Universal tumor DNA BRCA1/2 testing of ovarian cancer: prescreening PARPi treatment and genetic predisposition.

Vos JR1, Fakkert IE1, de Hullu JA2, van Altena AM2, Sie AS1, Ouchene H1, Willems RW3, Nagtegaal ID3, Jongmans MCJ1, Mensenkamp AR1, Woldringh GH1, Bulten J3, Leter EM4, Kets CM1, Simons M3, Ligtenberg MJL1,3, Hoogerbrugge N1.

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Abstract

BACKGROUND:

Women with epithelial ovarian cancer (OC) have a higher chance to benefit from PARP 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 prescreen for PARPi treatment and cancer predisposition testing.

METHODS:

Formalin fixed paraffin embedded (FFPE) 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% 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.