Germline testing and somatic tumor testing for BRCA1/2 pathogenic variants in ovarian cancer: What is the optimal sequence of testing?

person Janice S. Kwon University of British Columbia, Vancouver, BC, Canada info_outline Janice S. Kwon, Anna Tinker, Jennifer Santos, Katie Compton, Sophie Sun, Kasmintan A. Schrader, Aly Karsan

Authors person Janice S. Kwon University of British Columbia, Vancouver, BC, Canada info_outline Janice S. Kwon, Anna Tinker, Jennifer Santos, Katie Compton, Sophie Sun, Kasmintan A. Schrader, Aly Karsan Organizations University of British Columbia, Vancouver, BC, Canada, British Columbia Cancer Agency, Vancouver, BC, Canada, BC Cancer, Vancouver, BC, Canada, BC Cancer Agency, Vancouver, BC, Canada, British Columbia Cancer Research Centre, Vancouver, BC, Canada Abstract Disclosures Research Funding Other Foundation Michael Smith Foundation for Health Research, Pharmaceutical/Biotech Company Background: In 2020 ASCO recommended that all women with epithelial ovarian cancer have germline testing (GT) for BRCA1/2 mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing (TT), to determine eligibility for PARP inhibitor (PARPi) therapy (GT-TT strategy). An alternate strategy is to start with tumor testing first, and to conduct germline testing only in those with a PV in the tumor, or a significant family history (TT-GT strategy). The objective was to conduct a cost-effectiveness analysis comparing the 2 testing strategies. Methods: A Markov Monte Carlo simulation model compared the costs (USD) and benefits of the 2 testing strategies. According to local empiric data, a sufficient tissue sample for TT was available in 99% of cases, otherwise the patient would only have GT. Sensitivity of TT was 99% for detecting germline PV. Only those with BRCA1/2 PV were eligible for PARPi. Primary outcomes included the number of women eligible for PARPi, with progression-free years of life (PFLY) gained based on SOLO1 data, and the incremental cost-effectiveness ratio (ICER). Monte Carlo simulation estimated the number of women who would have GT and TT, and the total with germline or somatic BRCA1/2 PV eligible for PARPi. Sensitivity analyses accounted for uncertainty around various parameters. Results: The GT-TT strategy was more effective but more costly than TT-GT in identifying patients eligible for PARPi. Table summarizes the average lifetime costs, benefits, and Monte Carlo simulation estimates for 10,000 women diagnosed with advanced epithelial ovarian cancer annually in the USA. The incremental benefit from the GT-TT strategy would be achieved at substantial cost to the health care system, with an ICER of $119,340 per PFLY gained relative to the TT-GT strategy. The results were highly sensitive to the sensitivity of TT to detect germline PV, and the costs of GT and TT. Assuming that GT was less than 50% of the cost of TT, the sensitivity of TT had to exceed 98% for the TT-GT strategy to be cost-effective. Conclusions: Although the ASCO recommended strategy of BRCA germline testing followed by tumor testing for those without a pathogenic variant may be more effective in identifying ovarian cancer patients for PARP inhibitor therapy, it is more costly. The ASCO strategy is justified if the sensitivity of tumor testing is not sufficiently high. However, assuming high tumor testing performance rates, tumor testing first followed by germline testing if there is a PV in the tumor and/or family history is a cost-effective strategy. TT-GT GT-TT Average lifetime outcomes Cost $109,730 $111,115 Incremental cost - $1,384 Effectiveness (PFLY) 2.684 2.6956 Incremental benefit - 0.0116 ICER - $119,340 Monte Carlo simulation (n=10,000) Tumor testing 9902 8021 Germline testing 2748 10,000 Eligible for PARPi 2178 2197 Germline BRCA PV identified 1884 1898