Breast cancer is uncommon in men and knowledge about its causation limited. Obesity is a risk factor but there has been no investigation of whether weight change is an independent risk factor, as it is in women. In a national case-control study, 1998 men with breast cancer incident in England and Wales during 2005 to 2017 and 1597 male controls were interviewed about risk factors for breast cancer including anthropometric factors at several ages. Relative risks of breast cancer in relation to changes in body mass index (BMI) and waist/height ratios at these ages were obtained by logistic regression modelling. There were significant trends of increasing breast cancer risk with increase in BMI from age 20 to 40 (odds ratio [OR] 1.11 [95% confidence interval (CI) 1.05-1.17] per 2 kg/m2 increase in BMI; P < .001), and from age 40 to 60 (OR 1.12 [1.04-1.20]; P = .003), and with increase in self-reported adiposity compared to peers at age 11 to BMI compared with peers at age 20 (OR 1.19 [1.09-1.30]; P < .001). Increase in waist/height ratio from age 20 to 5 years before diagnosis was also highly significantly associated with risk (OR 1.13 [1.08-1.19]; P < .001). The associations with increases in BMI and waist/height ratio were significant independently of each other and of BMI or waist/height ratio at the start of the period of change analysed, and effects were similar for invasive and in situ tumours separately. Increases in BMI and abdominal obesity are each risk factors for breast cancer in men, independently of obesity per se. These associations might relate to increasing oestrogen levels with weight gain, but this needs investigation..

PURPOSE: Breast cancer is uncommon in men and its aetiology is largely unknown, reflecting the limited size of studies thus far conducted. In general, number of children fathered has been found a risk factor inconsistently, and infertility not. We therefore investigated in a case-control study, the relation of risk of breast cancer in men to infertility and number of children. PATIENTS AND METHODS: We conducted a national case-control study in England and Wales, interviewing 1998 cases incident 2005-17 and 1597 male controls, which included questions on infertility and offspring. RESULTS: Risk of breast cancer was statistically significantly associated with male-origin infertility (OR = 2.03 (95% confidence interval (CI) 1.18-3.49)) but not if a couple's infertility had been diagnosed as of origin from the female partner (OR = 0.86 (0.51-1.45)). Risk was statistically significantly raised for men who had not fathered any children (OR = 1.50 (95% CI 1.21-1.86)) compared with men who were fathers. These associations were statistically significantly present for invasive tumours but not statistically significant for in situ tumours. CONCLUSION: Our data give strong evidence that risk of breast cancer is increased for men who are infertile. The reason is not clear and needs investigation..

BACKGROUND: Breast cancer is rare in men, and information on its causes is very limited from studies that have generally been small. Adult obesity has been shown as a risk factor, but more detailed anthropometric relations have not been investigated. METHODS: We conducted an interview population-based case-control study of breast cancer in men in England and Wales including 1998 cases incident during 2005-2017 at ages younger than 80 years and 1597 male controls, with questions asked about a range of anthropometric variables at several ages. All tests of statistical significance were 2-sided. RESULTS: Risk of breast cancer statistically significantly increased with increasing body mass index (BMI) at ages 20 (odds ratio [OR] = 1.07, 95% confidence interval [CI] = 1.02 to 1.12 per 2-unit change in BMI), 40 (OR = 1.11, 95% CI = 1.07 to 1.16), and 60 (OR = 1.14, 95% CI = 1.09 to 1.19) years, but there was also an indication of raised risk for the lowest BMIs. Large waist circumference 5 years before interview was more strongly associated than was BMI with risk, and each showed independent associations. Associations were similar for invasive and in situ tumors separately and stronger for HER2-positive than HER2-negative tumors. Of the tumors, 99% were estrogen receptor positive. CONCLUSIONS: Obesity at all adult ages, particularly recent abdominal obesity, is associated with raised risk of breast cancer in men, probably because of the conversion of testosterone to estrogen by aromatase in adipose tissue. The association is particularly strong for HER2-expressing tumors..

BACKGROUND: It is plausible that night shift work could affect breast cancer risk, possibly by melatonin suppression or circadian clock disruption, but epidemiological evidence is inconclusive. METHODS: Using serial questionnaires from the Generations Study cohort, we estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for breast cancer in relation to being a night shift worker within the last 10 years, adjusted for potential confounders. RESULTS: Among 102,869 women recruited in 2003-2014, median follow-up 9.5 years, 2059 developed invasive breast cancer. The HR in relation to night shift work was 1.00 (95%CI: 0.86-1.15). There was a significant trend with average hours of night work per week (P = 0.035), but no significantly raised risks for hours worked per night, nights worked per week, average hours worked per week, cumulative years of employment, cumulative hours, time since cessation, type of occupation, age starting night shift work, or age starting in relation to first pregnancy. CONCLUSIONS: The lack of overall association, and no association with all but one measure of dose, duration, and intensity in our data, does not support an increased risk of breast cancer from night shift work in women..

BACKGROUND: Parity and age at first pregnancy are well-established risk factors for breast cancer, but the effects of other characteristics of pregnancies are uncertain and the literature is inconsistent. METHODS: In a cohort of 83,451 parous women from the general population of the UK, which collected detailed information on each pregnancy and a wide range of potential confounders, we investigated the associations of length of gestation and birthweight of offspring in a woman's pregnancies with her breast cancer risk, adjusting for a full range of non-reproductive as well as reproductive risk factors unlike in previous large studies. RESULTS: Gestation of the first-born offspring was significantly inversely related to the risk of pre-menopausal breast cancer (p trend = 0.03; hazard ratio (HR) for 26-31 compared with 40-41 weeks, the baseline group, = 2.38, 95% confidence interval (CI) 1.26-4.49), and was borderline significantly related to risk of breast cancer overall (p trend = 0.05). Risk was significantly raised in mothers of high birthweight first-born (HR for breast cancer overall = 1.53, 95% CI 1.06-2.21 for ≥ 4500 g compared with 3000-3499 g, the baseline group). For gestation and birthweight of most recent birth, there were no clear effects. Analyses without adjustment for confounders (other than age) gave similar results. CONCLUSIONS: Our data add to evidence that short gestation pregnancies may increase the risk of breast cancer, at least pre-menopausally, perhaps by hormonal stimulation and breast proliferation early in pregnancy without the opportunity for the differentiation that occurs in late pregnancy. High birthweight first pregnancies may increase breast cancer risk, possibly through the association of birthweight with oestrogen and insulin-like growth factor 1 levels..

BACKGROUND: Plausible biological reasons exist regarding why smoking could affect breast cancer risk, but epidemiological evidence is inconsistent. METHODS: We used serial questionnaire information from the Generations Study cohort (United Kingdom) to estimate HRs for breast cancer in relation to smoking adjusted for potentially confounding factors, including alcohol intake. RESULTS: Among 102,927 women recruited 2003-2013, with an average of 7.7 years of follow-up, 1815 developed invasive breast cancer. The HR (reference group was never smokers) was 1.14 (95% CI 1.03-1.25; P = 0.010) for ever smokers, 1.24 (95% CI 1.08-1.43; P = 0.002) for starting smoking at ages < 17 years, and 1.23 (1.07-1.41; P = 0.004) for starting smoking 1-4 years after menarche. Breast cancer risk was not statistically associated with interval from initiation of smoking to first birth (P-trend = 0.97). Women with a family history of breast cancer (ever smoker vs never smoker HR 1.35; 95% CI 1.12-1.62; P = 0.002) had a significantly larger HR in relation to ever smokers (P for interaction = 0.039) than women without (ever smoker vs never smoker HR 1.07; 95% CI 0.96-1.20; P = 0.22). The interaction was prominent for age at starting smoking (P = 0.003) and starting smoking relative to age at menarche (P = 0.0001). CONCLUSIONS: Smoking was associated with a modest but significantly increased risk of breast cancer, particularly among women who started smoking at adolescent or peri-menarcheal ages. The relative risk of breast cancer associated with smoking was greater for women with a family history of the disease..

BACKGROUND: Menopausal hormone therapy (MHT) increases breast cancer risk; however, most cohort studies omit MHT use after enrolment and many infer menopausal age. METHODS: We used information from serial questionnaires from the UK Generations Study cohort to estimate hazard ratios (HRs) for breast cancer among post-menopausal women with known menopausal age, and examined biases induced when not updating data on MHT use and including women with inferred menopausal age. RESULTS: Among women recruited in 2003-2009, at 6 years of follow-up, 58 148 had reached menopause and 96% had completed a follow-up questionnaire. Among 39 183 women with known menopausal age, 775 developed breast cancer, and the HR in relation to current oestrogen plus progestogen MHT use (based on 52 current oestrogen plus progestogen MHT users in breast cancer cases) relative to those with no previous MHT use was 2.74 (95% confidence interval (CI): 2.05-3.65) for a median duration of 5.4 years of current use, reaching 3.27 (95% CI: 1.53-6.99) at 15+ years of use. The excess HR was underestimated by 53% if oestrogen plus progestogen MHT use was not updated after recruitment, 13% if women with uncertain menopausal age were included, and 59% if both applied. The HR for oestrogen-only MHT was not increased (HR=1.00; 95% CI: 0.66-1.54). CONCLUSIONS: Lack of updating MHT status through follow-up and inclusion of women with inferred menopausal age is likely to result in substantial underestimation of the excess relative risks for oestrogen plus progestogen MHT use in studies with long follow-up, limited updating of exposures, and changing or short durations of use..

Prospective cohort studies examining sex hormones in relation to cancer risk have generally collected blood samples at 1 time point, with an assumption that hormone levels measured in these samples will be reliable markers of true levels at other times. In postmenopausal women, body fat is a major source of estradiol; therefore, changes in adiposity may affect the correlation of single measurements to more relevant long-term averages. To estimate the intraclass correlation coefficient (ICC) for estradiol and testosterone, we collected repeat blood samples from 119 postmenopausal women (average age = 59.4 (standard deviation, 4.7) years) from the United Kingdom during 2004-2005 and again during 2010-2011. The ICCs (adjusted for assay variation) were 0.73 (95% confidence interval: 0.63, 0.82) for total estradiol and 0.59 (95% confidence interval: 0.47, 0.72) for total testosterone. The ICCs were 3%-5% larger after adjustment for change in body mass index (weight (kg)/height (m)(2)) or leptin, which are 2 markers of change in adiposity. There was no increase in ICCs after adjustment for change in age, alcohol consumption, smoking, exercise, time between waking and blood collection, or season. The results suggest that other factors account for within-woman variation in these sex hormones..

CONTEXT: Endogenous sex hormones are risk factors for postmenopausal breast cancer. A potential route for favorable hormonal modification is weight loss. OBJECTIVE: The objective of the study was to measure change in plasma estradiol and testosterone levels in postmenopausal women in relation to change in body mass index (BMI) and plasma leptin. SETTING: The setting was a cohort study of over 100,000 female volunteers from the general population, United Kingdom. PARTICIPANTS: The participants were a sample of 177 postmenopausal women aged over 45 years who provided blood samples during 2004-2005 and again during 2010-2011. MAIN OUTCOME MEASURE: Outcomes were percentage change in plasma estradiol and testosterone levels per 1 kg/m² change in BMI and per 1 ng/mL change in plasma leptin. RESULTS: Among women with reduction in BMI, estradiol decreased 12.7% (95% confidence interval: [6.4%, 19.5%]; P < .0001) per kg/m² and among women with increased BMI estradiol increased 6.4% [0.2%, 12.9%] (P = .042). The corresponding figures for testosterone were 10.7% [3.0%, 19.0%] (P = .006) and 1.9% [-5.4%, 9.7%] (P = .61) per kg/m². For women with decreases and increases in leptin, estradiol decreased by 3.6% [1.3%, 6.0%] (P = .003) per ng/mL and increased by 1.7% [-0.3%, 3.6%] (P = .094), respectively. The corresponding figures for testosterone were 4.8% [2.0%, 7.8%] (P = .009) and 0.3% [-2.0%, 2.6%] (P = .82) per ng/mL. CONCLUSIONS: In postmenopausal women, changes in BMI and plasma leptin occurring over several years are associated with changes in estradiol and testosterone levels. The results suggest that fat loss by an individual can result in substantial decreases in postmenopausal estradiol and testosterone levels and provides support for weight management to lessen breast cancer risk..

BACKGROUND: The rationale, design, recruitment and follow-up methods are described for the Breakthrough Generations Study, a UK cohort study started in 2003, targeted at investigation of breast cancer aetiology. METHODS: Cohort members have been recruited by a participant referral method intended to assemble economically a large general population cohort from whom detailed questionnaire information and blood samples can be obtained repeatedly over decades, with high completeness of follow-up and inclusion of large numbers of related individuals. 'First-generation' recruits were women contacted directly, or who volunteered directly, to join the study. They nominated female friends and family, whom we contacted, and those who joined ('second generation') nominated others, reiterated for up to 28 generations. RESULTS: The method has successfully been used during 2003-2011 to recruit 112,049 motivated participants with a broad geographic and socioeconomic distribution, aged 16-102 years, who have completed detailed questionnaires; 92% of the participants gave blood samples at recruitment. When eligible, 2½ years after recruitment, >98% completed the first follow-up questionnaire. Thirty percent are first-degree relatives of other study members. CONCLUSION: The 'generational' recruitment method has enabled recruitment of a large cohort who appear to have the commitment to enable long-term continuing data and sample collection, to investigate the effects of changing endogenous and exogenous factors on cancer risk..

Time spent in transit may affect the concentration of various constituents of collected blood samples and, consequently, results of sex hormone assays. Whole blood was collected from 46 women, and one third was processed immediately, one third was stored at ambient conditions (22 degrees C) for 1 day, and one third was stored for 2 days. Estradiol concentration increased by 7.1% [95% confidence interval (95% CI), 3.2-11.3%] after a delay in processing of 1 day and by 5.6% (95% CI, 0.2-11.4%) after a delay in processing of 2 days; the change was most apparent at lower than median concentrations. Progesterone concentrations showed no substantial change. Testosterone concentrations changed by 23.9% (95% CI, 17.8-30.3%) after a delay of 1 day but little thereafter. The sex hormone-binding globulin concentration decreased by 6.6% (95% CI, 4.6-8.6%) and 10.9% (95% CI, 8.1-13.6%), follicle-stimulating hormone increased by 7.4% (95% CI, 4.2-10.7%) and 13.9% (95% CI, 8.7-19.3%), and luteinizing hormone increased by 4.9% (95% CI, 1.3-8.5%) and 6.7% (95% CI, 2.2-11.5%) after a delay in processing of 1 and 2 days. Increases in calculated values for biologically available levels of estradiol and testosterone were greater than the increases seen in measured total hormone concentrations. Similar changes are likely when samples are delayed in transit, and evidence of etiology may be obscured unless study designs or analyses take into account processing delays..

As tamoxifen stimulates ovarian steroidogenesis in premenopausal women, induces ovulation and increases the incidence of benign ovarian cysts, there has been concern that it might also increase ovarian cancer risk in women treated premenopausally. In a national case-control study in Britain, treatment histories were collected for 158 cases of ovarian cancer after breast cancer diagnosed at ages under 55 years and 464 controls who had breast cancer at these ages without subsequent ovarian cancer. Risk of ovarian cancer was not raised for women overall who had taken tamoxifen (odds ratio (OR)=0.9, 95% confidence interval (CI) 0.6-1.3) or for those treated when premenopausal (OR=1.0, 95% CI 0.6-1.6) or perimenopausal (OR=0.7, 95% CI 0.2-2.4). There was also no relation of risk to daily dose, duration or cumulative dose of tamoxifen, or time since last use. There was, however, a significantly raised risk in relation to non-hormonal chemotherapy. The results suggest that tamoxifen treatment of premenopausal or perimenopausal women does not materially affect ovarian cancer risk, but that non-hormonal chemotherapy might increase risk..

BACKGROUND: Tamoxifen treatment of breast cancer is associated with an increased risk of endometrial cancer, but tamoxifen-related risks of endometrial cancer are unclear in premenopausal women, in long-term users of tamoxifen, and in women for whom several years have passed since ending treatment. We conducted a case-control study in Britain to investigate these risks. METHODS: We compared treatment information on 813 case patients who had endometrial cancer after their diagnosis for breast cancer and 1067 control patients who had breast cancer but not subsequent endometrial cancer. We assessed risk by conditional logistic regression analysis. All statistical tests were two-sided. RESULTS: Overall, tamoxifen treatment, compared with no treatment, was associated with an increased risk of endometrial cancer (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.8 to 3.0). Risk increased statistically significantly (P(trend)<.001) with duration of treatment (for > or =5 years of treatment compared with no treatment, OR = 3.6, 95% CI = 2.6 to 4.8). As an indication of background levels of treatment, 16% of control patients received 5 years or more of treatment. Risk of endometrial cancer adjusted for treatment duration did not diminish in follow-up to at least 5 years after the last treatment ended. Risk of endometrial cancer was not associated with the daily dose of tamoxifen and was comparable in pre- and postmenopausal women. Ever treatment with tamoxifen was associated with a much greater risk of Mullerian and mesodermal mixed endometrial tumors (OR = 13.5, 95% CI = 4.1 to 44.5) than of adenocarcinoma (OR = 2.1, 95% CI = 1.6 to 2.7) or clear cell and papillary serous tumors (OR = 3.1, 95% CI = 0.8 to 17.9). CONCLUSIONS: There is an increasing risk of endometrial cancer associated with longer tamoxifen treatment, extending well beyond 5 years. The increased risk of endometrial cancer associated with tamoxifen treatment should be considered clinically for both premenopausal and postmenopausal women during treatment and for at least 5 years after the last treatment..

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OBJECTIVE: To establish how consultation rates in children for episodes of illness, preventive activities, and home visits vary by social class. DESIGN: Analysis of prospectively collected data from the fourth national survey of morbidity in general practice, carried out between September 1991 and August 1992. SETTING: 60 general practices in England and Wales. SUBJECTS: 106 102 children aged 0 to 15 years registered with the participating practices. MAIN OUTCOME MEASURES: Mean overall consultation rates for any reason, illness by severity of underlying disease, preventive episodes, home visits, and specific diagnostic category (infections, asthma, and injuries). RESULTS: Overall consultation rates increased from registrar general's social classes I-II to classes IV-V in a linear pattern (for IV-V v I-II rate ratio 1.18; 95% confidence interval 1.14 to 1. 22). Children from social classes IV-V consulted more frequently than children from classes I-II for illnesses (rate ratio 1.23; 1.15 to 1.30), including infections, asthma, and injuries and poisonings. They also had significantly higher consultation rates for minor, moderate, and serious illnesses and higher home visiting rates (rate ratio 2.00; 1.81 to 2.18). Consultations for preventive activities were lower in children from social classes IV-V than in children from social classes I-II (rate ratio 0.95; 0.86 to 1.05). CONCLUSIONS: Childhood consultation rates for episodes of illness increase from social classes I-II through to classes IV-V. The findings on severity of underlying illness suggest the health of children from lower social classes is worse than that of children from higher social classes. These results reinforce the need to identify and target children for preventive health care in their socioeconomic context..

Cohort studies often compare the observed number of cases arising in a group under investigation with the number expected to occur on the basis of general population rates. The general population is taken to represent unexposed persons, but it is almost inevitably biased in that it comprises all types of people including exposed ones. To identify circumstances when this bias matters, the authors modeled its effect in relation to the size of the observed standardized mortality ratio (SMR) and the prevalence of exposed individuals in the general population. The authors found that bias may be a major problem, causing substantial underestimation of the true relative risk, when either the prevalence of exposure in the general population or the SMR are large. The bias can cause an apparent trend in SMRs with age when none exists. It also places a limit on the maximum size of the observed SMR, no matter how large the true relative risk. A table is provided showing the extent of bias in different circumstances. Cohort studies of people with common diseases or exposures, or that find large SMRs, when using general population expectations, need to consider the extent of bias from this source..

Quantifying individual exposure to ultraviolet radiation (UVR) is critical to understanding the etiology of a number of diseases including nonmelanotic and melanotic skin cancers. Measurements of personal exposure to solar UVR were made in Hobart, Tasmania in February (summer) 1991 for six different outdoor activities using UVR-sensitive polysulfone (PS) film attached at seven anatomical sites. Concurrent behavioral and environmental observations were also made. To date many studies have relied on subject recall to quantify past solar UVR exposures. To gain insight into the accuracy of subject recall the measured UVR exposures received by different subjects using the PS film were compared to those calculated from personal diaries and ambient solar UVB levels from a monitoring station. In general, when UVR exposure activities took place under close supervision, good correlations were obtained between the PS badges and the ambient measurements/diaries approach. Ultraviolet radiation exposures for the field study involving 94 subjects engaged in a number of outdoor activities are presented..

As part of an epidemiological survey of myelodysplastic syndromes (MDS) in southern Tasmania, 62 MDS patients identified over a 2 year period were tested for the presence of CD34, the human progenitor cell antigen (HPCA), in their peripheral blood. The results were correlated with transformation to acute myeloid leukemia (AML) and patient survival, and CD34+ status was compared as a prognostic indicator with Bournemouth score, cytogenetics, and CFU-GM colony growth which were also assessed. Circulating CD34+ cells were found in 23 of the 62 MDS patients; 9 of the 23 patients with circulating CD34+ cells transformed to AML, as compared with none of the 39 CD34 negative patients (P less than 0.0001); and 11 of the 23 patients with circulating CD34+ cells were dead at the end of the 2 year period, as opposed to 6 of the 39 with no CD34+ cells (P less than 0.03). The Bournemouth score was also significantly associated with transformation to AML (P less than 0.0001) and poor survival (P less than 0.04). These were the only significant associations of the possible prognostic factors studied with either transformation or survival. In summary, the presence of circulating CD34+ cells was significantly associated with both progression to AML and poor survival and was found to be a better prognostic indicator than cytogenetics or CFU-GM colony growth..

OBJECTIVE: To investigate the patterns of cutaneous malignant melanoma (CMM) mortality in Australia. DESIGN: A descriptive analysis of melanoma incidence and mortality in Australia supplemented by a case series analysis of melanoma survival. Melanoma mortality rates were based on tabulations supplied by the Australian Bureau of Statistics for the years 1969-1989. Melanoma incidence rates were based on State cancer registry records for the years 1977-1990. The case series survival analysis was based on detailed individual records from the population-based cancer registries in Tasmania and South Australia. MAIN OUTCOME MEASURES: The level of and rise in melanoma mortality rates during 1969-1989 in Australia; the five-year survival rates for Tasmanian and South Australian cases; and male:female incidence ratios related to latitude. RESULTS: We found annual increases in melanoma mortality rates of 2.5% in men (P < 0.0001) and 1.1% in women (P < 0.0001) for all Australia. The five-year survival rates (with 95% confidence intervals [CI]) were: 67% (59%-75%) for Tasmanian men; 79% (76%-83%) for South Australian men; 80% (74%-86%) for Tasmanian women and 88% (86%-91%) for South Australian women. A change in the male:female incidence ratio with latitude was also found--women have significantly higher incidence rates at higher latitudes, but similar rates to men at lower latitudes. CONCLUSIONS: The age standardised mortality from CMM for the period 1969 to 1989 shows little variation by State for women, despite a considerable range in latitude. CMM mortality in men is increasing at a faster rate than that in women. Between 1982 and 1987 the male:female incidence ratio in high latitudes in the Southern Hemisphere showed an excess of cases in women, a finding which we believe has not been reported before..

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