SummaryBackgroundPublished findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.MethodsPrincipal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.FindingsDuring prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.InterpretationIf these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.FundingCancer Research UK and the Medical Research Council.

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58 515 women with invasive breast cancer and 95 067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19 -1.45, P50.00001) for an intake of 35 -44 g per day alcohol, and 1.46 (1.33 -1.61, P50.00001) for 545 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5 -8.7%; P50.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P50.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98 -1.07, and for current smokers=0.99, 0.92 -1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver. Many epidemiological studies have investigated the relationship between breast cancer and the consumption of alcohol and/or tobacco. References to over 80 studies that have collected relevant data, as well as to reviews of the subject, are given in Appendix II (www. bjcancer.com). The published results from these studies have general...

Background The relationships of circulating concentrations of oestrogens, progesterone and androgens with breast cancer and related risk factors in premenopausal women are not well understood. Methods Individual data on prediagnostic sex hormone and sex hormone binding globulin (SHBG) concentrations were contributed by 7 prospective studies. Analyses were restricted to women who were premenopausal and under age 50 at blood collection, and to breast cancer cases diagnosed before age 50. The odds ratios (ORs) with 95% confidence intervals (95% CIs) for breast cancer associated with hormone concentrations were estimated by conditional logistic regression in up to 767 cases and 1699 controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. The associations of hormones with risk factors for breast cancer in control women were examined by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle and body mass index (BMI). All statistical tests were two-sided. Findings ORs for breast cancer associated with a doubling in hormone concentration were 1.19 (95% CI 1.06–1.35) for oestradiol, 1.17 (1.03–1.33) for calculated free oestradiol, 1.27 (1.05–1.54) for oestrone, 1.30 (1.10–1.55) for androstenedione, 1.17 (1.04–1.32) for dehydroepiandrosterone sulphate, 1.18 (1.03–1.35) for testosterone and 1.08 (0.97–1.21) for calculated free testosterone. Breast cancer risk was not associated with luteal phase progesterone (for a doubling in concentration OR=1.00 (0.92–1.09)), and adjustment for other factors had little effect on any of these ORs. The cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. Interpretation Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

The relationship between menopausal oestrogen use and breast cancer risk has long been of interest, particularly given extensive evidence that endogenous hormones are involved in aetiology (Henderson et al., 1982) and that oestrogens can induce mammary neoplasms in experimental animals (IARC, 1979). Interest heightened when Hoover et al. (1976), in a retrospective cohort study of menopausal oestrogen users, showed that the risk of breast cancer increased with years since initial exposure, reaching a significant risk of 2.0 after 15 years. Subsequent case-control studies, however, yielded conflicting results (Jick et al., 1980;Ross et al., 1980;Hoover et al., 1981;Kelsey et al., 1981;Hulka et al., 1982;Hiatt et al., 1984;Kaufman et al., 1984;Nomura et al., 1986). Most failed to find evidence of any overall excess risk, although several indicated that long-term users might be adversely affected. A further complication was that hormone effects appeared to be modified by ovarian status, but various studies disagreed on which subgroups were at highest risk. The different subgroups included women with a natural menopause (Jick et al., 1980;Hulka et al., 1982), women whose ovaries were retained (Ross et al., 1980) and women having undergone a bilateral oophorectomy Hiatt et al., 1984). In addition, two large case-control studies (Kelsey et al., 1981;Kaufman et al., 1984) (Brinton et al., 1981). Although hormone use was not associated with any substantial overall risk, there was some hazard suggested among women who received hormones following bilateral oophorectomy, obliterating the protective effect normally associated with the operation. In this group, risk increased with years of oestrogen use, reaching risks of 2-3 for users of ten or more years.Higher risks were observed among oophorectomized women who used hormones in the presence of other risk factors, including nulliparity, family history of breast cancer, and benign breast disease.We subsequently had the opportunity to expand the original case-control study, concentrating on women whose breast cancer was detected during the latter years of the screening project. The extension of this study more than doubled our original sample size, enabling detailed evaluations of hypotheses raised by the initial investigation risks among hormone-susceptible subgroups, and relationships of hormone use to varying disease states. Subjects and methodsSubjects for this case-control study participated in the Breast Cancer Detection Demonstration Project (BCDDP), a multi-centre breast cancer screening program involving over 280,000 women at 29 widely dispersed centres. This program, jointly

Summary Dietary data from a population-based case-control study of 172 epithelial ovarian cancer cases and 172 controls were analysed. A significant (P<0.01) dose-response relationship was found between intake of fat from animal sources and risk of ovarian cancer, but plant fat was not associated. Although the effect of animal fat was confounded by education, an adjusted odds ratio of 1.8 persisted for those in the upper quartile compared to the lower quartile of consumption (P for trend=0.03). After adjustment for animal fat intake, calorific and protein intake had minimal effects on risk. Total vegetables were found to be somewhat protective, but the mechanism of action was unclear. Weight, height and relative weight (weight/height2) were not related to risk of ovarian cancer.Substantial evidence indicates that diet is a major factor in the cause of some of the most important and prevalent human cancers, especially cancers of the digestive tract and hormone-dependent cancers (Williams & Weisburger, 1986). An involvement of dietary fat in the aetiology of ovarian cancer has been suggested by some epidemiological studies (Armstrong & Doll, 1975;Cramer et al., 1984;Rose et al., 1986;La Vecchia et al., 1987). Experimental studies have shown that dietary fat is related to endogenous hormone levels, providing a plausible mechanism for the association (Willett & MacMahon, 1984b Information on usual adult consumption of 63 common foods in Shanghai was obtained. Study subjects were first asked about how often they ate each food (daily, weekly, monthly, yearly, seldom or never), followed by questions to derive the grams of food eaten per unit time. The women, who generally were responsible for buying and preparing the meals for their households, adjusted the quantities purchased by the fraction they consumed. The food composition table published by the Chinese Academy of Medical Sciences (1981) was employed to convert these foods into nutrients. The majority of nutrient values were based on data derived from the Shanghai area; when this information was missing, values from Jiangsu province, and occasionally from Beijing, were utilised. Data were not available on saturated and unsaturated fat in Chinese foods so it was not possible to examine these two variables. Multiplying the reported daily consumption (in grams) of each individual food by the nutrient content per gram in that food, and then summing over all foods, generated for each individual the total daily ingestion of each nutrient. In addition, food groups were formed based on dietary or botanical similarities. For example, meats included pork, pork chops, spareribs, pigs' feet, salted pork, pork liver, organ meats, beef, lamb, chicken and duck; the cruciferous vegetables included greens, cabbage, Chinese cabbage and cauliflower; and alium consisted of foods in the onion family (see Table VI for further details).The odds ratio (OR, estimated relative risk) was employed in measuring the association between diet and ovarian cancer. Based upon the distribution amon...