Elsevier

Gynecologic Oncology

Volume 130, Issue 1, July 2013, Pages 127-131
Gynecologic Oncology

The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: An international prospective cohort study

https://doi.org/10.1016/j.ygyno.2013.03.027Get rights and content

Highlights

  • The risk of endometrial cancer is higher in BRCA1 mutation carriers than in the general population.

  • Tamoxifen use is associated with an increase in the risk of endometrial cancer in BRCA1 and BRCA2 carriers.

  • A course of tamoxifen is associated with a two percent risk of endometrial cancer.

Abstract

Objective

To evaluate the risk of endometrial cancer in women who carry a mutation in the BRCA1 or the BRCA2 gene.

Methods

We followed 4456 women with a BRCA1 or a BRCA2 mutation for incident cases of endometrial cancer. The incidence of endometrial cancer was estimated per 100,000 women per year. The hazard ratios for endometrial cancer were estimated by calculating standardized incidence ratios (SIRs) according to age group and country of residence. We estimated the impact of tamoxifen and hormone replacement therapy on the incidence of endometrial cancer in BRCA1 and BRCA2 carriers.

Results

After a mean follow-up of 5.7 years, we identified 17 endometrial cancers (13 cases in BRCA1 and 4 cases in BRCA2). The SIR for BRCA1 carriers was 1.91 (95% CI: 1.06–3.19, p = 0.03) and for BRCA2 carriers was 1.75 (95% CI: 0.55–4.23, p = 0.2). The SIR was 4.14 (95% CI: 1.92 to 7.87) for women who received tamoxifen and was 1.67 (95% CI: 0.81 to 3.07) for women who did not receive tamoxifen. The ten-year cumulative risk of endometrial cancer in women who were treated with tamoxifen was 2.0%.

Conclusions

The risk of endometrial cancer is higher in BRCA1 mutation carriers than in the general population. The excessive risk is largely attributable to a history of tamoxifen use, but the actual risk of endometrial cancer associated with tamoxifen is small. It is important to discuss hysterectomy at the time of prophylactic bilateral salpingo-oophorectomy if tamoxifen is to be considered.

Introduction

Germline mutations in BRCA1 and BRCA2 have been implicated in the pathogenesis of endometrial cancer however, convincing evidence for a strong association is not yet established. It is important to have an accurate estimate of the risk of endometrial cancer in mutation carriers, because this information may be helpful for gynecologists and their patients when the issue of preventive oophorectomy is discussed. There are conflicting opinions regarding the advisability of performing a prophylactic hysterectomy concurrent with salpingo-oophorectomy and the risks and benefits of hysterectomy should be weighed. Although hysterectomy effectively prevents endometrial cancer, it can also be associated with higher peri-operative morbidity and a longer hospital length of stay and thus requires a careful risk–benefit analysis which would be informed by more precise estimates of endometrial cancer incidence in women with a hereditary predisposition to breast and ovarian cancer. Endometrial cancer is the most common gynecological malignancy [1], but it is not clear to what extent, if any, the risk is increased in women with a hereditary predisposition to breast and ovarian cancer.

In an earlier, smaller study, we estimated the risk of endometrial cancer in a cohort of 857 BRCA1 and BRCA2 mutation carrier women [2]. This study suggested the presence of an increased risk, but the sample was too small (six incident cases of endometrial cancer) to distinguish between a risk from the BRCA mutations per se or from tamoxifen used as treatment for breast cancer. Our cohort is now much larger and we sought to re-evaluate the risk of endometrial cancer in BRCA1 and the BRCA2 mutation carriers. We also sought to evaluate the importance of tamoxifen as a contributor to endometrial cancer risk and to quantify the potential benefit of prophylactic hysterectomy in BRCA mutation carriers at the time of oophorectomy.

Section snippets

Study cohort

Women with a BRCA1 or BRCA2 mutation were identified through a registry of mutation carriers at the Women's College Research Institute. A total of 4893 women were included in the cohort study. Data were collected from women with a known pathogenic BRCA1 or BRCA2 mutation at 50 different centers in eleven countries in North America and Europe. The ethics committees/human subjects review boards of all participating centers approved the study protocol. Informed consent was obtained from study

Incidence

The mean age at enrolment was 42.7 years. On average, the women were followed for 5.7 years. There were 17 incident cases of endometrial cancer diagnosed in the cohort (13 in BRCA1 carriers and four in BRCA2 carriers). The youngest case was diagnosed at age 34 and the mean age of diagnosis was 52.4 years. The incidence rate of endometrial cancer for the entire cohort was 67.1 per 100,000 per year. The incidence rates were similar for BRCA1 and BRCA2 carriers (Table 1). As expected, the incidence

Discussion

In this prospective study, we estimated the incidence of endometrial cancer in BRCA mutation carriers and found the risk increase to be similar for BRCA1 carriers (SIR 1.91, p = 0.02) and BRCA2 carriers (SIR 1.75, p = 0.2). There was a significant increase in the incidence of endometrial cancer in women who had breast cancer (SIR 2.18, p = 0.02), but this increase was restricted to women who had used tamoxifen in the past (SIR 4.39, p = < 0.001).

In a study by the Breast Cancer Linkage Consortium (BCLC),

Conflict of interest statement

The authors declare no conflict of interest.

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1

Other members of the Hereditary Breast Cancer Clinical Study Group:

Ophira Ginsburg, André Robidoux, Lovise Maehle, Kevin Sweet, Dawna Gilchrist, Olufunmilayo Olopade, Peter Ainsworth, Andrea Eisen, Fergus Couch, Claudine Isaacs, Charis Eng, Jeffrey N. Weitzel, Mary B. Daly, Judy E. Garber, Dana Zakalik, Carey A. Cullinane, Dominique Stoppa-Lyonnet, Howard Saal, Wendy Meschino, Wendy McKinnon, Marie Wood, Taya Fallen, Raluca Kurz, Siranoush Manoukian, Susan Armel, Rochelle Demsky, Jeanna McCuaig, Edmond Lemire, Jane Mclennan, Seema Panchal, Louise Bordeleau, Dawna Gilchrist, Albert E. Chudley, Susan T. Vadaparampil, Tuya Pal, Daniel Rayson, Adriana Valentini, Susan Friedman (on behalf of FORCE), Cezary Cybulski, Tomasz Byrski, and Tomasz Huzarski,

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