Elsevier

European Journal of Cancer

Volume 46, Issue 12, August 2010, Pages 2275-2284
European Journal of Cancer

Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: A meta-analysis

https://doi.org/10.1016/j.ejca.2010.04.018Get rights and content

Abstract

Background

Women with BRCA1 or BRCA2 mutations are at increased risk of breast and ovarian cancer. Oral contraceptives (OC) use has been associated with a reduction in ovarian cancer risk and with a moderately increased breast cancer risk, which tends to level off in the few years after stopping. The association between oral contraceptive and BRCA1 or BRCA2 gene mutations carriers is unclear.

Methods

We performed a comprehensive literature search updated to March 2010 of studies on the associations between OC users and breast or ovarian cancer for ascertained BRCA1/2 carriers. We obtained summary risk estimated for ever OC users, for duration of use and time since stopping.

Results

A total of 2855 breast cancer cases and 1503 ovarian cancer cases, carrying an ascertained BRCA1/2 mutation, were included in our meta-analyses, based on overall 18 studies. Use of OC was associated with a significant reduced risk of ovarian cancer for BRCA1/2 carriers (summary relative risk (SRR) = 0.50; 95% confidence interval (CI), 0.33–0.75). We also observed a significant 36% risk reduction for each additional 10 years of OC use (SRR: 0.64; 95% CI, 0.53–0.78; P trend < 0.01). We found no evidence of a significant association between OC and breast cancer risk in carriers (SRR: 1.13; 95% CI, 0.88–1.45) and with duration of use. OC formulations used before 1975 were associated with a significant increased risk of breast cancer (SRR: 1.47; 95% 1.06, 2.04), but no evidence of a significant association was found with use of more recent formulations (SRR: 1.17; 95% 0.74, 1.86).

Conclusions

OC users carrying an ascertained BRCA1/2 mutation have a reduced risk of ovarian cancer, proportional to the duration of use. There is no evidence that recent OC formulations increase breast cancer risk in carriers.

Section snippets

Background

There is clear evidence that germ line mutation in BRCA1 (MIM #113705) or BRCA2 (MIM #600185) account for a large proportion of familial breast/ovarian cancer and confer very high lifetime risks for both cancer sites.1 Approximately 5–10% of all epithelial ovarian carcinomas result from genetic predisposition2 and the great majority of these are associated with BRCA genes, as opposed to 25% of all hereditary breast cancers.3, 4 The lifetime risk of breast or ovarian cancer for women who

Search strategy, inclusion criteria and data abstraction

We conducted a literature search updated to March 2010 using validated search strategies23, 24, 25 on the following databases: PUBMED, EMBASE, Ovid MEDLINE®, using combinations of the following MeSH terms and keywords: ‘oral contraceptives’, ‘cancer’, ‘ovarian’ or ‘breast’, ‘BRCA1’ or ‘BRCA2’. We also identified the most cited articles on the topic using ISI Web of Knowledge® Science Citation Index Expanded™ (Journal Citation Report). In addition we reviewed the references of all articles of

Statistical methods

When available, we retained estimates adjusted for the maximum number of confounders.

We always presented random effects models to evaluate summary relative risk (SRRs) obtained with maximum likelihood estimates, in order to be more conservative.42 Homogeneity of effects across studies was assessed using the Chi-square statistic (which we considered statistically significant when the P-value was ⩽0.10)43 and quantified by I2, which represents the percentage of total variation across studies that

Results

Details on the search strategy and the data extrapolation are described in Fig. 1. The main characteristics of the studies included in the analyses are shown in Table 1.

Sensitivity analysis, meta-regression and publication bias

In this meta-analysis, the term ‘ever OC use’ was referred to any use of OC reported during lifetime. This is a general definition, which includes all meanings considered by the authors: Haile29 included in that definition OC users for at least 1 month, Heimdal28 for at least 3 months, while Whittemore33 evaluated OC users for at least 1 year. The influence of these different definitions of exposure was evaluated in sensitivity analyses with no substantial differences for breast/ovarian cancers

Association between OC use and mutation status in cancer patients

Features of the studies included in the analysis are detailed in Table 2. We evaluated estimates from case–case approaches to study whether mutation carriers were more likely than non-carriers to use OC.

The estimates were based on a total of 241 breast cancer cases and 371 ovarian cancer cases with a BRCA1/2 mutation. We found no significant associations between BRCA1/2 mutation status and use of OC for breast/ovarian cancer, even separately investigating the cancer sites and mutations (Fig. 3).

Discussion

Our meta-analysis was based on 2855 breast and 1503 ovarian cancer cases with a BRCA1/2 mutation. We found no evidence of a significant increased breast cancer risk in OC users overall, for recent formulation of OC and in the first 10 years after cessation.

Our outcomes differ from results obtained in a previous pooled-analysis, based on 54 studies. The authors investigated the association between OC use and breast cancer risk in the general population, showing a significant association between

Conflict of interest statement

None declared.

References (48)

  • R. DerSimonian et al.

    Meta-analysis in clinical trials

    Control Clin Trials

    (1986)
  • T. Pal et al.

    BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases

    Cancer

    (2005)
  • S. Narod et al.

    Genetic heterogeneity of breast-ovarian cancer revisited. Breast cancer linkage consortium

    Am J Hum Genet

    (1995)
  • D.F. Easton et al.

    Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast cancer linkage consortium

    Am J Hum Genet

    (1995)
  • D.F. Easton et al.

    Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12–13

    Am J Hum Genet

    (1997)
  • J.P. Struewing et al.

    The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews

    N Engl J Med

    (1997)
  • Parkin DM, Whelan SL, Ferlay J, Storm H. Cancer Incidence in Five Continents. Lyon;...
  • C.M. Perou et al.

    Molecular portraits of human breast tumours

    Nature

    (2000)
  • D.P. Atchley et al.

    Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer

    J Clin Oncol

    (2008)
  • J.M. Dolle et al.

    Risk factors for triple-negative breast cancer in women under the age of 45 years

    Cancer Epidemiol Biomarkers Prev

    (2009 Apr)
  • Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, et al., editors. SEER cancer statistics review,...
  • T. Riman et al.

    Hormonal aspects of epithelial ovarian cancer: review of epidemiological evidence

    Clin Endocrinol (Oxf)

    (1998)
  • V. McGuire et al.

    Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations

    Am J Epidemiol

    (2004)
  • A.S. Whittemore et al.

    Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case–control studies. II. Invasive epithelial ovarian cancers in white women

    Am J Epidemiol

    (1992)

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