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 We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.MethodsPrincipal analyses used individual participant data from all eligible prospective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.
#2072 Hereditary BC occurs at a younger age and is associated with more adverse tumor-related features than sporadic breast cancer (BC) (defined here as BC in those with no 1st or 2nd degree family history of breast or ovarian cancer). Using pre-specified criteria, we assembled a population-based cohort of newly diagnosed BC at 3 centers: Ontario, Canada (1996-98), San Francisco Bay area, USA (1995-2000), Melbourne/Sydney, Australia (1991-1998). Medical information was obtained from medical records; women were followed prospectively for recurrence, new cancers and death. Pathology data were obtained from central review or pathology reports. BRCA1 and BRCA2 mutation testing was performed on 77% and 70% of cases, respectively (sporadic BC cases were not tested at 2 centers). Hereditary and sporadic BC cases were compared using Cox proportional hazards (stratified by center). 3215 eligible cases were enrolled in the BCFR, with a mean age at diagnosis of 46.9 years. Median follow-up was 7.61 years; 565 women had distant recurrences and 547 died. There were 92 cases with BRCA1 and 72 with BRCA2 mutations; 1549 (48.2%) had sporadic BC; the remainder had familial BC as defined above. BRCA1 mutations were associated with young age, estrogen and progesterone receptor (ER and PgR) negativity and high grade; BRCA2 mutations were associated with node positivity and high grade. Distant disease-free survival (DDFS) and overall survival (OS) did not differ significantly between BRCA1 carriers and sporadic cases in univariate or multivariate analyses. DDFS and OS were worse in BRCA2 carriers than in sporadic cases (HR 1.6, p=0.04 and HR 1.8, p=0.01, respectively) in univariate analyses but not in multivariate analyses (DDFS HR 1.0, p=0.98; OS HR 1.13, p=0.61). The small group of BRCA2 carriers who did not receive adjuvant chemotherapy had a significantly worse OS (multivariate HR 3.63, p = 0.005). Furthermore, BRCA2 carriers who received adjuvant tamoxifen had significantly worse OS than women with sporadic BC (HR=2.0, p=0.03). We conclude that BRCA1 and BRCA2 mutations do not independently impact DDFS or OS. Significantly worse outcomes were seen in BRCA2 carrier subgroups defined by adjuvant treatment; this requires further investigation and may have implications for clinical practice. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2072.
The effect of parity and oral contraceptive (OC) use on breast cancer risk differs by cancer subtype as defined by histology. Family history of breast cancer impacts decisions regarding both parity and oral contraceptive use; it is unknown whether reproductive risk factors are related to uncommon histologies in women with and without a strong family history. Methods: Using population-based data from the Breast Cancer Family Registry, we conducted analyses using unordered polytomous regression to determine the role of family history in associations between parity, OC use, and breast cancer histologic subtype, among 3,260 cases and 2,997 controls. Histologic types examined included ductal and lobular as well as the uncommon histologies of mucinous, tubular, and medullary cancer. Results: Twenty-eight percent of cases and 9% of controls had a family history (defined as at least 1 first-degree relative with breast cancer). Cases with and without family history were similar in regards to OC use (75% and 73%, respectively were ever-users) and parity (2.08 children in cases with family history, 2.10 in cases without). In a multivariable model, when compared with controls, OC use was inversely associated with tumors of mucinous histology (OR ¼ 0.43, 95% CI 0.23-0.79 for use !5 years vs. never use). There was a stronger inverse association with OC use and the mucinous subtype among those without a family history (OR ¼ 0.27, 95% CI 0.13-0.57), and a nonsignificant positive association in those with family history (OR ¼ 2.19, 95% CI 0.40-11.84). High parity (!3 children) was positively associated with medullary histology (OR ¼ 2.62, 95% CI 1.16-5.91, compared with nulliparity); the association was stronger among women without a family history (OR ¼ 4.31, 95% CI 1.67-11.12), and was not significantly associated among those with a family history (OR ¼ 0.36, 95% CI 0.06-2.29). Parity was inversely associated with the mucinous type (OR ¼ 0.45, 95% CI 0.21-0.96, compared with nulliparity), and this effect remained stable in women with and without family history. Conclusion: This study suggests that selected reproductive risk factors may only be related to uncommon breast cancer histologies among women without a family history of breast cancer.
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