Projected Benefit of Bilateral Salpingo-Oophorectomy by Age in BRCA Carriers

Patients with BRCA mutations should consider prophylactic ovariectomies prior to age 50 based upon this epidemiological simulation. James W. Mold, MD, MPH

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Importance Women with a BRCA1 or BRCA2 variant face a high lifetime risk of ovarian cancer and are often advised to undergo preventive surgery (bilateral salpingo-oophorectomy [BSO]) before cancer develops. The recommended age of BSO is 35 years for BRCA1 carriers and is 45 years for BRCA2 carriers, but some women choose to delay surgery until the age of menopause; there is no standard upper age at which surgery is no longer advised.

Objective To estimate the residual lifetime risk of ovarian cancer among BRCA carriers by current age and projected age at BSO.

Design, Setting, and Participants This was a prospective cohort study in an international cohort of BRCA carriers monitored for incident ovarian cancer. A life table analysis used age-specific ovarian cancer incidence rates and competing mortality rates to estimate lifetime risk of ovarian cancer among women with a BRCA1 or BRCA2 pathogenic variant with both ovaries intact and no prior ovarian cancer at baseline. Patients were recruited between 1995 and 2024 across 24 international centers, and the mean (SD) follow-up was 4.4 (3.9) years.

Exposure Timing of BSO, defined as immediate BSO, delayed BSO, or no BSO.

Main Outcome and Measures Residual lifetime risk of ovarian cancer.

Results The cohort consisted of 4286 BRCA1 and 1427 BRCA2 carriers between the ages of 30 and 74 years at baseline (mean [SD] age, 42.0 [10.8] years). There were 249 incident ovarian cancers in the follow-up period. The lifetime risk of ovarian cancer was 55.0% (95% CI, 48.8-61.9) for a BRCA1 carrier and 24.1% (95% CI, 15.1-36.6) for a BRCA2 carrier. A 30-year-old BRCA1 carrier with BSO delayed to age 50 years had a projected residual ovarian cancer risk of 23.9% (95% CI, 20.7-27.4). At age 75 years, the residual risk of ovarian cancer was estimated to be 8.4% (95% CI, 1.7-22.7) for a BRCA1 carrier and 3.7% (95% CI, 0.1-22.7) for a BRCA2 carrier.

Conclusions and Relevance The residual risk of ovarian cancer for older women in good health is sufficiently high to consider preventive surgery. BRCA1 carriers who defer BSO until age 50 years may face a substantial risk of developing ovarian cancer.

Author/s:

Vasily Giannakeas, PhD, Adriana I. Apostol, MD, Claudia Diella, et al.

Quick Uptakes: Taking the Uncertainty Out of Interpreting BRCA Variants

Jeffrey Wilson — Thu, 21 Mar 2019 17:46:06 +0000

Date Added:

March 21, 2019

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

March 20, 2019

URL:

Quick Uptakes: Taking the Uncertainty Out of Interpreting BRCA Variants

Type:

Clinical Decision Aids

Format:

Article

DOI (1):

10.1001/jama.2019.0967

Keywords

BRCA

BRCA variants

PMID (1):

30892570

MeSH

Genes, BRCA2

BRCA2 protein

BRCA1 protein

For those who are trying to answer patients’ questions about BRCA variants, there’s a free app for that (BRCA Exchange). James W. Mold, MD, MPH

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The Problem

Testing for BRCA1 and BRCA2 mutations identifies both benign and pathogenic genetic variants. But information about specific variants, particularly those of uncertain clinical significance (VUS), often isn’t systematically curated, expertly reviewed, or easily searchable. In addition, different laboratories sometimes interpret test results differently.

Downstream Risk

Some patients whose variants don’t have a clear clinical meaning might seek or receive unnecessary care.

Statistically Speaking

About 3% of BRCA1 and BRCA2 findings on genetic tests are VUS. An estimated 15% to 20% of them are likely to be disease causing. As more people undergo genetic testing, clinicians will continue to see VUS.

Strategic Move

The Global Alliance for Genomics and Health in 2014 decided that “big data” could shine a spotlight on VUS in BRCA1 and BRCA2 genes. Plans emerged to launch an international effort aimed at creating a 1-stop shop to share information about BRCA1 and BRCA2 variants.

The Solution

Instead of wading through many databases with information that sometimes hasn’t been properly vetted, the BRCA Exchange was created as a central repository for expertly reviewed genetic variation data. It’s a web portal containing information from clinicians, clinical laboratories, and researchers around the world as well as existing clinical databases, including:

ClinVar, a publicly available archive of genetic variants and their association with human phenotypes.
Breast Cancer Information Core, an open access breast cancer mutation database.
Leiden Open Variation Database—an open source database of gene variants.

Currently, the BRCA Exchange includes more than 20 000 unique BRCA1 and BRCA2 variants. The international Evidence-based Network for the Interpretation of Germline Mutant Alleles consortium provides expert classification of more than 6100 of those variants. So far, 3700 are classified as pathogenic.

Author/s:

Voelker, Rebecca