Diana Bull’s research while affiliated with University of Oxford and other places

Background: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. Methods: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. Findings: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31-1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29-1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40-1·66; p<0·0001) and endometrioid (1·42, 1·20-1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07-1·46, p=0·005). Interpretation: The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users. Funding: Medical Research Council, Cancer Research UK.

Little is known about the etiology of in situ ductal breast cancer (DCIS) or what influences its possible progression to invasive ductal disease. Comparison of risk factors for DCIS and invasive ductal cancer may throw some light on these issues. We estimated relative risks for DCIS and invasive ductal breast cancer according to 12 genetic and eight environmental risk factors among 1.1 million postmenopausal women in a large prospective UK study. There was no strong evidence of a different association with DCIS versus invasive ductal cancer for any of the 12 susceptibility loci examined. We also found similar associations of age at menarche, age at first birth, parity, age at menopause, family history of breast cancer and use of hormone replacement therapy with DCIS and invasive ductal cancer. Only body mass index (BMI) showed a clear difference in association in that it was positively associated with the risk of invasive ductal cancer but not DCIS (RRs per 5 kg/m(2) = 1.20 and 1.01, respectively; p-value for heterogeneity = 0.002). The very similar risk factor profiles observed here for DCIS and invasive ductal cancer suggest that DCIS is a precursor of invasive ductal cancer and most risk factors affect the risk of invasive ductal cancer primarily through their effects on the risk of DCIS. The lack of association between BMI and DCIS suggests a greater influence of BMI on disease progression.

Background Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships.Methods and findingsIndividual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index. Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05-1.09; p

Although breast cancer risk is greater in users of estrogen-progestin than estrogen-only formulations of menopausal hormonal therapy, reports on their effects have been somewhat inconsistent. We investigated whether the timing of these therapies affected breast cancer incidence. A total of 1,129,025 postmenopausal UK women provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk. We used Cox regression to estimate adjusted relative risks (RRs) of breast cancer in hormonal therapy users vs never users and calculated standardized incidence rates. All statistical tests were two-sided. During 4.05 million woman-years of follow-up, 15,759 incident breast cancers occurred, with 7107 in current users of hormonal therapy. Breast cancer incidence was increased in current users of hormonal therapy, returning to that of never users a few years after use had ceased. The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap (P(heterogeneity) < .001, for both estrogen-only and estrogen-progestin formulations). Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% confidence interval [CI] = 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51). A similar pattern was observed among current users of estrogen-progestin formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 to 2.14, respectively). At 50-59 years of age, annual standardized incidence rates for breast cancer were 0.30% (95% CI = 0.29% to 0.31%) among never users of hormone therapy and 0.43% (95% CI = 0.42% to 0.45%) and 0.61% (95% CI = 0.59% to 0.64%), respectively, among current users of estrogen-only and estrogen-progestin formulations who began use less than 5 years after menopause. There was substantial heterogeneity in breast cancer risk among current users of hormonal therapy. Risks were greater among users of estrogen-progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later.

We examined the relation between the use of hormone replacement therapy (HRT) and the incidence of central nervous system (CNS) tumours in a large prospective study of 1,147,894 postmenopausal women. Women were aged 56.6 years on average at entry, and HRT use was recorded at recruitment and updated, where possible, about 3 years later. During a mean follow-up of 5.3 years per woman, 1,266 CNS tumours were diagnosed, including 557 gliomas, 311 meningiomas and 117 acoustic neuromas. Compared with never users of HRT, the relative risks (RRs) for all incident CNS tumours, gliomas, meningiomas and acoustic neuromas in current users of HRT were 1.20 (95% CI: 1.05-1.36), 1.09 (95% CI: 0.89-1.32), 1.34 (95% CI: 1.03-1.75) and 1.58 (95% CI: 1.02-2.45), respectively, and there was no significant difference in the relative risks by tumour type (heterogeneity p = 0.2). In past users of HRT the relative risk was 1.07 (95% CI: 0.93-1.24) for all CNS tumours. Among current users of HRT, there was significant heterogeneity by the type of HRT with the users of oestrogen-only HRT at higher risk of all CNS tumours than users of oestrogen-progestagen HRT (RR = 1.42, 95% CI: 1.21-1.67 versus RR = 0.97, 95% CI: 0.82-1.16) (heterogeneity p < 0.001). Among current users of oestrogen-only and oestrogen-progestagen HRT, there was no significant heterogeneity by duration of use, hormonal constituent or mode of administration of HRT.

There is limited evidence on how the risk of breast cancer and its subtypes depend on low-penetrance susceptibility loci, individually or in combination. To analyze breast cancer risk, overall and by tumor subtype, in relation to 14 individual single-nucleotide polymorphisms (SNPs) previously linked to the disease, and in relation to a polygenic risk score. Study of 10,306 women with breast cancer (mean age at diagnosis, 58 years) and 10,393 women without breast cancer who in 2005-2008 provided blood samples for genotyping in a large prospective study of UK women; and meta-analysis of these results and of other published results. Estimated per-allele odds ratio (OR) for individual SNPs, and cumulative incidence of breast cancer to age 70 years in relation to a polygenic risk score based on the 4, 7, or 10 SNPs most strongly associated with risk. Odds ratios for breast cancer were greatest for FGFR2-rs2981582 and TNRC9-rs3803662 and, for these 2 SNPs, were significantly greater for estrogen receptor (ER)-positive than for ER-negative disease, both in our data and in meta-analyses of all published data (pooled per-allele ORs [95% confidence intervals] for ER-positive vs ER-negative disease: 1.30 [1.26-1.33] vs 1.05 [1.01-1.10] for FGFR2; interaction P < .001; and 1.24 [1.21-1.28] vs 1.12 [1.07-1.17] for TNRC9; interaction P < .001). The next strongest association was for 2q-rs13387042, for which the per-allele OR was significantly greater for bilateral than unilateral disease (1.39 [1.21-1.60] vs 1.15 [1.11-1.20]; interaction P = .008) and for lobular than ductal tumors (1.35 [1.23-1.49] vs 1.10 [1.05-1.15]; interaction P < .001). The estimated cumulative incidence (95% confidence interval) of breast cancer to age 70 years among women in the top and bottom fifths of a polygenic risk score based on 7 SNPs was 8.8% (8.3%-9.4%) and 4.4% (4.2%-4.8%), respectively. For ER-positive disease the corresponding risks were 7.4% (6.9%-8.0%) and 3.4% (3.1%-3.8%), respectively; while for ER-negative disease they were 1.4% (1.2%-1.6%) and 1.0% (0.8%-1.2%). The findings did not differ materially according to the number of SNPs included in the polygenic risk model. The polygenic risk score was substantially more predictive of ER-positive than of ER-negative breast cancer, particularly for absolute risk.

Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study. We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption). After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing). Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors. Cancer Research UK and the UK Medical Research Council.