SummaryBackgroundMenarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.MethodsIndividual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.FindingsBreast cancer risk increased by a factor of 1·050 (95% CI 1·044–1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025–1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45–54 years 1·43, 1·33–1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons).InterpretationThe effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.FundingCancer Research UK.

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...

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.

After a 3-mo intervention, both diets significantly reduced cardiovascular disease risk factors to an overall comparable extent.

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Experimental models showed consistently a modulation of carcinogenesis by omega 3 polyunsaturated fatty acids (v3 PUFA). Fish intake is often described as part of a beneficial dietary pattern. However, observational epidemiological studies on the relationship between v3 PUFA reported conflicting results. The objective of this systematic review is to determine whether there exists any progress in the evaluation of the causal relationship between dietary v3 PUFA and cancers since the previous FAO/OMS expert consultation and whether it is possible to propose preventive and/or adjuvant therapeutic recommendations. Prospective and case-control observational studies published since 2007 and meeting validity criteria were considered together with RCT. Experimental studies are mentioned to provide for biological plausibility. When evaluating the level of evidence, a portfolio approach was used, weighted by a hierarchy giving higher importance to prospective studies followed by RCT if any. There is a probable level of evidence that ALA per se is neither a risk factor nor a beneficial factor with regards to cancers. Observational studies on colorectal, prostate and breast cancers only provided limited evidence suggesting a possible role of LC-v3PUFA in cancer prevention because insufficient homogeneity of the observations. Explanation for heterogeneity might be the inherent difficulties associated with epidemiology (confounding and dietary pattern context, measurement error, level of intake, genetic polymorphism). The role of LC-v3PUFA as adjuvant, might be considered of possible use, in view of the latest RCT on lung cancers even if RCT on other cancers still need to be undertaken.Key words: Omega 3 fatty acids: EPA: DHA: alpha linolenic acid: cancers: epidemiologic studies Rationale: The incidence of cancers affected almost 13 million people and caused more than 7 million deaths worldwide in 2008. Incidence is expected to increase to 15 million in 2015 and death to more than 9 million due to demographic effects alone. However increased longevity is not the only explanation, e.g. in France the incidence of cancers in males increased by 35 % and in females by 43 % after controlling for the demographic effect (1) Thus it is generally acknowledged that changes in exposure to carcinogenic environment and in nutrition are factors of this evolution.If changes in food patterns are more often associated with an increased incidence of cancers, as illustrated in migrant studies (2) , it happens that nutritional recommendations are followed by a decreased incidence (3) . This underlines the search for beneficial nutrients. Several epidemiological studies have shown a risk reduction of some cancers associated with long chain omega3 fatty acids (v3 LC-PUFA) or fish intake (4) , but the limited evidence or the absence of consistency required further investigations.A systematic review of the epidemiological studies published since 2007 is undertaken here focusing on v3 LC-PUFA either from dietary intake (but not considering fis...