBC cell lines improved sensitivity to docetaxel and inhibited mammosphere formation. RNAi-mediated knockdown of DUSP4 in BLBC cells enhanced ETS-1 phosphorylation, mammosphere formation, and MAPK-dependent secretion of the cancer stem cell-promoting cytokines IL6 and IL8. CONCLUSIONS: Low levels of DUSP4 correlate with high tumor cell proliferation after NAC. Downregulation of DUSP4 may underlie activation of the MAPK pathway in the absence of KRAS mutations in BLBC while conferring resistance to chemotherapy and a stem cell-like phenotype that is therapeutically targetable with MAPK inhibitors..

Smith, I.E. Johnson, L. Dowsett, M. Robertson, J.F. Robison, L.E. Kokan, J.S. Evans, A.A. Holcombe, C. Horgan, K. Skene, A. Prasad, R. Absar, M.S. Vidya, R. Bundred, N.J. Harding-Mackean, C. Wheatley, D.A. Kissin, M.W. Pinhel, I.F. Kilburn, L.S. Bliss, J.M. POETIC Trialists, (2011). Trial of perioperative endocrine therapy: Individualizing care (POETIC). J clin oncol, Vol.29 (15_suppl), p. TPS117. show abstract

TPS117 Background: The neoadjuvant IMPACT trial suggested Ki67 levels after 2 weeks endocrine therapy predicts long-term outcome. Major changes in gene expression have also been seen in ER+ breast cancer after aromatase inhibitor (AI) treatment. POETIC evaluates whether changes in Ki67 level after 2 weeks treatment predicts for relapse-free survival (RFS) more effectively than the baseline value. It also tests whether gene expression profile at this timepoint provides more accurate prognostic and predictive information than the pre-treatment profile. Experimental evidence suggests peri-operative endocrine therapy may improve disease outcome. This hypothesis is also addressed in POETIC. ( ISRCTN63882543 ) With a sample size of 4000, an improvement in 5 year relapse from 10% to 7% could be detected with 91% power (two sided alpha of 5%), as would a 1.3 fold difference in the ability of Ki67 to predict RFS (90% power, two sided 5% significance level). Target recruitment is 4000 patients from 100 UK hospitals over 3-4 years. METHODS: Patients are randomised in the ratio of 2:1 to perioperative AI (letrozole 2.5mg or anastrozole 1mg daily) starting 2 weeks before planned surgery until 2 weeks after surgery. FFPE and RNA-later samples are taken prior to trial entry (baseline) and at surgery. Eligible patients are postmenopausal with ER+ invasive breast cancer. Consent to take additional research tissue is sought from patients undergoing diagnostic biopsy. Consenting patients donate tumour tissue in RNA-later and/or a FFPE research sample and enter POETIC following diagnosis of ER+ breast cancer. Matching tumour tissue is taken at surgery. Where an RNA-later sample at baseline is unavailable, consenting patients may undergo a further biopsy for research tissue immediately before study entry. Where consent procedures at diagnosis present logistical challenges, sites may provide FFPE tissue left over from diagnosis only. The 1(st) patient was entered in September 2008, and by January 2011 102 UK hospitals open and 1200 patients were entered. 182 optional RNA-later samples at both timepoints are available. Current success is due to a flexible approach to tissue sample collection and overcoming local and national logistical challenges..

Arnedos, M. Ferraldeschi, R. A'Hern, R. Hadfield, K. Roberts, S. Drury, S. Howell, A. Evans, D.G. Wardley, A.M. Smith, I.E. Newman, W.G. Dowsett, M. (2011). Polymorphisms of the aromatase gene (CYP19A1) and benefit of aromatase inhibitors (AIs) in metastatic breast cancer (mBC) patients. J clin oncol, Vol.29 (15_suppl), p. 608. show abstract

608 Background: Germline genotypic polymorphisms in CYP19A1 have been associated with differential benefit from treatment with AIs in patients with mBC, but validation is lacking. METHODS: We retrospectively identified patients with ER-positive mBC treated with a 3(rd) generation AI. DNA was obtained from archival paraffin-embedded tumors and genotyped for 74 polymorphisms in 20 candidate genes, including CYP19A1 using the Sequenom MassARRAY Platform. The CYP19A1 Arg264Cys ( rs700519 ) variant was analyzed by Pyrosequencing. The CYP19A1 (TTTA)n(rs60271534) and TCT Ins/Del (rs11575899) variants were genotyped by fragment analysis.Primary endpoint was time to treatment failure (TTF), analyses being undertaken using Cox's regression to estimate the hazard ratio for risk of failure per allele. RESULTS: 308 patients were included. Mean TTF was 15 months (range 1 to 58). Two sets of analyses were undertaken. The first were confirmatory analyses for the CYP19A1 variants rs4646, rs10459592 and rs4775936, previously associated with letrozole efficacy in mBC.TTF was significantly improved in patients carrying the T allele of rs4775936 compared to homozygous wild-type patients [HR=0.79 (0.66-0.95); p=0.012]. However, this association lost significance when adjusted for other prognostic factors. When the analysis was limited to letrozole treated patients (n=165), the difference was no longer significant (p=0.068). None of the 60 other SNPs with MAF ≥5%, included as an exploratory set, showed significant association with TTF. Patients with >7 TTTA repeats on either allele of CYP19A1 had lower risk of failure than those without it [HR=0.84 (0.7-0.99); p=0.04]. This association also lost significance when adjusted for clinical factors. CONCLUSIONS: In this retrospective cohort of patients with mBC treated with a 3(rd) generation AI, carriage of the minor allele of the CYP19A1 variant rs4775936 and greater than seven repeats of the TTTA polymorphism within intron 4 of CYP19A1 were significantly associated with improved AI treatment efficacy in univariate analysis and require further study. There was no significant association of any other candidate SNP with efficacy of AIs..

Guerrero-Zotano, A. Gavila, J. Folkerd, E. Ortiz, B. Labrador, T. Martinez, F. Garcia, A. Climent, M.A. Guillem, V. Dowsett, M. Ruiz, A. (2011). Incidence and predictors of ovarian function recovery (OFR) in exemestane patients with breast cancer (BC) with chemotherapy-induced amenorrhea (CIA) using two estradiol assays. J clin oncol, Vol.29 (15_suppl), p. 521. show abstract

521 Background: Aromatase inhibitors (AIs) may promote OFR in patients with CIA. True incidence of OFR is unknown partly because estradiol (E2) assays used in the clinical setting lacking sensitivity. We studied incidence and predictors of OFR measuring E2 by a clinical assay (direct) or by a highly sensitive (indirect) immunoassay, together with other markers of ovarian reserve. METHODS: Prospective exploratory study in ER positive BC patients, who had CIA lasting at least two years and postmenopausal E2 levels, while on tamoxifen. Patients received exemestane and underwent assessments of E2 (indirect and direct assay), FSH, antimullerian hormone (AMH), and antral follicule count (AFC) at baseline and at month 1, 3 and 6. We considered OFR if: resumption of menses, or developed (i) both E2 levels inconsistent with postmenopausal women on AI (indirect: >8 pmol/L; direct >165 pmol/L) and FSH (<26 IU/L) levels), or (ii) frankly non-postmenopausal E2 values (indirect >55 pmol/L; direct >220 pmol/L). RESULTS: Fifty-three consecutive patients were enrolled; median age: 48y (41-55). By indirect assay, 15 patients (28.3%; CI95%:16.1-40.4) had OFR, (11 menses, 4 OFR without menses). By direct assay 14 had OFR (11 menses, 3 OFR without menses). Mean time to OFR by indirect assay was 5.7 months (CI95%: 3.1-8.3) and 6.4 months (CI95%: 3.7-9.1) by direct assay. There was no difference in baseline E2 levels among those who recover or not OFR. Mean age was the only baseline marker different between patients who had OFR or not (45.7 vs 49.1 years, t-test p<0.0001). In patients ≤48 years (n=26) rate of OFR was 46%. AMH at baseline was below detection limit in all patients and it did not change during exemestane. Baseline and serial values for AFC were not different among patients who had OFR or not. CONCLUSIONS: There is a high incidence (28%) of OFR, in patients with CIA treated with AIs, especially in women ≤48y. The two E2 assays showed similar incidence of OFR and time to OFR, despite having markedly different performance characteristics. AMH was not helpful in defining ovarian reserve and likelihood of OFR..

Sestak, I. Harvie, M. Howell, A. Forbes, J.F. Dowsett, M. Cuzick, J.M. (2011). Weight change associated with anastrozole and tamoxifen treatment in postmenopausal women with breast cancer or at high risk of developing it. Journal of clinical oncology, Vol.29 (27).

Tang, G. Cuzick, J. Costantino, J.P. Dowsett, M. Forbes, J.F. Crager, M. Mamounas, E.P. Shak, S. Wolmark, N. (2011). Risk of recurrence and chemotherapy benefit for patients with node-negative, estrogen receptor-positive breast cancer: recurrence score alone and integrated with pathologic and clinical factors. J clin oncol, Vol.29 (33), pp. 4365-4372. show abstract

Key, T.J. Appleby, P.N. Reeves, G.K. Roddam, A.W. Helzlsouer, K.J. Alberg, A.J. Rollison, D.E. Dorgan, J.F. Brinton, L.A. Overvad, K. Kaaks, R. Trichopoulou, A. Clavel-Chapelon, F. Panico, S. Duell, E.J. Peeters, P.H. Rinaldi, S. Riboli, E. Fentiman, I.S. Dowsett, M. Manjer, J. Lenner, P. Hallmans, G. Baglietto, L. English, D.R. Giles, G.G. Hopper, J.L. Severi, G. Morris, H.A. Koenig, K. Zeleniuch-Jacquotte, A. Arslan, A.A. Toniolo, P. Shore, R.E. Krogh, V. Micheli, A. Berrino, F. Muti, P. Barrett-Connor, E. Laughlin, G.A. Kabuto, M. Akiba, S. Stevens, R.G. Neriishi, K. Land, C.E. Cauley, J.A. Lui, L.Y. Cummings, S.R. Gunter, M.J. Rohan, T.E. Strickler, H.D. (2011). Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. British journal of cancer, Vol.105 (5), pp. 709-14.

Dowsett, M. Smith, I. Robertson, J. Robison, L. Pinhel, I. Johnson, L. Salter, J. Dunbier, A. Anderson, H. Ghazoui, Z. Skene, T. Evans, A. A'Hern, R. Iskender, A. Wilcox, M. Bliss, J. (2011). Endocrine therapy, new biologicals, and new study designs for presurgical studies in breast cancer. J natl cancer inst monogr, Vol.2011 (43), pp. 120-123. show abstract

Early Breast Cancer Trialists' Collaborative, G. (2011). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet, Vol.378 (9793), pp. 771-784. show abstract

SummaryBackground As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen. Methods We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21 457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment. Findings In oestrogen receptor (ER)-positive disease (n=10 645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0–4 and RR 0·68 [0·06] during years 5–9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10–14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10–19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0–4, 0·66 [0·05] during years 5–9, and 0·68 [0·08] during years 10–14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality. Interpretation 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen. Funding Cancer Research UK, British Heart Foundation, and Medical Research Council..

Weigelt, B. Mackay, A. Natrajan, R. Tan, D.S. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2010). The importance of gene-centring microarray data Reply. Lancet oncology, Vol.11 (8), pp. 720-2.

Jones, R.L. Salter, J. A'Hern, R. Nerurkar, A. Parton, M. Reis-Filho, J.S. Smith, I.E. Dowsett, M. (2010). Relationship between oestrogen receptor status and proliferation in predicting response and long-term outcome to neoadjuvant chemotherapy for breast cancer. Breast cancer res treat, Vol.119 (2), pp. 315-323. show abstract

Dunbier, A.K. Anderson, H. Ghazoui, Z. Folkerd, E.J. A'hern, R. Crowder, R.J. Hoog, J. Smith, I.E. Osin, P. Nerurkar, A. Parker, J.S. Perou, C.M. Ellis, M.J. Dowsett, M. (2010). Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women. J clin oncol, Vol.28 (7), pp. 1161-1167. show abstract

Leary, A.F. Drury, S. Detre, S. Pancholi, S. Lykkesfeldt, A.E. Martin, L.-. Dowsett, M. Johnston, S.R. (2010). Lapatinib restores hormone sensitivity with differential effects on estrogen receptor signaling in cell models of human epidermal growth factor receptor 2-negative breast cancer with acquired endocrine resistance. Clin cancer res, Vol.16 (5), pp. 1486-1497. show abstract

PURPOSE: Acquired endocrine resistance in estrogen receptor (ER)alpha+/human epidermal growth factor receptor 2-negative (HER2-) breast cancer has been associated with modest adaptive increases in HER2, although exactly how aberrant HER2 signaling affects the ERalpha pathway is poorly understood. We investigated (a) whether the epidermal growth factor receptor/HER2 inhibitor lapatinib could restore endocrine responsiveness in cell models of acquired endocrine resistance with modest increases in HER2, and (b) the nature of ERalpha-HER2 cross-talk in this process. METHODS: Combination growth studies, ERalpha transcription, immunoblot, and gene expression assays were conducted in two models of acquired resistance to (a) estrogen deprivation (long-term estrogen-deprived cells) and (b) tamoxifen (long-term tamoxifen-treated cells), and in hormone sensitive controls. Changes in ERalpha, PgR, and HER2 were assessed in samples from patients treated with tamoxifen. RESULTS: Both cell models of acquired endocrine resistance showed modest adaptive upregulation in HER2, and lapatinib restored endocrine sensitivity in both. The effect of lapatinib on ERalpha signaling varied markedly depending on the nature of the HER2/ERalpha cross-talk. In long-term estrogen-deprived cells characterized by enhanced ERalpha function, lapatinib suppressed ERalpha genomic activity (as measured by pERSer118, ERalpha transcriptional activity, and PGR gene expression). In contrast, in long-term tamoxifen-treated cells with reduced ERalpha activation, lapatinib reactivated ERalpha genomic function. Twenty percent of tamoxifen-resistant patients relapsed with modest increases in HER2 and either suppressed or enhanced ERalpha/PgR expression. CONCLUSIONS: Aberrant GFR signaling can augment or suppress ERalpha function. Regardless, interrupting the HER2/ERalpha cross-talk with lapatinib can restore endocrine sensitivity and should be investigated as a therapeutic strategy in combination with endocrine therapy in ERalpha+/HER2- patients with acquired endocrine resistance..

Cheung, K.L. Agrawal, A. Folkerd, E. Dowsett, M. Robertson, J.F. Winterbottom, L. (2010). Suppression of ovarian function in combination with an aromatase inhibitor as treatment for advanced breast cancer in pre-menopausal women. European journal of cancer, Vol.46 (16), pp. 2936-7.

Pinhel, I.F. MacNeill, F.A. Hills, M.J. Salter, J. Detre, S. A'Hern, R. Nerurkar, A. Osin, P. Smith, I.E. Dowsett, M. (2010). Extreme loss of immunoreactive p-Akt and p-Erk1/2 during routine fixation of primary breast cancer. Breast cancer research, Vol.12 (5), p. 7.

Cuzick, J. Sestak, I. Baum, M. Buzdar, A. Howell, A. Dowsett, M. Forbes, J.F. (2010). Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet oncology, Vol.11 (12), pp. 1135-7.

Dowsett, M. Pineda, S. Cuzick, J. (2010). What Is the Value of the 21 Gene Recurrence Score in HER2-Negative Patients? Reply. Journal of clinical oncology, Vol.28 (31), pp. E648-1.

Hammond, M.E. Hayes, D.F. Dowsett, M. Allred, D.C. Hagerty, K.L. Badve, S. Fitzgibbons, P.L. Francis, G. Goldstein, N.S. Hayes, M. Hicks, D.G. Lester, S. Love, R. Mangu, P.B. McShane, L. Miller, K. Osborne, C.K. Paik, S. Perlmutter, J. Rhodes, A. Sasano, H. Schwartz, J.N. Sweep, F.C. Taube, S. Torlakovic, E.E. Valenstein, P. Viale, G. Visscher, D. Wheeler, T. Williams, R.B. Wittliff, J.L. Wolff, A.C. (2010). American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer (Unabridged Version). Archives of pathology & laboratory medicine, Vol.134 (7), pp. E48-25.

Hammond, M.E. Hayes, D.F. Dowsett, M. Allred, D.C. Hagerty, K.L. Badve, S. Fitzgibbons, P.L. Francis, G. Goldstein, N.S. Hayes, M. Hicks, D.G. Lester, S. Love, R. Mangu, P.B. McShane, L. Miller, K. Osborne, C.K. Paik, S. Perlmutter, J. Rhodes, A. Sasano, H. Schwartz, J.N. Sweep, F.C. Taube, S. Torlakovic, E.E. Valenstein, P. Viale, G. Visscher, D. Wheeler, T. Williams, R.B. Wittliff, J.L. Wolff, A.C. (2010). American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer. Archives of pathology & laboratory medicine, Vol.134 (6), pp. 907-16.

Hammond, M.E. Hayes, D.F. Dowsett, M. Allred, D.C. Hagerty, K.L. Badve, S. Fitzgibbons, P.L. Francis, G. Goldstein, N.S. Hayes, M. Hicks, D.G. Lester, S. Love, R. Mangu, P.B. McShane, L. Miller, K. Osborne, C.K. Paik, S. Perlmutter, J. Rhodes, A. Sasano, H. Schwartz, J.N. Sweep, F.C. Taube, S. Torlakovic, E.E. Valenstein, P. Viale, G. Visscher, D. Wheeler, T. Williams, R.B. Wittliff, J.L. Wolff, A.C. (2010). American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer. Journal of clinical oncology, Vol.28 (16), pp. 2784-12.

Freedman, O.C. Amir, E. Hanna, W. Kahn, H. O'Malley, F. Dranitsaris, G. Cole, D.E. Verma, S. Folkerd, E. Dowsett, M. Clemons, M. (2010). A randomized trial exploring the biomarker effects of neoadjuvant sequential treatment with exemestane and anastrozole in post-menopausal women with hormone receptor-positive breast cancer. Breast cancer research and treatment, Vol.119 (1), pp. 155-7.

Weigelt, B. Mackay, A. A'hern, R. Natrajan, R. Tan, D.S. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2010). Breast cancer molecular profiling with single sample predictors: a retrospective analysis. Lancet oncol, Vol.11 (4), pp. 339-349. show abstract

Drury, S. Salter, J. Baehner, F.L. Shak, S. Dowsett, M. (2010). Feasibility of using tissue microarray cores of paraffin-embedded breast cancer tissue for measurement of gene expression: a proof-of-concept study. J clin pathol, Vol.63 (6), pp. 513-517. show abstract

Weigelt, B. Mackay, A. Natrajan, R. Tan, D.S. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2010). The importance of gene-centring microarray data – Authors' reply. The lancet oncology, Vol.11 (8), pp. 720-721.

Zabaglo, L. Salter, J. Anderson, H. Quinn, E. Hills, M. Detre, S. A'Hern, R. Dowsett, M. (2010). Comparative validation of the SP6 antibody to Ki67 in breast cancer. J clin pathol, Vol.63 (9), pp. 800-804. show abstract

Martin, L.-. Davies, G.L. Weigel, M.T. Betambeau, N. Hills, M.J. Salter, J. Walsh, G. A'Hern, R. Dowsett, M. (2010). Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer. Breast cancer res treat, Vol.123 (3), pp. 829-836. show abstract

Folkerd, E.J. Dowsett, M. (2010). Influence of Sex Hormones on Cancer Progression. Journal of clinical oncology, Vol.28 (26), pp. 4038-7.

Folkerd, E.J. Dowsett, M. (2010). Influence of sex hormones on cancer progression. J clin oncol, Vol.28 (26), pp. 4038-4044. show abstract

Dowsett, M. Cuzick, J. Wale, C. Forbes, J. Mallon, E.A. Salter, J. Quinn, E. Dunbier, A. Baum, M. Buzdar, A. Howell, A. Bugarini, R. Baehner, F.L. Shak, S. (2010). Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J clin oncol, Vol.28 (11), pp. 1829-1834. show abstract

Dowsett, M. (2010). Absolute Benefits of Aromatase Inhibitors in Adjuvant Treatment of Breast Cancer: Should We Know More? Reply to B Seruga et al. Journal of clinical oncology, Vol.28 (20), pp. E348-1.

Bonelli, M.A. Fumarola, C. Alfieri, R.R. La Monica, S. Cavazzoni, A. Galetti, M. Gatti, R. Belletti, S. Harris, A.L. Fox, S.B. Evans, D.B. Dowsett, M. Martin, L.-. Bottini, A. Generali, D. Petronini, P.G. (2010). Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast cancer res treat, Vol.124 (1), pp. 79-88. show abstract

Weigel, M.T. Dowsett, M. (2010). Current and emerging biomarkers in breast cancer: prognosis and prediction. Endocr relat cancer, Vol.17 (4), pp. R245-R262. show abstract

Breast cancer treatment has experienced several changes in the past decades due to the discovery of specific prognostic and predictive biomarkers that enable the application of more individualized therapies to different molecular subgroups. These subgroups show specific differences regarding biological clinical behavior. In addition to the classical clinical prognostic factors of breast cancer, established molecular biomarkers such as estrogen receptor and progesterone receptor have played a significant role in the selection of patients benefiting from endocrine therapy for many years. More recently, the human epidermal growth factor receptor 2 (HER2) has been validated to be not only a prognostic factor, but also a predictor of response to HER2 targeting therapy. The shift toward an earlier diagnosis of breast cancer due to improved imaging methods and screening programs highlights the need for new factors and combinations of biomarkers to quantify the residual risk of patients and to indicate the potential value of additional treatment strategies. The marker of proliferation Ki67 has recently emerged as an important marker due to several applications in neoadjuvant therapy in addition to its moderate prognostic value. With the introduction of high-throughput technologies, numerous multigene signatures have been identified that aim to outperform traditional markers: current prospective clinical trials are seeking evidence for their definitive role in breast cancer. There exist many more factors and approaches that have the potential to become relevant in the near future including the detection of single disseminating and circulating tumor cells in blood and bone marrow as well as of circulating cell-free DNA and microRNA. Careful randomized prospective testing and comparison with existing established factors will be required to select those emerging markers that offer substantial cost-effective benefit and thereby justify their routine use for breast cancer therapy decision-making..

Evans, A.H. Pancholi, S. Farmer, I. Thornhill, A. Evans, D.B. Johnston, S.R. Dowsett, M. Martin, L.-. (2010). EGFR/HER2 inhibitor AEE788 increases ER-mediated transcription in HER2/ER-positive breast cancer cells but functions synergistically with endocrine therapy. Br j cancer, Vol.102 (8), pp. 1235-1243. show abstract

Banerjee, S. A'Hern, R. Detre, S. Littlewood-Evans, A.J. Evans, D.B. Dowsett, M. Martin, L.-. (2010). Biological Evidence for Dual Antiangiogenic-Antiaromatase Activity of the VEGFR Inhibitor PTK787/ZK222584 In vivo. Clinical cancer research, Vol.16 (16), pp. 4178-10.

Haynes, B.P. Straume, A.H. Geisler, J. A'Hern, R. Helle, H. Smith, I.E. Lønning, P.E. Dowsett, M. (2010). Intratumoral estrogen disposition in breast cancer. Clin cancer res, Vol.16 (6), pp. 1790-1801. show abstract

Banerjee, S. A'Hern, R. Detre, S. Littlewood-Evans, A.J. Evans, D.B. Dowsett, M. Martin, L.-. (2010). Biological evidence for dual antiangiogenic-antiaromatase activity of the VEGFR inhibitor PTK787/ZK222584 in vivo. Clin cancer res, Vol.16 (16), pp. 4178-4187. show abstract

Graeser, M. McCarthy, A. Lord, C.J. Savage, K. Hills, M. Salter, J. Orr, N. Parton, M. Smith, I.E. Reis-Filho, J.S. Dowsett, M. Ashworth, A. Turner, N.C. (2010). A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin cancer res, Vol.16 (24), pp. 6159-6168. show abstract

Leary, A.F. Martin, L.-. Thornhill, A. Dowsett, M. Johnston, S.R. (2010). Abstract P3-14-03: Combining or Sequencing Targeted Therapies in ER+/HER2 Amplified Breast Cancer (BC):In VitroandIn VivoStudies of Letrozole and Lapatinib in an ER+/HER2+ Aromatase-Transfected BC Model. Poster session abstracts, .

Walker, K. Johnson, N. Palles, C. Folkerd, E. Hillier, S.G. Moss, S. Gibson, L. Dowsett, M. Peto, J. dos Santos Silva, I. Fletcher, O. (2010). Abstract P3-12-02: Polymorphisms, Endogenous Hormone Levels and Breast Cancer Risk in Premenopausal Women. Poster session abstracts, .

Balko, J.M. Sanders, M.E. Granja-Ingram, N.M. Sanchez, V. Meszoely, I.M. Salter, J. Dowsett, M. Arteaga, C.L. (2010). Abstract P6-04-05: Digital Quantification of Post-Neoadjuvant Chemotherapy Breast Tumor RNA Reveals a Basal-Derived Gene Signature Associated with Post-Treatment Ki67. Poster session abstracts, .

Dunbier, A.K. Ghazoui, Z. Anderson, H. Smith, I.E. Dowsett, M. (2010). Abstract S2-5: Molecular Profiling of Aromatase Inhibitor-Treated Post-Menopausal Breast Tumours Identifies Determinants of Response. General session abstracts, .

Ghazoui, Z. Anderson, H. Dunbier, A. Anderson, E. Lindemann, J. Wellings, B. Walker, J. Kuter, I. Dowsett, M. (2010). Abstract P1-12-02: Transcriptional Changes Induced by Anastrozole and Fulvestrant Treatment in ER-Positive Breast Cancers. Poster session abstracts, .

Rae, J.M. Drury, S. Hayes, D.F. Stearns, V. Thibert, J.N. Haynes, B.P. Salter, J. Pineda, S. Cuzick, J. Dowsett, M. (2010). Abstract S1-7: Lack of Correlation between Gene Variants in Tamoxifen Metabolizing Enymes with Primary Endpoints in the ATAC Trial. General session abstracts, .

Ring, A.E. Sestak, I. Baum, M. Howell, A. Buzdar, A. Dowsett, M. Forbes, J.F. Cuzick, J. (2010). Abstract P5-13-03: The Influences of Co-Morbidities and Age on Risk of Death without Recurrence: A Retrospective Analysis of the ATAC Trial. Poster session abstracts, .

Zabaglo, L. Stoss, O. Rueschoff, J. Zielinski, D. Salter, J. Bradbury, I. Arfi, M. Dafni, O. Procter, M. Dowsett, M. (2010). Abstract PD10-01: Impact of HER2 Staining Intensity on Prognosis and Treatment Benefit of Adjuvant Trastuzumab Given after Chemotherapy: the HERA Trial Experience. Poster discussion abstracts, .

Plaza-Menacho, I. Morandi, A. Robertson, D. Pancholi, S. Drury, S. Dowsett, M. Martin, L.-. Isacke, C.M. (2010). Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance. Oncogene, Vol.29 (33), pp. 4648-4657. show abstract

Dowsett, M. Cuzick, J. Ingle, J. Coates, A. Forbes, J. Bliss, J. Buyse, M. Baum, M. Buzdar, A. Colleoni, M. Coombes, C. Snowdon, C. Gnant, M. Jakesz, R. Kaufmann, M. Boccardo, F. Godwin, J. Davies, C. Peto, R. (2010). Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J clin oncol, Vol.28 (3), pp. 509-518. show abstract

Dowsett, M. (2010). Predictive and prognostic factors. Breast cancer res, Vol.12 Suppl 4, p. S2.

Sestak, I. Distler, W. Forbes, J.F. Dowsett, M. Howell, A. Cuzick, J. (2010). Effect of Body Mass Index on Recurrences in Tamoxifen and Anastrozole Treated Women: An Exploratory Analysis From the ATAC Trial. Journal of clinical oncology, Vol.28 (21), pp. 3411-5.

Lonning, P.E. Dowsett, M. (2010). Endocrine Effects of Aromatase Inhibitors. Journal of clinical oncology, Vol.28 (6), pp. E101-2.

Jones, R.L. Rojo, F.G. A'Hern, R. Villena, N. Corominas, J. Servitja, S. Rovira, A. Reis-Filho, J.S. Dowsett, M. Albaneli, J. (2010). Nuclear NF-kb/p65 expression and response to neoadjuvant chemotherapy in breast cancer. Journal of clinical oncology, Vol.28 (15).

Arnedos, M. Drury, S. Afentakis, M. Hills, M. Salter, J. Smith, I.E. Dowsett, M. (2010). Biomarker changes associated with the development of resistance to aromatase inhibitors (AIs) in ER-positive breast cancer. Journal of clinical oncology, Vol.28 (15).

Tang, G. Cuzick, J. Wale, C. Costantino, J.P. Crager, M. Shak, S. Wolmark, N. Dowsett, M. Forbes, J.F. (2010). Recurrence risk of node-negative and ER-positive early-stage breast cancer patients by combining recurrence score, pathologic, and clinical information: A meta-analysis approach. Journal of clinical oncology, Vol.28 (15).

Banerjee, S. Zvelebil, M. Furet, P. Mueller-Vieira, U. Evans, D.B. Dowsett, M. Martin, L.-. (2009). The vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 inhibits aromatase. Cancer res, Vol.69 (11), pp. 4716-4723. show abstract

Dowsett, M. (2009). The potential of new technologies/approaches Introduction to Sessions 3 and 4. Breast cancer research, Vol.11, p. 2.

McCormack, V.A. Dowsett, M. Folkerd, E. Johnson, N. Palles, C. Coupland, B. Holly, J.M. Vinnicombe, S.J. Perry, N.M. Silva, I.D. (2009). Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women. Breast cancer research, Vol.11 (3), p. 10.

Leary, A.F. Hanna, W.M. van de Vijver, M.J. Penault-Llorca, F. Rüschoff, J. Osamura, R.Y. Bilous, M. Dowsett, M. (2009). Value and limitations of measuring HER-2 extracellular domain in the serum of breast cancer patients. J clin oncol, Vol.27 (10), pp. 1694-1705. show abstract

Penault-Llorca, F. Bilous, M. Dowsett, M. Hanna, W. Osamura, R.Y. Rueschoff, J. van de Vijver, M. (2009). Emerging Technologies for Assessing HER2 Amplification. American journal of clinical pathology, Vol.132 (4), pp. 539-10.

Roddam, A.W. Appleby, P. Neale, R. Dowsett, M. Folkerd, E. Tipper, S. Allen, N.E. Key, T.J. (2009). Association between endogenous plasma hormone concentrations and fracture risk in men and women: the EPIC-Oxford prospective cohort study. Journal of bone and mineral metabolism, Vol.27 (4), pp. 485-9.

Drury, S. Anderson, H. Dowsett, M. (2009). Selection of Reference Genes for Normalization of qRT-PCR Data Derived From FFPE Breast Tumors. Diagnostic molecular pathology, Vol.18 (2), pp. 103-5.

Murray, J. Young, O.E. Renshaw, L. White, S. Williams, L. Evans, D.B. Thomas, J.S. Dowsett, M. Dixon, J.M. (2009). A randomised study of the effects of letrozole and anastrozole on oestrogen receptor positive breast cancers in postmenopausal women. Breast cancer research and treatment, Vol.114 (3), pp. 495-7.

Stone, J. Folkerd, E. Doody, D. Schroen, C. Treloar, S.A. Giles, G.G. Pike, M.C. English, D.R. Southey, M.C. Hopper, J.L. Dowsett, M. (2009). Familial Correlations in Postmenopausal Serum Concentrations of Sex Steroid Hormones and Other Mitogens: A Twins and Sisters Study. Journal of clinical endocrinology & metabolism, Vol.94 (12), pp. 4793-8.

Hilmi, C. Pancholi, S. Chaussade, C. Lykkesfeldt, A. Dowsett, M. Martin, L.-. (2009). PI3K associates with the ER/NCoR1 complex leading to suppression of ER genomic activity in tamoxifen resistant cells. Cancer research, Vol.69.

Sikora, M. Thibert, J. Salter, J. Dowsett, M. Johnson, M. Rae, J. (2009). High throughput SNP analysis from formalin-fixed, paraffin-embedded tumor tissues. Cancer research, Vol.69.

Jones, R.L. Salter, J. A'Hern, R. Nerurkar, A. Parton, M. Reis-Filho, J.S. Smith, I.E. Dowsett, M. (2009). The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast cancer res treat, Vol.116 (1), pp. 53-68. show abstract

Attard, G. Reid, A.H. A'Hern, R. Parker, C. Oommen, N.B. Folkerd, E. Messiou, C. Molife, L.R. Maier, G. Thompson, E. Olmos, D. Sinha, R. Lee, G. Dowsett, M. Kaye, S.B. Dearnaley, D. Kheoh, T. Molina, A. de Bono, J.S. (2009). Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J clin oncol, Vol.27 (23), pp. 3742-3748. show abstract

PURPOSE: It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis. PATIENTS AND METHODS: This was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of > or = 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; alpha = .05; beta = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued. RESULTS: A decline in PSA of > or = 50% was observed in 28 (67%) of 42 phase II patients, and declines of > or = 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of > or = 50% PSA decline and TTPP on abiraterone acetate and dexamethasone. CONCLUSION: CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven..

Arnedos, M. Nerurkar, A. Osin, P. A'Hern, R. Smith, I.E. Dowsett, M. (2009). Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC). Ann oncol, Vol.20 (12), pp. 1948-1952. show abstract

Walker, K. Fletcher, O. Johnson, N. Coupland, B. McCormack, V.A. Folkerd, E. Gibson, L. Hillier, S.G. Holly, J.M. Moss, S. Dowsett, M. Peto, J. dos Santos Silva, I. (2009). Premenopausal mammographic density in relation to cyclic variations in endogenous sex hormone levels, prolactin, and insulin-like growth factors. Cancer res, Vol.69 (16), pp. 6490-6499. show abstract

Ellis, P. Barrett-Lee, P. Johnson, L. Cameron, D. Wardley, A. O'Reilly, S. Verrill, M. Smith, I. Yarnold, J. Coleman, R. Earl, H. Canney, P. Twelves, C. Poole, C. Bloomfield, D. Hopwood, P. Johnston, S. Dowsett, M. Bartlett, J.M. Ellis, I. Peckitt, C. Hall, E. Bliss, J.M. TACT Trial Management Group, TACT Trialists, (2009). Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet, Vol.373 (9676), pp. 1681-1692. show abstract

BACKGROUND: Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. METHODS: In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. FINDINGS: All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). INTERPRETATION: This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. FUNDING: Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche..

Dowsett, M. Procter, M. McCaskill-Stevens, W. de Azambuja, E. Dafni, U. Rueschoff, J. Jordan, B. Dolci, S. Abramovitz, M. Stoss, O. Viale, G. Gelber, R.D. Piccart-Gebhart, M. Leyland-Jones, B. (2009). Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J clin oncol, Vol.27 (18), pp. 2962-2969. show abstract

Dowsett, M. A'Hern, R. Salter, J. Zabaglo, L. Smith, I.E. (2009). Who would have thought a single Ki67 measurement would predict long-term outcome?. Breast cancer res, Vol.11 Suppl 3, p. S15.

Dixon, J.M. Renshaw, L. Young, O. Murray, J. Macaskill, E.J. McHugh, M. Folkerd, E. Cameron, D.A. A'Hern, R.P. Dowsett, M. (2008). Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer. J clin oncol, Vol.26 (10), pp. 1671-1676. show abstract

Banerjee, S. Pancholi, S. A'hern, R. Ghazoui, Z. Smith, I.E. Dowsett, M. Martin, L.-. (2008). The effects of neoadjuvant anastrozole and tamoxifen on circulating vascular endothelial growth factor and soluble vascular endothelial growth factor receptor 1 in breast cancer. Clin cancer res, Vol.14 (9), pp. 2656-2663. show abstract

Attard, G. Reid, A.H. Yap, T.A. Raynaud, F. Dowsett, M. Settatree, S. Barrett, M. Parker, C. Martins, V. Folkerd, E. Clark, J. Cooper, C.S. Kaye, S.B. Dearnaley, D. Lee, G. de Bono, J.S. (2008). Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J clin oncol, Vol.26 (28), pp. 4563-4571. show abstract

Ellis, M.J. Tao, Y. Luo, J. A'Hern, R. Evans, D.B. Bhatnagar, A.S. Chaudri Ross, H.A. von Kameke, A. Miller, W.R. Smith, I. Eiermann, W. Dowsett, M. (2008). Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J natl cancer inst, Vol.100 (19), pp. 1380-1388. show abstract

Urruticoechea, A. Arnedos, M. Walsh, G. Dowsett, M. Smith, I.E. (2008). Ovarian protection with goserelin during adjuvant chemotherapy for pre-menopausal women with early breast cancer (EBC). Breast cancer research and treatment, Vol.110 (3), pp. 411-6.

Kendall, A. Anderson, H. Dunbier, A.K. Mackay, A. Dexter, T. Urruticoechea, A. Harper-Wynne, C. Dowsett, M. (2008). Impact of estrogen deprivation on gene expression profiles of normal postmenopausal breast tissue in vivo. Cancer epidemiology biomarkers & prevention, Vol.17 (4), pp. 855-9.

Sanders, M.E. Dias, E.C. Xu, B.J. Mobley, J.A. Billheimer, D. Roder, H. Grigorieva, J. Dowsett, M. Arteaga, C.L. Caprioli, R.M. (2008). Differentiating proteomic biomarkers in breast cancer by laser capture microdissection and MALDI MS. Journal of proteome research, Vol.7 (4), pp. 1500-8.

Dowsett, M. Allred, C. Knox, J. Quinn, E. Salter, J. Wale, C. Cuzick, J. Houghton, J. Williams, N. Mallon, E. Bishop, H. Ellis, I. Larsimont, D. Sasano, H. Carder, P. Cussac, A.L. Knox, F. Speirs, V. Forbes, J. Buzdar, A. (2008). Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J clin oncol, Vol.26 (7), pp. 1059-1065. show abstract

Dowsett, M. (2008). Introduction to sessions on 'Predicting personal risk for breast cancer'. Breast cancer research, Vol.10, p. 2.

Thompson, D.J. Healey, C.S. Baynes, C. Kalmyrzaev, B. Ahmed, S. Dowsett, M. Folkerd, E. Luben, R.N. Cox, D. Ballinger, D. Pharoah, P.D. Ponder, B.A. Dunning, A.M. Easton, D.F. (2008). Identification of Common Variants on the SHBG Gene Affecting Sex Hormone-Binding Globulin Levels and Breast Cancer Risk in Postmenopausal Women. Cancer epidemiology biomarkers & prevention, Vol.17 (12), pp. 3490-9.

Walker, R.A. Bartlett, J.M. Dowsett, M. Ellis, I.O. Hanby, A.M. Jasani, B. Miller, K. Pinder, S.E. (2008). HER2 testing in the UK: further update to recommendations. Journal of clinical pathology, Vol.61 (7), pp. 818-7.

Fiegl, H. Jones, A. Hauser-Kronberger, C. Hutarew, G. Reitsamer, R. Jones, R.L. Dowsett, M. Mueller-Holzner, E. Windbichler, G. Daxenbichler, G. Goebel, G. Ensinger, C. Jacobs, I. Widschwendter, M. (2008). Methylated NEUROD1 promoter is a marker for chemosensitivity in breast cancer. Clinical cancer research, Vol.14 (11), pp. 3494-9.

Chan, M.-. Dowsett, M. Folkerd, E. Wareham, N. Luben, R. Welch, A. Bingham, S. Khaw, K.-. (2008). Past oral contraceptive and hormone therapy use and endogenous hormone concentrations in postmenopausal women. Menopause-the journal of the north american menopause society, Vol.15 (2), pp. 332-8.

Arriola, E. Marchio, C. Tan, D.S. Drury, S.C. Lambros, M.B. Natrajan, R. Rodriguez-Pinilla, S.M. Mackay, A. Tamber, N. Fenwick, K. Jones, C. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2008). Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines. Lab invest, Vol.88 (5), pp. 491-503. show abstract

HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of approximately 1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets..

Urruticoechea, A. Aguilar, H. Solé, X. Capellà, G. Martin, L.-. Dowsett, M. Germà-Lluch, J.R. (2008). Pre-clinical validation of early molecular markers of sensitivity to aromatase inhibitors in a mouse model of post-menopausal hormone-sensitive breast cancer. Breast cancer res treat, Vol.109 (3), pp. 463-470. show abstract

Reis-Filho, J.S. Drury, S. Lambros, M.B. Marchio, C. Johnson, N. Natrajan, R. Salter, J. Levey, P. Fletcher, O. Peto, J. Ashworth, A. Dowsett, M. (2008). ESR1 gene amplification in breast cancer: a common phenomenon?. Nat genet, Vol.40 (7), pp. 809-810.

Thorpe, H. Brown, S.R. Sainsbury, J.R. Perren, T.J. Hiley, V. Dowsett, M. Nejim, A. Brown, J.M. (2008). Timing of breast cancer surgery in relation to menstrual cycle phase: no effect on 3-year prognosis: The ITS Study. British journal of cancer, Vol.98 (1), pp. 39-6.

Tan, D.S. Marchió, C. Jones, R.L. Savage, K. Smith, I.E. Dowsett, M. Reis-Filho, J.S. (2008). Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast cancer res treat, Vol.111 (1), pp. 27-44. show abstract

Wolff, A.C. Berry, D. Carey, L.A. Colleoni, M. Dowsett, M. Ellis, M. Garber, J.E. Mankoff, D. Paik, S. Pusztai, L. Smith, M.L. Zujewski, J. (2008). Research issues affecting preoperative systemic therapy for operable breast cancer. Journal of clinical oncology, Vol.26 (5), pp. 806-8.

Pancholi, S. Lykkesfeldt, A.E. Hilmi, C. Banerjee, S. Leary, A. Drury, S. Johnston, S. Dowsett, M. Martin, L.-. (2008). ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2. Endocr relat cancer, Vol.15 (4), pp. 985-1002. show abstract

Dowsett, M. Dunbier, A.K. (2008). Emerging Biomarkers and New Understanding of Traditional Markers in Personalized Therapy for Breast Cancer. Clinical cancer research, Vol.14 (24), pp. 8019-8.

De Bono, J.S. Attard, G. Reid, A.H. Parker, C. Dowsett, M. Mollife, R. Yap, T.A. Molina, A. Lee, G. Dearnaley, D. (2008). Anti-tumor activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, in chemotherapy naive and docetaxel pre-treated castration resistant prostate cancer (CRPC). Journal of clinical oncology, Vol.26 (15).

Dowsett, M. (2008). Optimizing the implementation of future treatment using surrogate end-points. Breast cancer res, Vol.10 Suppl 4, p. S26.

Arriola, E. Lambros, M.B. Jones, C. Dexter, T. Mackay, A. Tan, D.S. Tamber, N. Fenwick, K. Ashworth, A. Dowsett, M. Reis-Filho, J.S. (2007). Evaluation of Phi29-based whole-genome amplification for microarray-based comparative genomic hybridisation. Lab invest, Vol.87 (1), pp. 75-83. show abstract

For the optimal performance of high throughput genomic technologies sufficient yields of high-quality DNA are crucial. Following microdissection, most samples fail to produce sufficient quantities of DNA for genome-wide experiments. Various PCR-based amplification methods have been used, but these usually produce nonuniform representations of the genome. Bacteriophage Phi29 DNA polymerase random-primed DNA amplification is based on isothermal multiple displacement amplification. We sought to define the genome representation of this method in a bacterial artificial chromosome microarray comparative genomic hybridisation (aCGH) platform. Test genomic female DNA was amplified using Phi29 amplification at four different starting concentrations (0.5, 5, 10 and 50 ng). These products were combined with unamplified and amplified genomic female DNA as reference. In addition, 50 ng of DNA from five microdissected breast cancer frozen samples, were amplified using the same method. Three combinations were performed: unamplified test with unamplified reference, amplified test with unamplified reference and both amplified tumour and reference DNA. aCGH was performed with an in-house 16 K BAC platform (a resolution of approximately 100 Kb). Pearson's correlation tests and hierarchical clustering were performed to compare the profiles obtained. aCGH profiles obtained with amplified test and unamplified reference female genomic DNA showed copy number biases throughout the genome. These biases were more conspicuous with smaller amounts of starting material and mapped to regions of known copy number polymorphisms. When similar concentrations of test and reference DNA were amplified, the biases were significantly reduced, rendering accurate profiles. For the tumours, representative profiles were obtained when both test and reference DNA were amplified. Phi29 amplification induces copy number biases and unamplified material remains the gold standard for copy number analysis. For accurate results using Phi29 amplification, samples subjected to aCGH analysis should be combined with reference DNA amplified with the same method, using similar amounts of starting template..

Bartlett, J.M. Ellis, I.O. Dowsett, M. Mallon, E.A. Cameron, D.A. Johnston, S. Hall, E. A'Hern, R. Peckitt, C. Bliss, J.M. Johnson, L. Barrett-Lee, P. Ellis, P. (2007). Human epidermal growth factor receptor 2 status correlates with lymph node involvement in patients with estrogen receptor (ER) negative, but with grade in those with ER-positive early-stage breast cancer suitable for cytotoxic chemotherapy. J clin oncol, Vol.25 (28), pp. 4423-4430. show abstract

Dowsett, M. Salter, J. Hills, M. Detre, S. A'Hern, R. Smith, I.E. (2007). Short-term presurgical treatment for all?. Breast cancer research, Vol.9, p. 3.

Attard, G. Reid, A.H. Sinha, R. Molife, R. Raynaud, F. Dowsett, M. Barrett, M. Thompson, E. Yap, T.A. Settatree, S. Martins, V. Parker, C. Dearnaley, D. Folkerd, E. Lee, G. De Bono, J.S. (2007). Selective inhibition of CYP17 with abiraterone acetate is well tolerated and results in a high response rate in castration-resistant prostate cancer (CRPC). Molecular cancer therapeutics, Vol.6 (12), pp. 3455S-1.

Smith, I.E. Walsh, G. Skene, A. Llombart, A. Mayordomo, J.I. Detre, S. Salter, J. Clark, E. Magill, P. Dowsett, M. (2007). A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J clin oncol, Vol.25 (25), pp. 3816-3822. show abstract

PURPOSE: Increased epidermal growth factor receptor (EGFR) expression may promote breast cancer resistance to endocrine therapy. We have therefore investigated whether neoadjuvant gefitinib, an EGFR inhibitor, might overcome biologic and clinical resistance to neoadjuvant anastrozole in a phase II placebo-controlled trial. PATIENTS AND METHODS: Postmenopausal women with stage I to IIIB hormone receptor-positive early breast cancer received anastrozole 1 mg daily for 16 weeks and were randomly assigned at a ratio of 2:5:5 to receive, in addition, gefitinib 250 mg/d orally for 16 weeks: placebo 1 tablet/d orally for 2 weeks and then gefitinib for 14 weeks or placebo for 16 weeks. The primary end point was biologic change in proliferation as measured by Ki67 at 2 and 16 weeks; the main secondary end point was overall objective response (OR). RESULTS: Two hundred six women were randomly assigned. Mean changes in Ki67 with anastrozole and gefitinib versus anastrozole alone were -77.4% and -83.6%, respectively, between baseline and 16 weeks (geometric mean ratio = 1.37; 95% CI, 0.79 to 2.39; P = .26), -80.1% and -71.3% between baseline and 2 weeks (geometric mean ratio = 0.70; 95% CI, 0.39 to 1.25; P = .22) and -19.3% and -43% (geometric mean ratio = 1.42; 95% CI, 0.86 to 2.35; P = .16) between 2 and 16 weeks. ORs in the combination and anastrozole alone groups were 48% and 61% (estimated difference = -13.1%; 95% CI, -27.3% to 1.2%), respectively, with a nonsignificant trend against the combination (P = .08) and 48% versus 72% (estimated difference = -24.1%; 95% CI, -45.3% to -2.9%) in the progesterone-receptor-positive subgroup, which was significant (P = .03) and consistent with Ki67 changes. Common treatment-related adverse events included diarrhea, rash, alopecia, dry skin, and nausea. There was no evidence of a pharmacokinetic interaction. CONCLUSION: Addition of gefitinib to neoadjuvant anastrozole had no additional clinical or biologic effect, failing to support our original hypothesis..

Santen, R.J. Boyd, N.F. Chlebowski, R.T. Cummings, S. Cuzick, J. Dowsett, M. Easton, D. Forbes, J.F. Key, T. Hankinson, S.E. Howell, A. Ingle, J. (2007). Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model. Endocrine-related cancer, Vol.14 (2), pp. 169-19.

Tworoger, S.S. Missmer, S.A. Eliassen, A.H. Barbieri, R.L. Dowsett, M. Hankinson, S.E. (2007). Physical activity and inactivity in relation to sex hormone, prolactin, and insulin-like growth factor concentrations in premenopausal women - Exercise and premenopausal hormones. Cancer causes & control, Vol.18 (7), pp. 743-10.

Chan, M.-. Dowsett, M. Folkerd, E. Bingham, S. Wareham, N. Luben, R. Welch, A. Khaw, K.-. (2007). Usual physical activity and endogenous sex hormones in postmenopausal women: The European prospective investigation into cancer - Norfolk Population Study. Cancer epidemiology biomarkers & prevention, Vol.16 (5), pp. 900-6.

Kaptoge, S. Dalzell, N. Folkerd, E. Doody, D. Khaw, K.-. Beck, T.J. Loveridge, N. Mawer, E.B. Berry, J.L. Shearer, M.J. Dowsett, M. Reeve, J. (2007). Sex hormone status may modulate rate of expansion of proximal femur diameter in older women alongside other skeletal regulators. Journal of clinical endocrinology & metabolism, Vol.92 (1), pp. 304-10.

Dowsett, M. Miller, W.R. (2007). Introduction to sessions on Personalising treatment. Breast cancer research, Vol.9, p. 2.

Dowsett, M. (2007). Chairperson's introduction. Ejc supplements, Vol.5 (5), pp. 75-1.

Low, Y.-. Dunning, A.M. Dowsett, M. Folkerd, E. Doody, D. Taylor, J. Bhaniani, A. Luben, R. Khaw, K.-. Wareham, N.J. Bingham, S.A. (2007). Phytoestrogen Exposure Is Associated with Circulating Sex Hormone Levels in Postmenopausal Women and Interact with ESR1 and NR1I2 Gene Variants. Cancer epidemiology biomarkers & prevention, Vol.16 (5), pp. 1009-1016.

Kendall, A. Folkerd, E.J. Dowsett, M. (2007). Influences on circulating oestrogens in postmenopausal women: relationship with breast cancer. J steroid biochem mol biol, Vol.103 (2), pp. 99-109. show abstract

Arriola, E. Hui, E. Dowsett, M. Smith, I.E. (2007). Aromatase inhibitors and male breast cancer. Clin transl oncol, Vol.9 (3), pp. 192-194. show abstract

Dowsett, M. Smith, I.E. (2007). Re: Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer - Response. Jnci-journal of the national cancer institute, Vol.99 (13), pp. 1053-2.

Khaw, K.-. Dowsett, M. Folkerd, E. Bingham, S. Wareham, N. Luben, R. Welch, A. Day, N. (2007). Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation, Vol.116 (23), pp. 2694-8.

Dowsett, M. Hanna, W.M. Kockx, M. Penault-Llorca, F. Rüschoff, J. Gutjahr, T. Habben, K. van de Vijver, M.J. (2007). Standardization of HER2 testing: results of an international proficiency-testing ring study. Mod pathol, Vol.20 (5), pp. 584-591. show abstract

Human epidermal growth factor receptor 2 (HER2) positivity in breast cancer is a prognostic factor regarding tumor aggressiveness and a predictive factor for response to trastuzumab (Herceptin). Early and accurate HER2 testing of all breast cancer patients at primary diagnosis is essential for optimal disease management. Routine HER2 tests, such as immunohistochemistry and fluorescence in situ hybridization (FISH), are subject to interlaboratory variation, and validation by laboratory proficiency testing is important to improve standardization. This study compared immunohistochemistry and FISH testing between five international pathology reference centers. Each center evaluated 20 immunohistochemistry and 20 FISH breast cancer specimens in five testing rounds. In each round, one center selected two sets of four different invasive tumor specimens (set A for immunohistochemistry and set B for FISH) and sent samples to the other four centers in a blinded manner, while retaining samples for its own evaluation. Results were analyzed by an independent coordinator. With immunohistochemistry, there were no differences between the five centers for any of the specimens at the level of diagnostic decision (positive or negative HER2 status). However, differences between laboratories were observed in immunohistochemistry scoring. Of the 20 specimens, four were scored as negative (0/1+) and five as positive (3+) in all centers; eight were negative or equivocal (2+), and three positive or equivocal. After FISH retesting of nine of the 11 equivocal immunohistochemistry cases, consensus was achieved in 15 of 18 (83%) specimens. FISH analysis of set B specimens resulted in consensus between centers in 16 of 20 (80%) specimens (six negative and 10 positive). All four discordant FISH specimens were scored as having HER2:CEP17 ratios within the range 1.7-2.3 by at least one center. Equivocal immunohistochemistry and borderline FISH cases are difficult to interpret, even for highly experienced and validated laboratories, highlighting the need for quality-control procedures..

Smith, I. Procter, M. Gelber, R.D. Guillaume, S. Feyereislova, A. Dowsett, M. Goldhirsch, A. Untch, M. Mariani, G. Baselga, J. Kaufmann, M. Cameron, D. Bell, R. Bergh, J. Coleman, R. Wardley, A. Harbeck, N. Lopez, R.I. Mallmann, P. Gelmon, K. Wilcken, N. Wist, E. Sánchez Rovira, P. Piccart-Gebhart, M.J. HERA study team, (2007). 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet, Vol.369 (9555), pp. 29-36. show abstract

BACKGROUND: Trastuzumab--a humanised monoclonal antibody against HER2--has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drug's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study. METHODS: HERA is an international multicentre randomised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer. 5102 women participated in the trial; we analysed data from 1703 women who had been randomised for treatment with trastuzumab for 1 year and 1698 women from the control group, with median follow-up of 23.5 months (range 0-48 months). The primary endpoint of the trial was disease-free survival. Here, we assess overall survival, a secondary endpoint. Analyses were done on an intent-to-treat basis. This trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS: 97 (5.7%) patients randomised to observation alone and 58 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up. 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47-0.91; p=0.0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54-0.76; p<0.0001). INTERPRETATION: Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years. The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer..

Jones, M.E. Folkerd, E.J. Doody, D.A. Iqbal, J. Dowsett, M. Ashworth, A. Swerdlow, A.J. (2007). Effect of delays in processing blood samples on measured endogenous plasma sex hormone levels in women. Cancer epidemiol biomarkers prev, Vol.16 (6), pp. 1136-1139. show abstract

Dowsett, M. Hanby, A.M. Laing, R. Walker, R. National HER2 Consultation Steering Group, (2007). HER2 testing in the UK: consensus from a national consultation. J clin pathol, Vol.60 (6), pp. 685-689. show abstract

Powles, T.J. Ashley, S. Smith, I.E. Dowsett, M. (2007). "Untitled". Jnci-journal of the national cancer institute, Vol.99 (21), pp. 1645-2.

Johnston, S.R. Martin, L.-. Leary, A. Head, J. Dowsett, M. (2007). Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer. J steroid biochem mol biol, Vol.106 (1-5), pp. 180-186. show abstract

Anderson, H. Bulun, S. Smith, I. Dowsett, M. (2007). Predictors of response to aromatase inhibitors. J steroid biochem mol biol, Vol.106 (1-5), pp. 49-54. show abstract

Martin, L.-. Head, J.E. Pancholi, S. Salter, J. Quinn, E. Detre, S. Kaye, S. Howes, A. Dowsett, M. Johnston, S.R. (2007). The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol cancer ther, Vol.6 (9), pp. 2458-2467. show abstract

Banerjee, S. Dowsett, M. Ashworth, A. Martin, L.-. (2007). Mechanisms of disease: angiogenesis and the management of breast cancer. Nat clin pract oncol, Vol.4 (9), pp. 536-550. show abstract

Arriola, E. Rodriguez-Pinilla, S.M. Lambros, M.B. Jones, R.L. James, M. Savage, K. Smith, I.E. Dowsett, M. Reis-Filho, J.S. (2007). Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast cancer res treat, Vol.106 (2), pp. 181-189. show abstract

Kubista, E. Gomez, J.V. Dowsett, M. Foidart, J.-. Pohlodek, K. Serreyn, R. Nechushkin, M. Manikhas, A.G. Semiglazov, V.F. Hageluken, C.C. Singer, C.F. (2007). Effect of tibolone on breast cancer cell proliferation in postmenopausal ER+ patients: Results from STEM trial. Clinical cancer research, Vol.13 (14), pp. 4185-6.

Dowsett, M. Smith, I.E. Ebbs, S.R. Dixon, J.M. Skene, A. A'Hern, R. Salter, J. Detre, S. Hills, M. Walsh, G. IMPACT Trialists Group, (2007). Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J natl cancer inst, Vol.99 (2), pp. 167-170. show abstract

Kote-Jarai, Z. Powles, T.J. Mitchell, G. Tidy, A. Ashley, S. Easton, D. Assersohn, L. Sodha, N. Salter, J. Gusterson, B. Dowsett, M. Eeles, R. (2007). BRCA1/BRCA2 mutation status and analysis of cancer family history in participants of the Royal Marsden Hospital tamoxifen chemoprevention trial. Cancer lett, Vol.247 (2), pp. 259-265. show abstract

Powles, T.J. Ashley, S. Tidy, A. Dowsett, M. (2007). Twenty-year follow-up of the royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. Jnci-journal of the national cancer institute, Vol.99 (4), pp. 283-8.

Pierga, J.-. Reis-Filho, J.S. Cleator, S.J. Dexter, T. Mackay, A. Simpson, P. Fenwick, K. Iravani, M. Salter, J. Hills, M. Jones, C. Ashworth, A. Smith, I.E. Powles, T. Dowsett, M. (2007). Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy. Br j cancer, Vol.96 (2), pp. 341-351. show abstract

Mackay, A. Urruticoechea, A. Dixon, J.M. Dexter, T. Fenwick, K. Ashworth, A. Drury, S. Larionov, A. Young, O. White, S. Miller, W.R. Evans, D.B. Dowsett, M. (2007). Molecular response to aromatase inhibitor treatment in primary breast cancer. Breast cancer res, Vol.9 (3), p. R37. show abstract

Dowsett, M. Goldhirsch, A. Hayes, D.F. Senn, H.-. Wood, W. Viale, G. (2007). International Web-based consultation on priorities for translational breast cancer research. Breast cancer res, Vol.9 (6), p. R81. show abstract

Dowsett, M. Smith, I.E. Ebbs, S.R. Dixon, J.M. Skene, A. Griffith, C. Boeddinghaus, I. Salter, J. Detre, S. Hills, M. Ashley, S. Francis, S. Walsh, G. A'Hern, R. (2006). Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer. Clin cancer res, Vol.12 (3 Pt 2), pp. 1024s-1030s. show abstract

Smith, I.E. Dowsett, M. Yap, Y.-. Walsh, G. Lønning, P.E. Santen, R.J. Hayes, D. (2006). Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J clin oncol, Vol.24 (16), pp. 2444-2447. show abstract

Tworoger, S.S. Eliassen, A.H. Missmer, S.A. Baer, H. Rich-Edwards, J. Michels, K.B. Barbieri, R.L. Barbieri, R.L. Dowsett, M. Hankinson, S.E. (2006). Birthweight and body size throughout life in relation to sex hormones and prolactin concentrations in premenopausal women. Cancer epidemiology biomarkers & prevention, Vol.15 (12), pp. 2494-8.

Lee, J.S. Ettinger, B. Stanczyk, F.Z. Vittinghoff, E. Hanes, V. Cauley, J.A. Chandler, W. Settlage, J. Beattie, M.S. Folkerd, E. Dowsett, M. Grady, D. Cummings, S.R. (2006). Comparison of methods to measure low serum estradiol levels in postmenopausal women. Journal of clinical endocrinology & metabolism, Vol.91 (10), pp. 3791-7.

Warren, R. Skinner, J. Sala, E. Denton, E. Dowsett, M. Folkerd, E. Healey, C.S. Dunning, A. Doody, D. Ponder, B. Luben, R.N. Day, N.E. Easton, D. (2006). Associations among mammographic density, circulating sex hormones, and polymorphisms in sex hormone metabolism genes in postmenopausal women. Cancer epidemiology biomarkers & prevention, Vol.15 (8), pp. 1502-7.

Eastell, R. Hannon, R.A. Cuzick, J. Dowsett, M. Clack, G. Adams, J.E. (2006). Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). Journal of bone and mineral research, Vol.21 (8), pp. 1215-9.

Burcombe, R. D Wilson, G. Dowsett, M. Khan, I. Richman, P.I. Daley, F. Detre, S. Makris, A. (2006). Evaluation of Ki-67 proliferation and apoptotic index before, during and after neoadjuvant chemotherapy for primary breast cancer. Breast cancer research, Vol.8 (3), p. 10.

Tworoger, S.S. Missmer, S.A. Eliassen, A.H. Spiegelman, D. Folkerd, E. Dowsett, M. Barbieri, R.L. Hankinson, S.E. (2006). The association of plasma DHEA and DHEA sulfate with breast cancer risk in predominantly premenopausal women. Cancer epidemiology biomarkers & prevention, Vol.15 (5), pp. 967-5.

Schernhammer, E.S. Kroenke, C.H. Dowsett, M. Folkerd, E. Hankinson, S.E. (2006). Urinary 6-sulfatoxymelatonin levels and their correlations with lifestyle factors and steroid hormone levels. Journal of pineal research, Vol.40 (2), pp. 116-9.

Cleator, S. Tsimelzon, A. Ashworth, A. Dowsett, M. Dexter, T. Powles, T. Hilsenbeck, S. Wong, H. Osborne, C.K. O'Connell, P. Chang, J.C. (2006). Gene expression patterns for doxorubicin (Adriamycin) and cyclophosphamide (cytoxan) (AC) response and resistance. Breast cancer res treat, Vol.95 (3), pp. 229-233. show abstract

Kendall, A. Dowsett, M. Folkerd, E. Smith, I. (2006). Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann oncol, Vol.17 (4), pp. 584-587. show abstract

Eliassen, A.H. Missmer, S.A. Tworoger, S.S. Spiegelman, D. Barbieri, R.L. Dowsett, M. Hankinson, S.E. (2006). Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. Jnci-journal of the national cancer institute, Vol.98 (19), pp. 1406-10.

Dowsett, M. Houghton, J. Iden, C. Salter, J. Farndon, J. A'Hern, R. Sainsbury, R. Baum, M. (2006). Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann oncol, Vol.17 (5), pp. 818-826. show abstract

Reis-Filho, J.S. Savage, K. Lambros, M.B. James, M. Steele, D. Jones, R.L. Dowsett, M. (2006). Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Mod pathol, Vol.19 (7), pp. 999-1009. show abstract

Conflicting results on the prevalence of cyclin D1 ovexpression and its correlation with CCND1 amplification and outcome of breast cancer patients have been reported. Owing to limited sensitivity and specificity of most antibodies against cyclin D1, evaluation of cyclin D1 immunoexpression is reported to be problematic. The aims of this study were to assess the prevalence of cyclin D1 expression in breast carcinomas using the SP4 rabbit monoclonal antibody; to correlate cyclin D1 expression with amplification, assessed using chromogenic in situ hybridisation (CISH); and to analyse the relationship between CCND1 amplification and overexpression with clinicopathological parameters and outcome in a tissue microarray containing replicate tumour samples from 245 breast cancer patients. Immunohistochemistry for cyclin D1 was performed using the SP4 and the results were scored according to the Allred scoring system. CISH was carried out using the Zymed CCND1 SpotLight probe. CISH signals were counted in 60 morphologically unequivocal neoplastic cells. Amplification was defined as >5 signals per nucleus in more than 50% of cancer cells, or when large gene copy clusters were seen. Strong cyclin D1 expression and CCND1 amplification were found in 67.4 and 14.5% of the cases, respectively. A strong correlation between cyclin D1 overexpression and CCND1 amplification was demonstrated (P<0.0001). Cyclin D1 expression showed a positive correlation with hormone receptor expression (both ER and PgR, P<0.0001). An inverse correlation was observed between an immunohistochemical panel of 'basal-like' markers and both cyclin D1 overexpression (P<0.0001) and CCND1 amplification (P<0.0001). On univariate analysis cyclin D1 expression showed a correlation with longer overall survival (OS). Neither cyclin D1 nor CCND1 were independent prognostic factors for disease-free survival or OS. The results of this study confirm the association between cyclin D1 overexpression and positivity for hormone receptors and the lack of CCND1 amplification in basal-like breast carcinomas..

Kendall, A. Dowsett, M. (2006). Novel concepts for the chemoprevention of breast cancer through aromatase inhibition. Endocr relat cancer, Vol.13 (3), pp. 827-837. show abstract

Dowsett, M. Urruticoechea, A. Smith, I.E. (2006). Ki-67 correlates with in vivo bromodeoxyuridine labeling index in operable breast cancer - Reply. Journal of clinical oncology, Vol.24 (23), pp. 3809-1.

Amin, A.A. Huang, C.-. Reierstad, S. Lin, Z. Arbieva, Z. Wiley, E. Saborian, H. Haynes, B. Cotterill, H. Dowsett, M. Bulun, S.E. (2006). Paracrine-stimulated gene expression profile favors estradiol production in breast tumors. Molecular and cellular endocrinology, Vol.253 (1-2), pp. 44-12.

Folkerd, E.J. Martin, L.-. Kendall, A. Dowsett, M. (2006). The relationship between factors affecting endogenous oestradiol levels in postmenopausal women and breast cancer. J steroid biochem mol biol, Vol.102 (1-5), pp. 250-255. show abstract

Low, Y.-. Dunning, A.M. Dowsett, M. Luben, R.N. Khaw, K.-. Wareham, N.J. Bingham, S.A. (2006). Implications of gene-environment interaction in studies of gene variants in breast cancer: An example of dietary isoflavones and the D356N polymorphism in the sex hormone-binding globulin gene. Cancer research, Vol.66 (18), pp. 8980-4.

Leary, A. Dowsett, M. (2006). Combination therapy with aromatase inhibitors: the next era of breast cancer treatment?. Br j cancer, Vol.95 (6), pp. 661-666. show abstract

Beattie, M.S. Costantino, J.P. Cummings, S.R. Wickerham, D.L. Vogel, V.G. Dowsett, M. Folkerd, E.J. Willett, W.C. Wolmark, N. Hankinson, S.E. (2006). Endogenous sex hormones, breast cancer risk, and tamoxifen response: An ancillary study in the NSABP Breast Cancer Prevention Trial (P-1). Jnci-journal of the national cancer institute, Vol.98 (2), pp. 110-6.

Beattie, M.S. Costantino, J.P. Cummings, S.R. Wickerham, D.L. Vogel, V.G. Dowsett, M. Folkerd, E.J. Willett, W.C. Wolmark, N. Hankinson, S.E. (2006). Endogenous Sex Hormones, Breast Cancer Risk, and Tamoxifen Response: An Ancillary Study in the NSABP Breast Cancer Prevention Trial (P-1). Jnci: journal of the national cancer institute, Vol.98 (2), pp. 110-115.

Dowsett, M. (2006). Estrogen receptor: Methodology matters. Journal of clinical oncology, Vol.24 (36), pp. 5626-3.

Dowsett, M. Cuzick, J. Wale, C. Howell, T. Houghton, J. Baum, M. Buzdar, A. (2006). Progesterone receptor and human epidermal growth factor receptor 2 status: An independent influence on the efficacy of endocrine therapy in breast cancer? Reply. Journal of clinical oncology, Vol.24 (9), pp. 1482-1.

Dixon, J.M. Renshaw, L. Young, O. Murray, J. Macaskill, E.J. McHugh, M. Folkerd, E. Cameron, D. Dowsett, M. (2006). Letrozole suppresses plasma oestradiol (E2) levels more completely than anastrozole in postmenopausal women with breast cancer. J clin oncol, Vol.24 (18_suppl), p. 552. show abstract

Kendall, A. Smith, I. Folkerd, E. Dowsett, M. (2006). Aromatase inhibition and very low dose estradiol add-back: A pilot study for novel breast cancer prevention. J clin oncol, Vol.24 (18_suppl), p. 1014. show abstract

1014 Background: Aromatase inhibitors (AIs) are important agents for the treatment of hormone receptor positive breast cancer in post menopausal women. They are being assessed as chemopreventives of breast cancer in large clinical trials, but there are known issues of tolerability notably affecting bone. It is possible that decreasing, but not abolishing, circulating estradiol levels may reduce breast cancer risk without such side effects. We have undertaken a novel pilot study to establish whether healthy volunteers on an AI could be delivered very low dose estradiol replacement to a predictable serum level of 10-20 pmol/L using a transdermal patch, and whether this would reverse changes in the bone resorption biomarker CTx. METHODS: Ten healthy postmenopausal women with normal estradiol levels received letrozole 2.5mg/day for 16 weeks. From weeks 6-16 they were also given a quarter of Estraderm MX25 transdermal patch (6.25 μg of estradiol) replaced, twice weekly. Fasting blood samples were taken at baseline, 6, 10, 12, 14 and 16 weeks for estradiol, FSH, LH, SHBG and CTx. RESULTS: Serum estradiol levels fell to <3pmol/L at 6 weeks consistent with AI therapy. The quarter patch successfully replaced estradiol levels to a median of 12pmol/L although there was marked inter and intrasubject variability. FSH rose significantly with AI therapy with no appreciable change in SHBG or LH. There is encouraging evidence that CTx levels which increased with AI (p=0.076) can be corrected with low dose estradiol replacement although this did not reach statistical significance in this initial group. We continue to collect data on a further 8 subjects already recruited into the study. CONCLUSIONS: A quarter of Estraderm MX25 transdermal patch can be used to provide a serum estradiol level of 10-20 pmol/l in postmenopausal women given an AI. Further data will confirm whether this novel approach to chemoprevention can reverse the negative impact of AIs on bone metabolism and be suitable for extending to a full chemoprevention trial. [Table: see text] No significant financial relationships to disclose..

Dowsett, M. Smith, I. Skene, A. Llombart, A. Mayordomo, J. Detre, S. Salter, J. Beresford, E. Magill, P. Study 0223 Trialists, (2006). Biological and clinical outcomes from a phase II placebo-controlled neoadjuvant study of anastrozole alone or with gefitinib in postmenopausal women with ER/PgR+ breast cancer (Study 223). J clin oncol, Vol.24 (18_suppl), p. 515. show abstract

Cleator, S.J. Powles, T.J. Dexter, T. Fulford, L. Mackay, A. Smith, I.E. Valgeirsson, H. Ashworth, A. Dowsett, M. (2006). The effect of the stromal component of breast tumours on prediction of clinical outcome using gene expression microarray analysis. Breast cancer res, Vol.8 (3), p. R32. show abstract

Low, Y.L. Taylor, J.I. Grace, P.B. Dowsett, M. Folkerd, E. Doody, D. Dunning, A.M. Scollen, S. Mulligan, A.A. Welch, A.A. Luben, R.N. Khaw, K.T. Day, N.E. Wareham, N.J. Bingham, S.A. (2005). Polymorphisms in the CYP19 gene may affect the positive correlations between serum and urine phytoestrogen metabolites and plasma androgen concentrations in men. Journal of nutrition, Vol.135 (11), pp. 2680-7.

Low, Y.L. Taylor, J.I. Grace, P.B. Dowsett, M. Scollen, S. Dunning, A.M. Mulligan, A.A. Welch, A.A. Luben, R.N. Khaw, K.T. Day, N.E. Wareham, N.J. Bingham, S.A. (2005). Phytoestrogen exposure correlation with plasma estradiol in postmenopausal women in European Prospective Investigation of Cancer and Nutrition-Norfolk may involve diet-gene interactions. Cancer epidemiology biomarkers & prevention, Vol.14 (1), pp. 213-8.

Smith, I.E. Dowsett, M. Ebbs, S.R. Dixon, J.M. Skene, A. Blohmer, J.-. Ashley, S.E. Francis, S. Boeddinghaus, I. Walsh, G. IMPACT Trialists Group, (2005). Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J clin oncol, Vol.23 (22), pp. 5108-5116. show abstract

PURPOSE: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) trial was designed to test the hypothesis that the clinical and/or biologic effects of neoadjuvant tamoxifen compared with anastrozole and with the combination of tamoxifen and anastrozole before surgery in postmenopausal women with estrogen receptor (ER) -positive, invasive, nonmetastatic breast cancer might predict for outcome in the Arimidex, Tamoxifen Alone or in Combination (ATAC) adjuvant therapy trial. PATIENTS AND METHODS: Postmenopausal women with ER-positive, invasive, nonmetastatic, and operable or locally advanced potentially operable breast cancer were randomly assigned to neoadjuvant tamoxifen (20 mg daily), anastrozole (1 mg daily), or a combination of tamoxifen and anastrozole for 3 months. The tumor objective response (OR) was assessed by both caliper and ultrasound. Comparisons were also made of clinical response with ultrasound response, actual and feasible surgery with feasible surgery at baseline, OR in human epidermal growth factor receptor 2 (HER2)-positive cancers, and tolerability. RESULTS: There were no significant differences in OR in the intent-to-treat population between patients receiving tamoxifen, anastrozole, or the combination. In patients who were assessed as requiring mastectomy at baseline (n = 124), 44% of patients received breast-conserving surgery (BCS) after anastrozole compared with 31% of patients after tamoxifen (P = .23); this difference became significant for patients who were deemed feasible for BCS by their surgeon (46% v 22%, respectively; P = .03). The OR for patients with HER2-positive cancer (n = 34) was 58% for anastrozole compared with 22% for tamoxifen (P = .18). All treatments were well tolerated. CONCLUSION: Neoadjuvant anastrozole is as effective and well tolerated as tamoxifen in ER-positive operable breast cancer in postmenopausal women, but the hypothesis that clinical outcome might predict for long-term outcome in adjuvant therapy was not fulfilled..

Urruticoechea, A. Smith, I.E. Dowsett, M. (2005). Proliferation marker Ki-67 in early breast cancer. J clin oncol, Vol.23 (28), pp. 7212-7220. show abstract

Martin, L.A. Pancholi, S. Chan, C.M. Farmer, I. Kimberley, C. Dowsett, M. Johnston, S.R. (2005). The anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 breast cancer cells refractory to long-term oestrogen deprivation through down-regulation of oestrogen receptor and IGF signalling. Endocrine-related cancer, Vol.12 (4), pp. 1017-20.

Chen, B. Gajdos, C. Dardes, R. Kidwai, N. Johnston, S.R. Dowsett, M. Jordan, V.C. (2005). Potential of endogenous estrogen receptor beta to influence the selective ER modulator ER beta complex. International journal of oncology, Vol.27 (2), pp. 327-9.

Howell, A. Cuzick, J. Baum, M. Buzdar, A. Dowsett, M. Forbes, J.F. Hoctin-Boes, G. Houghton, I. Locker, G.Y. Tobias, J.S. (2005). Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet, Vol.365 (9453), pp. 60-3.

Dowsett, M. Hanna, W. Kockx, M. Penault-Llorca, F. Rueschoff, J. Gutjahr, T. Habben, K. van de Vijver, M. (2005). Standardisation of HER2 testing: results of an international proficiency testing ring study. Ejc supplements, Vol.3 (2), pp. 72-1.

Esserman, L.J. Ozanne, E.M. Dowsett, M. Slingerland, J.M. (2005). Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis. Breast cancer research, Vol.7 (6), pp. R1153-6.

Johnston, S.R. Martin, L.-. Head, J. Smith, I. Dowsett, M. (2005). Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance. J steroid biochem mol biol, Vol.95 (1-5), pp. 173-181. show abstract

Dowsett, M. Martin, L.-. Smith, I. Johnston, S. (2005). Mechanisms of resistance to aromatase inhibitors. J steroid biochem mol biol, Vol.95 (1-5), pp. 167-172. show abstract

Martin, L.-. Farmer, I. Johnston, S.R. Ali, S. Dowsett, M. (2005). Elevated ERK1/ERK2/estrogen receptor cross-talk enhances estrogen-mediated signaling during long-term estrogen deprivation. Endocr relat cancer, Vol.12 Suppl 1, pp. S75-S84. show abstract

The knowledge that steroids play a pivotal role in the development of breast cancer has been exploited clinically by the development of endocrine treatments. These have sought to perturb the steroid hormone environment of the tumour cells, predominately by withdrawal or antagonism of oestrogen. Unfortunately, the beneficial actions of existing endocrine treatments are attenuated by the ability of tumours to circumvent the need for steroid hormones, whilst in most cases, retaining the nuclear steroid receptors. The mechanisms involved in resistance to estrogen deprivation are of major clinical relevance for optimal treatment of breast cancer patients and the development of new therapeutic regimes. We have shown that long-term culture of MCF7 cells in medium depleted of oestrogen (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of both ERalpha phosphorylated on Ser(118) and ERK1/ERK2. Our data suggest elevated ERK1/ERK2 activity results wholly or in part from enhanced ERBB2 expression in the LTED cells. These cells showed greater sensitivity to the tyrosine kinase inhibitor ZD1839 in both ERalpha-mediated transcription and growth assays compared with the wt-MCF7. Similarly the MEK inhibitor U0126 decreased basal ERalpha-mediated transcription and proliferation in the LTED cells by 50% and reduced their sensitivity to the proliferative effects of E2 10-fold, whilst having no effect on the wild type (wt). However, complete suppression of ERK1/ERK2 activity in the LTED cells did not inhibit ERalpha Ser(118) phosphorylation suggesting that the cells remained ligand-dependent. This was further confirmed by the increased sensitivity of the LTED cells to the growth suppressive effects of ICI 182,780 and suggested that the LTED cells remained wholly or partially dependent on oestrogen receptor (ER)/oestrogen responsive elements directed growth. These findings suggest that treatments targeted at growth factor signalling pathways may be useful in patients acquiring resistance to oestrogen deprivation with aromatase inhibitors and that the pure anti-oestrogen ICI 182,780 may also be effective by blocking or destabilizing ER and hence disrupting cross-talk..

Dowsett, M. Johnston, S. Martin, L.-. Salter, J. Hills, M. Detre, S. Gutierrez, M.C. Mohsin, S.K. Shou, J. Allred, D.C. Schiff, R. Osborne, C.K. Smith, I. (2005). Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience. Endocr relat cancer, Vol.12 Suppl 1, pp. S113-S117. show abstract

Dowsett, M. Ebbs, S.R. Dixon, J.M. Skene, A. Griffith, C. Boeddinghaus, I. Salter, J. Detre, S. Hills, M. Ashley, S. Francis, S. Walsh, G. Smith, I.E. (2005). Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J clin oncol, Vol.23 (11), pp. 2477-2492. show abstract

Banerjee, S. Smith, I.E. Folkerd, L. Iqbal, J. Barker, P. Dowsett, M. IMPACT trialists, (2005). Comparative effects of anastrozole, tamoxifen alone and in combination on plasma lipids and bone-derived resorption during neoadjuvant therapy in the impact trial. Ann oncol, Vol.16 (10), pp. 1632-1638. show abstract

Gutierrez, M.C. Detre, S. Johnston, S. Mohsin, S.K. Shou, J.N. Allred, D.C. Schiff, R. Osborne, C.K. Dowsett, M. (2005). Molecular changes in tamoxifen-resistant breast cancer: Relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. Journal of clinical oncology, Vol.23 (11), pp. 2469-8.

Dowsett, M. Folkerd, E. Doody, D. Haynes, B. (2005). The biology of steroid hormones and endocrine treatment of breast cancer. Breast, Vol.14 (6), pp. 452-457. show abstract

Ring, A.E. Zabaglo, L. Ormerod, M.G. Smith, I.E. Dowsett, M. (2005). Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques. Br j cancer, Vol.92 (5), pp. 906-912. show abstract

Dowsett, M. Smith, I.E. Ebbs, S.R. Dixon, J.M. Skene, A. Griffith, C. Boeddinghaus, I. Salter, J. Detre, S. Hills, M. Ashley, S. Francis, S. Walsh, G. IMPACT Trialists, (2005). Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin cancer res, Vol.11 (2 Pt 2), pp. 951s-958s. show abstract

Dunning, A.M. Dowsett, M. Healey, C.S. Luben, R.N. Folkerd, E. Pharoah, P.D. Easton, D.F. Bruce, N.E. Ponder, A.J. (2005). Re: Polymorphisms associated with circulating sex hormone levels in postmenopausal women - Response. Jnci-journal of the national cancer institute, Vol.97 (2), pp. 153-2.

Piccart-Gebhart, M.J. Procter, M. Leyland-Jones, B. Goldhirsch, A. Untch, M. Smith, I. Gianni, L. Baselga, J. Bell, R. Jackisch, C. Cameron, D. Dowsett, M. Barrios, C.H. Steger, G. Huang, C.S. Andersson, M. Inbar, M. Lichinitser, M. Lang, I. Nitz, U. Iwata, H. Thomssen, C. Lohrisch, C. Suter, T.M. Ruschoff, J. Suto, T. Greatorex, V. Ward, C. Straehle, C. McFadden, E. Dolci, M.S. Gelber, R.D. (2005). Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. New england journal of medicine, Vol.353 (16), pp. 1659-14.

Dowsett, M. Cuzick, J. Wale, C. Howell, T. Houghton, J. Baum, M. (2005). Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: an hypothesis-generating study. J clin oncol, Vol.23 (30), pp. 7512-7517. show abstract

Johnston, S.R. Martin, L.-. Dowsett, M. (2005). Life following aromatase inhibitors--where now for endocrine sequencing?. Breast cancer res treat, Vol.93 Suppl 1, pp. S19-S25. show abstract

Dowsett, M. Folkerd, E. (2005). Deficits in plasma oestradiol measurement in studies and management of breast cancer. Breast cancer res, Vol.7 (1), pp. 1-4. show abstract

Dowsett, M. Nicholson, R.I. Pietras, R.J. (2005). Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance. Breast cancer res treat, Vol.93 Suppl 1, pp. S11-S18. show abstract

Dowsett, M. (2004). Molecular basis of endocrine therapy. Ejc supplements, Vol.2 (3), pp. 12-2.

Grace, P.B. Taylor, J.I. Low, Y.L. Luben, R.N. Mulligan, A.A. Botting, N.P. Dowsett, M. Welch, A.A. Khaw, K.T. Wareham, N.J. Day, N.E. Bingham, S.A. (2004). Phytoestrogen concentrations in serum and spot urine as biomarkers for dietary phytoestrogen intake and their relation to breast cancer risk in European prospective Investigation of Cancer and Nutrition-Norfolk. Cancer epidemiology biomarkers & prevention, Vol.13 (5), pp. 698-11.

Atkinson, C. Warren, R.M. Sala, E. Dowsett, M. Dunning, A.M. Healey, C.S. Runswick, S. Day, N.E. Bingham, S.A. (2004). Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165]. Breast cancer research, Vol.6 (3), pp. R170-10.

Ellis, I.O. Bartlett, J. Dowsett, M. Humphreys, S. Jasani, B. Miller, K. Pinder, S.E. Rhodes, A. Walker, R. (2004). Updated recommendations for HER2 testing in the UK. Journal of clinical pathology, Vol.57 (3), pp. 233-5.

Atkinson, C. Compston, J.E. Day, N.E. Dowsett, M. Bingham, S.A. (2004). The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial. American journal of clinical nutrition, Vol.79 (2), pp. 326-8.

Dixon, J.M. Jackson, J. Hills, M. Renshaw, L. Cameron, D.A. Anderson, T.J. Miller, W.R. Dowsett, M. (2004). Anastrozole demonstrates clinical and biological effectiveness in oestrogen receptor-positive breast cancers, irrespective of the erbB2 status. European journal of cancer, Vol.40 (18), pp. 2742-6.

Howell, A. Dowsett, M. (2004). Endocrinology and hormone therapy in breast cancer - Aromatase inhibitors versus antioestrogens. Breast cancer research, Vol.6 (6), pp. 269-6.

Gumbrell, L.A. Evans, T.R. Coleman, R.E. Smith, I.E. Twelves, C.J. Soukop, M. Rea, D.W. Earl, H.M. Howell, A. Jones, A. Canney, P. Powles, T.J. Haynes, B.P. Nutley, B. Grimshaw, R. Jarman, M. Halbert, G.W. Brampton, M. Haviland, J. Dowsett, M. Coombes, R.C. Johnston, S.R. (2004). A Cancer Research (UK) randomized phase II study of idoxifene in patients with locally advanced/metastatic breast cancer resistant to tamoxifen. Cancer chemotherapy and pharmacology, Vol.53 (4), pp. 341-348.

Ring, A. Smith, I.E. Dowsett, M. (2004). Circulating tumour cells in breast cancer. Lancet oncol, Vol.5 (2), pp. 79-88. show abstract

Parton, M. Dowsett, M. Ashley, S. Hills, M. Lowe, F. Smith, I.E. (2004). High incidence of HER-2 positivity in inflammatory breast cancer. Breast, Vol.13 (2), pp. 97-103. show abstract

Ring, A. Dowsett, M. (2004). Mechanisms of tamoxifen resistance. Endocr relat cancer, Vol.11 (4), pp. 643-658. show abstract

O'Donnell, A. Judson, I. Dowsett, M. Raynaud, F. Dearnaley, D. Mason, M. Harland, S. Robbins, A. Halbert, G. Nutley, B. Jarman, M. (2004). Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br j cancer, Vol.90 (12), pp. 2317-2325. show abstract

Cuzick, J. Buzdar, A. Baum, M. Bianco, R. Coleman, R. Constenla, M. Distler, W. Dowsett, M. Forbes, J. Guastalla, J.P. Houghton, J. Williams, N. Howell, A. Locker, G. MacKey, J. Sainsbury, R. Tobias, J. (2004). Adjuvant use of anastrozole in breast cancer. Journal of clinical oncology, Vol.22 (8), pp. 1524-3.

Dowsett, M. Smith, I.E. IMPACT Trialists, (2004). Molecular effects of anastrozole (A) and tamoxifen (T) alone and combined (C) in the IMPACT trial of neoadjuvant treatment of primary breast cancer. J clin oncol, Vol.22 (14_suppl), p. 537. show abstract

Smith, I.E. Dowsett, M. IMPACT Trialists, (2004). Assessment of lipids and bone-derived resorption products during neoadjuvant therapy with anastrozole (A), v tamoxifen (T), v combination (C) in the IMPACT trial. J clin oncol, Vol.22 (14_suppl), p. 675. show abstract

Dunning, A.M. Dowsett, M. Healey, C.S. Tee, L. Luben, R.N. Folkerd, E. Novik, K.L. Kelemen, L. Ogata, S. Pharoah, P.D. Easton, D.F. Day, N.E. Ponder, B.A. (2004). Polymorphisms associated with circulating sex hormone levels in postmenopausal women. Jnci-journal of the national cancer institute, Vol.96 (12), pp. 936-10.

Dowsett, M. (2004). Translational research and the changing face of breast cancer. Breast cancer res treat, Vol.87 Suppl 1, pp. S1-S2. show abstract

Dowsett, M. (2004). Biomarker investigations from the ATAC trial: the role of TA01. Breast cancer res treat, Vol.87 Suppl 1, pp. S11-S18. show abstract

Dowsett, M. (2004). Designing the future shape of breast cancer diagnosis, prognosis and treatment. Breast cancer res treat, Vol.87 Suppl 1, pp. S27-S29. show abstract

Johnston, S.R. Hickish, T. Ellis, P. Houston, S. Kelland, L. Dowsett, M. Salter, J. Michiels, B. Perez-Ruixo, J.J. Palmer, P. Howes, A. (2003). Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. Journal of clinical oncology, Vol.21 (13), pp. 2492-8.

Johnston, S.R. Head, J. Pancholi, S. Detre, S. Martin, L.-. Smith, I.E. Dowsett, M. (2003). Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. Clin cancer res, Vol.9 (1 Pt 2), pp. 524S-532S. show abstract

Types of Publications

Journal Articles

Background

Patients and methods

Results

Conclusion