Universal Tumor DNA BRCA1/2 Testing of Ovarian Cancer: Prescreening PARPi Treatment and Genetic Predisposition

Abstract

Background Women with epithelial ovarian cancer (OC) have a higher chance to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as a prescreen for PARPi treatment and cancer predisposition testing. Methods Formalin-fixed paraffin-embedded tissue was obtained from OC patients in seven hospitals immediately after diagnosis or primary surgery. DNA was extracted, and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated. Results Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients, pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% of patients. Participating gynecologists and patients were overwhelmingly positive about the workflow. Conclusions Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective, and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.

Year 1: Experiences of a tertiary cancer centre following implementation of reflex BRCA1 and BRCA2 tumor testing for all high-grade serous ovarian cancers in a universal healthcare system

“…In addition to the requirement of germline testing to discern whether a BRCA1/2 PV identified through tumor testing is germline or somatic in origin, continued germline testing of all cases of HGSOC remains essential as previous research has shown that inherited PVs in at least 7 genes confer a ≥ 5-fold risk of ovarian cancer [29]. Several groups have suggested that tumor results can be used to limit the number of genetics referrals for HGSOC patients by referring only those with an identified PV on tumor tissue or a suggestive clinical/family history [22,25,26]; however, a study of 7768 ovarian cancer cases found negative family history did not significantly alter ovarian cancer risk ratios, and the frequency of non-BRCA1/2 PVs increased among patients with an older age at diagnosis [29]. PVs in these non-BRCA1/2 ovarian cancer risk genes will be missed via Ontario's current targeted tumor testing, but are routinely analyzed during germline multi-gene panel testing.…”

“…Tumor testing has been used by others to preserve scarce genetic counseling and testing resources by identifying the subset of HGSOC patients who warrant germline testing. For example, in a feasibility study of universal BRCA1/2 tumor testing for all newly diagnosed ovarian cancer patients in the Netherlands, Vos et al reported a 38.7% reduction in the number of required genetic tests, compared to germline-first models [25]. Yet, to provide a comprehensive assessment of hereditary cancer risk, such patient care algorithms should only be implemented when tumor testing includes analysis of all genes relevant to hereditary ovarian cancer risk.…”

“…While tumor testing will detect both germline and somatic PVs, additional germline testing is required to determine whether any identified PV confers a hereditary cancer risk. Some groups have suggested that tumor results could be used to triage genetics referrals, whereby germline testing would only be offered to the subset of HGSOC patients with a PV identified via tumor testing [22,25,26]. This may be particularly useful in countries where patients are required to pay for genetic testing, or where insurance coverage for genetic testing may be limited; however, in Ontario, both tumor and germline genetic testing for HGSOC patients is funded through a universal healthcare system.…”

Patterns and predictors of genetic referral among ovarian cancer patients at a National Cancer Institute‐Comprehensive Cancer Center

“…19 Pilot testing has found somatic GT to be feasible, effective, and acceptable to patients and providers. 20 multiple institutions is needed to validate the predictors identified here. Future work should prospectively identify factors that will further enhance our current understanding, ultimately improving quality of care for OVCA patients.…”

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

“…Under current guidelines, women presenting with breast or ovarian tumors are routinely tested for hereditary mutations in BRCA1/2 and this guides whether they are treated with PARP inhibitors. A recent study showed that over 40% of BRCA1/2 mutations were somatic, suggesting that the tumors should also be tested, to identify more patients that would benefit from PARP inhibitor treatment (Vos et al, 2020. ) However, growing evidence suggests that BRCA1/2 mutational status does not always accurately correlate with PARPi sensitivity (Jonsson et al, 2019) and there is a need to find more accurate predictive PARPi biomarkers.…”