Original ResearchRisk of uterine cancer for BRCA1 and BRCA2 mutation carriers
Introduction
Women carrying a deleterious germline BRCA1 or BRCA2 mutation are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) by peak bodies, such as the United States National Comprehensive Cancer Network [1] and Cancer Australia [2]. This is due to the established elevated risk of high grade pelvic serous cancer in these women, with a lifetime cumulative risk ranging from 6% to 54% [3], [4], [5], [6]. RRSO is associated with an 85% reduced risk of pelvic serous cancer in mutation carriers [7], [8], [9] and reduced cancer-specific and all-cause mortality [7], [10]. The term ‘pelvic serous cancer’ is used because the majority of BRCA1 and BRCA2 mutation-associated gynaecologic cancers (ovarian, fallopian tube or primary peritoneal) appear to arise from the fallopian tube fimbriae rather than the ovary, although they have often been labelled as ‘ovarian cancer’ at diagnosis [11], [12], [13].
An ongoing area of controversy is whether risk-reducing hysterectomy should be performed at the time of RRSO [14], [15]. The risk of uterine cancer for BRCA1 and BRCA2 mutation carriers remains unclear with conflicting findings in different studies possibly confounded by prior tamoxifen use. Although, most studies have suggested about a two-fold increase in risk relative compared to the general population [16], [17], [18], [19], the findings were statistically significant in only two of these studies [16], [17]. A recent study suggested a much higher relative risk (RR) but only when the analysis was limited to the serous uterine cancer subtype and the finding was only statistically significant for BRCA1 mutation carriers [19].
Performing abdominal hysterectomy in conjunction with RRSO is associated with higher risk of complications compared to RRSO alone, although the complications are less with minimally invasive surgery [20], [21]. Therefore, a more precise estimate of the incidence and RR of uterine cancer for BRCA1 and BRCA2 mutation carriers would help guide clinicians in weighing up risk-reduction benefits against the peri-operative and long-term morbidity [22]. We sought to assess, using data from a prospective cohort study, whether BRCA1 and BRCA2 mutation carriers are at increased risk of developing uterine cancer compared to the general population. If mutation carriers are at significantly increased risk of developing uterine cancer, there may be an added benefit of prophylactic hysterectomy at the time of RRSO.
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Participants
Eligible women were a subset of females enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), a resource of data and biospecimens from multiple-case breast and ovarian cancer families [23], [24], [25]. Eligibility criteria for kConFab are detailed on the website [23]. Families are recruited via 24 familial cancer clinics in Australia and New Zealand. At enrolment, blood is drawn for BRCA1 and BRCA2 mutation analysis.
Women were included in
Results
A total of 1,111 BRCA1 and BRCA2 mutation carriers with systematic prospective follow-up were identified. Of those, 283 women (25%) were excluded as they had hysterectomy (for non-malignant reasons) before cohort entry (N = 278), prior history of uterine cancer (N = 2) or they did not reside in Australia or New Zealand (N = 3). The remaining 828 women, 438 (53%) BRCA1 mutation carriers and 390 (47%) BRCA2 mutation carriers, were prospectively followed from cohort entry for a median of 9.0 years.
Discussion
Our study investigated the incidence of uterine cancer for BRCA1 and BRCA2 mutation carriers residing in Australia and New Zealand. Compared to the general population, women with a deleterious BRCA1 or BRCA2 mutation had about 2.5-fold increased risk of developing uterine cancer, although this was not statistically significant. More specifically the SIR was 2.87 for BRCA1 mutation carriers and 2.01 for BRCA2 mutation carriers. This finding is consistent with the literature which generally
Role of funding
This work was supported by grants to kConFab and the kConFab Follow-Up Study from Cancer Australia [grant number 809195], the Australian National Breast Cancer Foundation [grant number IF 17 kConFab], the National Health and Medical Research Council [grant numbers 454508, 288704, 145684], the National Institute of Health U.S.A. [grant number 1RO1CA159868], the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of
Conflict of interest statement
None declared.
Acknowledgements
The authors thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the many families who contribute to kConFab for their contributions to this resource.
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Cited by (0)
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
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Research Department, Peter MacCallum Cancer Centre, Melbourne, Australia.