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  • Calpain Inhibitor I ALLN a Department of Obstetrics and Gyne


    a Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
    b Department of Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada
    c Hereditary Cancer Program, BC Cancer Agency, Vancouver, BC, Canada
    • Women with high-grade serous ovarian cancer (HGSC) have a 20% risk of carrying a BRCA mutation.
    • Many women with HGSC are untested for BRCA mutations, and their first-degree relatives may be ineligible for BRCA testing.
    • BRCA testing for first-degree relatives of women with HGSC is cost-effective when BRCA status is unknown.
    • BRCA testing with subsequent risk-reducing surgery is more effective and less costly than surgery alone.
    Article history:
    Ovarian cancer, high-grade serous carcinoma
    BRCA mutation
    First-degree relatives
    Risk-reducing bilateral salpingo-oophorectomy (RRBSO) 
    Background. Women with high-grade serous ovarian cancer (HGSC) have a 20% chance of carrying a BRCA1 or 2 mutation. Not all undergo genetic testing, and there is a large legacy group of untested patients. Their female first-degree relatives (FDR) may not qualify for testing unless they have specific ethnicity, or personal/family can-cer history. We conducted a cost-effectiveness analysis to evaluate risk-reducing strategies for these FDR who are ineligible for testing.
    Methods. A Markov Monte Carlo simulation model estimated the costs and benefits of 3 strategies for female FDR of HGSC patients whose BRCA status is unknown: (1) no BRCA testing; (2) universal BRCA testing, followed by risk-reducing bilateral salpingo-oophorectomy (RRBSO) for Calpain Inhibitor I ALLN carriers; (3) universal RRBSO, without BRCA testing. Effectiveness was estimated in quality-adjusted life year (QALY) gains over a 50-year time horizon. Sensitivity analyses accounted for uncertainty around various parameters.
    Results. Universal BRCA testing for female FDR of women with HGSC yielded a higher average QALY gain at acceptable cost compared to no BRCA testing, with an incremental cost-effectiveness ratio of $7888 per QALY. Universal BRCA testing was more effective and less costly than universal RRBSO (19.20 QALYs vs. 18.52 QALYs, and $10,135 vs. $14,231, respectively). Results were stable over wide ranges of plausible costs and estimates. Compliance with hormone replacement therapy had to exceed 79.3% for universal RRBSO to be the most effective strategy.
    Conclusion. BRCA mutation testing should be offered to all female first-degree relatives of women with high-grade serous ovarian cancer when BRCA mutation status is unknown. © 2018 Elsevier Inc. All rights reserved.
    1. Introduction
    Women with high-grade serous ovarian carcinoma (HGSC), the most common epithelial ovarian cancer, are usually diagnosed at an ad-vanced stage and have a poor prognosis. These women have about a 20%
    Corresponding author at: University of British Columbia, 2775 Laurel Street, 6th Calpain Inhibitor I ALLN Floor, Vancouver, BC V5Z 1M9, Canada.
    chance of carrying a mutation in BRCA1 or BRCA2 (herein BRCA1/2), ir-respective of family history or ethnicity [1,2], and in many jurisdictions around the world, they are all eligible for BRCA mutation testing [3]. When BRCA mutation carriers are identified, genetic counseling and testing can be extended to relatives, with the goal of identifying unaf-fected carriers and when appropriate, offering them highly effective surgery and other interventions to reduce their cancer risks. However, for a variety of reasons, not all eligible women undergo genetic testing, eliminating the opportunity to identify unaffected carriers. Furthermore,
    there is a large legacy group of women with HGSC who never had the opportunity to undergo BRCA mutation testing, which translates into thousands of untested ovarian cancer patients who may have surviving first-degree relatives (FDR) at risk of carrying a BRCA1/2 mutation. These FDR are not always eligible for BRCA mutation testing unless they have a personal history of cancer, there are other family members diagnosed with ovarian or breast cancer, or they have Ashkenazi Jewish or other specific heritage [4]. Without genetic testing, some of these FDR of HGSC patients are being referred for elective surgery (bilateral salpingo-oophorectomy) to avert the diagnosis of ovarian cancer. While this may be a sensible decision for an individual, on a population level, elective risk-reducing surgeries are best applied to the highest risk individuals, i.e. those with BRCA1/2 germline mutations, especially when considering the adverse effects of poorly managed surgically-induced early menopause.