Germline Testing and Somatic Tumor Testing forBRCA1/2Pathogenic Variants in Ovarian Cancer: What Is the Optimal Sequence of Testing?

Abstract

PURPOSE In 2020, ASCO recommended that all women with epithelial ovarian cancer have germline testing for BRCA1/2 mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing to determine eligibility for a poly (ADP-ribose) polymerase inhibitor. Consequently, the majority of patients with ovarian cancer will have both germline testing and somatic testing. An alternate strategy is tumor testing first and then germline testing if there is a PV in the tumor and/or significant family history. The objective was to conduct a cost-effectiveness analysis comparing the two testing strategies. METHODS The Markov model compared the costs (US dollars) and benefits of two testing strategies for newly diagnosed ovarian cancer: (1) ASCO strategy and (2) tumor testing triage for germline testing. Data were applied from SOLO-1, and costs were from wholesale acquisition prices, Medicare, and published sources. Sensitivity analyses accounted for uncertainty around various parameters. Monte Carlo simulation estimated the number tested and identified with germline and somatic BRCA PV for olaparib maintenance treatment annually in the US population. RESULTS The ASCO strategy was more effective but more costly than tumor testing triage in identifying patients for olaparib, with an incremental cost-effectiveness ratio of $281,296 US dollars per progression-free life year gained. Assuming 10,000 eligible patients with ovarian cancer annually, Monte Carlo simulation yielded comparable numbers of patients with BRCA PV in the germline and tumor with the ASCO and tumor testing triage strategies (2,080 v 2,062, respectively), but substantially higher number of patients tested using the ASCO strategy (8,052 v 3,076). CONCLUSION The ASCO strategy may identify more BRCA PVs but is not cost-effective. Tumor testing in epithelial ovarian cancer as triage for germline testing is the favored strategy in this health care system.

Hereditary cancer predispositions: Comparison of multigene panel sequencing on fresh‐frozen breast/ovarian tumor versus blood

“…Moreover, PPV was relatively low in our study (60%), although it was overestimated because we selected only patients with true gPV. This observation raises an issue for proposed tumor‐first strategies to diagnose gPV 3,12 . To keep a high sensitivity, laboratories should perform a large number of confirmation tests on blood to diagnose few true gPV.…”

“…This observation raises an issue for proposed tumor-first strategies to diagnose gPV. 3,12 To keep a high sensitivity, laboratories should perform a large number of confirmation tests on blood to diagnose few true gPV.…”

Real-World Concordance between Germline and Tumour BRCA1/2 Status in Epithelial Ovarian Cancer

“…The implementation of mainstream BRCA1/2 testing for patients diagnosed with epithelial ovarian cancer occurred due to the development of PARPi as standard therapy. Tumour and germline BRCA1/2 testing can be performed in parallel (i.e., together) or sequentially (i.e., germline-first then tumour, or tumour-first then germline) [ 27 , 28 ]. In the parallel model of testing, germline (often blood) and tumour DNA are tested for all patients, regardless of the result of each test.…”

Patient‐reported outcomes associated with reflex BRCA1/2 tumor and subsequent germline panel genetic testing for high‐grade serous ovarian cancer

“…While the number of individuals in this study is too small to make meaningful conclusions, it is interesting to note that individuals who received positive tumor itive results have germline testing) models of care. In their analysis, the germline-first strategy was more effective in identifying individuals with a PV in BRCA1/2; however, was not cost-effective and required testing a substantially higher number of patients (Kwon et al, 2022).…”