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  • It would be valuable to know

    2020-08-18

    It would be valuable to know whether it is cost-effective to offer BRCA Calpain Inhibitor I ALLN testing to all first-degree relatives of women with HGSC, alive or deceased, whose BRCA mutation status is unknown. This question cannot be answered in the context of a clinical trial. The objective of this study was to conduct a cost-effectiveness analysis of BRCA mutation testing for first-degree relatives of women with ovarian cancer (HGSC) whose BRCA mutation status is unknown, and would not otherwise qualify for genetic testing.
    2. Materials and methods
    We developed a Markov Monte Carlo simulation model to estimate the costs and benefits of BRCA mutation testing in a hypothetical cohort of unaffected female first-degree relatives (FDR) of women with ovar-ian, fallopian tube or peritoneal high-grade serous carcinoma (HGSC). In this model, testing was offered to unaffected female FDR only, recog-nizing that these women could undergo risk-reducing interventions if proven to be BRCA mutation carriers. Although male relatives could have daughters who would benefit from testing and risk-reducing strat-egies, the benefit was measured in terms of life expectancy gain for the FDR being tested, and not second-degree relatives. This project was ex-empt from Research Ethics Board review, as no individual level data were used for this study. The model was populated with data from pub-lished sources, including the estimated BRCA mutation rate in HGSC pa-tients, breast and ovarian cancer risks according to BRCA mutation status, uptake of risk-reducing surgery, and use of hormone replace-ment therapy after surgery [5–9]. We applied Canadian health care costs from the Canadian Institute for Health Information [10], and the BC Medical Services Plan schedule for physician services [11]. We as-sumed that the female FDR in this model were currently ineligible for genetic testing, because they had no personal or family history of cancer, apart from the index case with ovarian cancer, and they were not of Ashkenazi Jewish ethnicity. Three strategies were compared: (1) no testing (reference strategy); (2) BRCA mutation testing for all, followed by risk-reducing surgery (bilateral salpingo-oophorectomy, with or without mastectomy and reconstruction) for confirmed mutation carriers (“universal BRCA testing”); and (3) risk-reducing bilateral salpingo-oophorectomy for all, without BRCA testing (“universal RRBSO”).
    The benefits of each risk-reducing strategy were calculated in terms of average discounted quality-adjusted life expectancy. Average discounted lifetime costs were estimated in Canadian dollars (CAD$) in the year 2018. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), defined as the additional cost divided by the incremental health benefit compared to an alternate strategy. If the ICER was less than $100,000 per year of life gained, the strategy would be considered cost-effective. According to the Panel on Cost-effectiveness in Health and Medicine, all costs and benefits were discounted at a rate of 3% per year. The model was programmed using decision analytic software from TreeAge Pro 2014 (Williamstown, MA). 
    We assumed that women entered the model at an average age of 40, they had not yet undergone a mastectomy or oophorectomy, and they had not yet been diagnosed with breast or ovarian cancer. Those who had BRCA mutation testing and were confirmed mutation carriers did not necessarily have immediate risk-reducing surgery, and they could choose to undergo risk-reducing bilateral salpingo-oophorectomy (RRBSO), with or without bilateral mastectomy and reconstruction. Those who underwent universal RRBSO had surgery upfront, which was accomplished as an outpatient laparoscopic procedure. Women would be advised of the risks of premature menopause after RRBSO, and the potential risks and benefits of hormone replacement therapy (HRT). Based on current estimates of compliance with HRT, 35% of those undergoing RRBSO would use HRT for up to 5 years after this pro-cedure [12–14]. The Markov model has various health states (at risk, un-dergoing risk-reducing surgery, being diagnosed with breast or ovarian cancer, dying of these cancers or other age-associated causes according to national Life Tables [15]). The basic framework for this model is illus-trated in Fig. 1. Women transition from one health Calpain Inhibitor I ALLN state to another ac-cording to probabilities governed by age, BRCA mutation status, and risk-reducing interventions. To calculate quality-adjusted life expec-tancy, utilities for various health states were included for post-surgery (RRBSO with or without mastectomy), depending on intraoperative and postoperative complications (including injury to bowel, bladder, ureters, hemorrhage, wound infection, bowel obstruction or ileus) [16], the use of HRT, as well as breast cancer and ovarian cancer, which were derived from published sources [17–24]. For those who un-dergo premenopausal RRBSO but do not use HRT, it was assumed there was an increased risk of mortality secondary to events from osteoporo-sis, coronary heart disease and stroke, based on estimates from the Nurses' Health Study [25]. The time horizon for this model was 50 years. Data for the base case of the model are provided in Table 1.