Perez, E.A., Ballman, K.V., Mashadi-Hossein, A., Tenner, K.S., Kachergus, J.M., Norton, N., Necela, B.M., Carr, J.M., Ferree, S., Perou, C.M., et al.
(2017). Intrinsic Subtype and Therapeutic Response Among HER2-Positive Breast Tumors from the NCCTG (Alliance) N9831 Trial. J natl cancer inst,
Vol.109
(2),
pp. 1-8.
show abstract
Background: Genomic data from human epidermal growth factor receptor 2-positive (HER2+) tumors were analyzed to assess the association between intrinsic subtype and clinical outcome in a large, well-annotated patient cohort. Methods: Samples from the NCCTG (Alliance) N9831 trial were analyzed using the Prosigna algorithm on the NanoString platform to define intrinsic subtype, risk of recurrence scores, and risk categories for 1392 HER2+ tumors. Subtypes were evaluated for recurrence-free survival (RFS) using Kaplan-Meier and Cox model analysis following adjuvant chemotherapy (n = 484) or chemotherapy plus trastuzumab (n = 908). All statistical tests were two-sided. Results: Patients with HER2+ tumors from N9831 were primarily scored as HER2-enriched (72.1%). These individuals received statistically significant benefit from trastuzumab (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.52 to 0.89, P = .005), as did the patients (291 of 1392) with luminal-type tumors (HR = 0.52, 95% CI = 0.32 to 0.85, P = .01). Patients with basal-like tumors (97 of 1392) did not have statistically significantly better RFS when treated with trastuzumab and chemotherapy compared with chemotherapy alone (HR = 1.06, 95% CI = 0.53 to 2.13, P = .87). Conclusions: The majority of clinically defined HER2-positive tumors were classified as HER2-enriched or luminal using the Prosigna algorithm. Intrinsic subtype alone cannot replace conventional histopathological evaluation of HER2 status because many tumors that are classified as luminal A or luminal B will benefit from adjuvant trastuzumab if that subtype is accompanied by HER2 overexpression. However, among tumors that overexpress HER2, we speculate that assessment of intrinsic subtype may influence treatment, particularly with respect to evaluating alternative therapeutic approaches for that subset of HER2-positive tumors of the basal-like subtype..
Prat, A., Cheang, M.C., Galván, P., Nuciforo, P., Paré, L., Adamo, B., Muñoz, M., Viladot, M., Press, M.F., Gagnon, R., et al.
(2016). Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib. Jama oncol,
Vol.2
(10),
pp. 1287-1294.
show abstract
Importance: The value of the intrinsic subtypes of breast cancer (luminal A, luminal B, human epidermal growth factor receptor 2 [currently known as ERBB2, but referred to as HER2 in this study]-enriched, and basal-like) in the metastatic setting is currently unknown. Objective: To evaluate the association of the intrinsic subtypes of breast cancer with outcome and/or benefit in hormone receptor (HR)-positive metastatic breast cancer. Design, Setting, and Participants: Unplanned retrospective analysis of 821 tumor samples (85.7% primary and 14.3% metastatic) from the EGF30008 phase 3 clinical trial (NCT00073528), in which postmenopausal women with HR-positive invasive breast cancer and no prior therapy for advanced or metastatic disease were randomized to letrozole with or without lapatinib, an epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor. Tumor samples were classified into each subtype using the research-based PAM50 classifier. Prior neoadjuvant/adjuvant antiestrogen therapy was allowed. Patients with extensive symptomatic visceral disease were excluded. Treatment effects were evaluated using interaction tests. Main Outcomes and Measures: Primary and secondary end points were progression-free survival and overall survival. Results: The median (range) age was 62 (31-94) years. Intrinsic subtype was the strongest prognostic factor independently associated with progression-free survival and overall survival in all patients, and in patients with HER2-negative (n = 644) or HER2-positive (n = 157) diseases. Median progression-free survival differed across the intrinsic subtypes of clinically HER2-negative disease: luminal A (16.9 [95% CI, 14.1-19.9] months), luminal B (11.0 [95% CI, 9.6-13.6] months), HER2-enriched (4.7 [95% CI, 2.7-10.8] months), and basal-like (4.1 [95% CI, 2.5-13.8] months). Median OS also differed across the intrinsic subtypes: luminal A (45 [95% CI, 41-not applicable {NA}] months), luminal B (37 [95% CI, 31-42] months), HER2-enriched (16 [95% CI, 10-NA] months), and basal-like (23 [95% CI, 12-NA] months). Patients with HER2-negative/HER2-enriched disease benefited from lapatinib therapy (median PFS, 6.49 vs 2.60 months; progression-free survival hazard ratio, 0.238 [95% CI, 0.066-0.863]; interaction P = .02). Conclusions and Relevance: This is the first study to reveal an association between intrinsic subtype and outcome in first-line HR-positive metastatic breast cancer. Patients with HR-positive/HER2-negative disease with a HER2-enriched profile may benefit from lapatinib in combination with endocrine therapy. The clinical value of intrinsic subtyping in hormone receptor-positive metastatic breast cancer warrants further investigation, but patients with luminal A/HER2-negative metastatic breast cancer might be good candidates for letrozole monotherapy in the first-line setting regardless of visceral disease and number of metastases..
Sun, Z., Prat, A., Cheang, M.C., Gelber, R.D. & Perou, C.M.
(2015). Chemotherapy benefit for 'ER-positive' breast cancer and contamination of nonluminal subtypes—waiting for TAILORx and RxPONDER. Ann oncol,
Vol.26
(1),
pp. 70-74.
show abstract
BACKGROUND: Retrospective analyses of NSABP B20 and SWOG 8814 showed a large benefit of chemotherapy in patients with ER-positive tumors and high OncotypeDX Recurrence Score (RS≥31). However, it might be possible that both studies may be contaminated by non-luminal tumors, especially in high-risk RS group. METHODS: We conducted simulations in order to obtain a better understanding of how the NSABP B20 and SWOG 8814 results would have been if non-luminal breast cancer would have been excluded. Simulations were done separately for the node-negative and node-positive cohorts. RESULTS AND CONCLUSION: The results of the simulations suggest that the non-luminal tumors are augmenting the apparent benefit of chemotherapy, but do not appear to be responsible for the entire effect. These simulations could provide information about the potential influence of contamination by unexpected tumor subtypes on the future results of TAILORx and RxPONDER clinical trials..
Cheang, M.C., Martin, M., Nielsen, T.O., Prat, A., Voduc, D., Rodriguez-Lescure, A., Ruiz, A., Chia, S., Shepherd, L., Ruiz-Borrego, M., et al.
(2015). Defining Breast Cancer Intrinsic Subtypes by Quantitative Receptor Expression. The oncologist,
Vol.20
(5),
pp. 474-482.
Voduc, K.D., Nielsen, T.O., Perou, C.M., Harrell, J.C., Cheng, F., Kennecke, H., Minn, A., Cryns, V.L. & Cheang, M.C.
(2015). αB-crystallin expression in breast cancer is associated with brain metastasis. Npj breast cancer,
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(2015). Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Science translational medicine,
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pp. 302ra133-302ra133.
Prat, A., Cheang, M.C., Martin, M., Parker, J.S., Carrasco, E., Caballero, R., Tyldesley, S., Gelmon, K., Bernard, P.S., Nielsen, T.O., et al.
(2013). Prognostic Significance of Progesterone Receptor-Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer. Journal of clinical oncology,
Vol.31
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Cheang, M.C., Voduc, K.D., Tu, D., Jiang, S., Leung, S., Chia, S.K., Shepherd, L.E., Levine, M.N., Pritchard, K.I., Davies, S., et al.
(2012). Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC CTG MA 5 Randomized Trial. Clinical cancer research,
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Cheang, M.C., Chia, S.K., Voduc, D., Gao, D., Leung, S., Snider, J., Watson, M., Davies, S., Bernard, P.S., Parker, J.S., et al.
(2009). Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer. Jnci-journal of the national cancer institute,
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Cheang, M.C., Voduc, D., Bajdik, C., Leung, S., McKinney, S., Chia, S.K., Perou, C.M. & Nielsen, T.O.
(2008). Basal-like breast cancer defined by five biomarkers has superior prognostic value then triple-negative phenotype. Clinical cancer research,
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Parker, J., Mullins, M., Cheang, M.C., Davies, S., Mardis, E., Nielsen, T.O., Ellis, M.J., Marron, S., Perou, C.M. & Bernard, P.S., et al.
(2008). A supervised risk predictor of breast cancer based on biological subtypes. Journal of clinical oncology,
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Cheang, M.C., van de Rijn, M. & Nielsen, T.O.
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Tutt, A., Tovey, H., Cheang, M., Kernaghan, S., Kilburn, L., Gazinska, P., Owen, J., Abraham, J., Barrett, S., Barrett-Lee, P., et al.
A randomised phase III trial of carboplatin compared with docetaxel in BRCA1/2 mutated and 2 pre-specified triple negative breast cancer “BRCAness” subgroups: the TNT Trial 3 4. Nature medicine,
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