A commentary on the discrepancy between blood and tumor BRCA testing: an open question

Abstract

Molecular evaluation of BRCA1/2 (BRCA ) genes represents a well-known example of precision oncology. The availability of Poly ADP Ribose Polymerase inhibitors (PARPi) as target therapy option for several BRCA mutated cancers types (e.g. ovarian, breast, prostate, and pancreatic) 1 changed the course ofBRCA testing over the last years. In this context, an emerging path of molecular evaluation is represented by the BRCA testing performed directly on tumor tissue (tBRCA ): this increased the chance to identify more patients with higher likelihood of benefiting from PARPi treatment. This approach leads to the simultaneous identification of both constitutional and somatically acquired variants, with a lower turnaround time: the identification of BRCApathogenic variants (PVs) could lead to a secondary "reflex" germlineBRCA (gBRCA) testing in order to assess personal and familiar risks. In contrast, performing gBRCA as first molecular test causes the loss of a relevant proportion of patients with tissue acquired BRCA PVs, needing of a following tumor test 2;3 . However, challenges exist in tBRCA that may lead to inefficient germline variant call. A recently published paper by Kordes et al. reported a pancreatic adenocarcinoma patient with a germlinenovel BRCA2 c.516+4A>G variant classified as deleterious by the authors based on in silico and functional data 4 . Also the tumor tissue was sequenced in order to achieve the enrolment criteria for a clinical trial of Olaparib in