BRCA and Homologous Recombination Deficiency assessment on tissue and liquid biopsy: implementation of diagnostic algorithms for tailoring treatment

The aim of this study is to profile BRCA and other genes involved in homologous recombination (HR) by applying a combined somatic-germline approach where possible in a prospective series of metastatic FFPE breast, pancreatic and prostate cancer samples, in order to offer a therapeutic option with PARP inhibitors.This analysis allows to uncover the prevalence of BRCA1/2 mutations and HR-related genes in a real-world setting and to characterize these alterations in a patient population where PARPi is gaining momentum as an effective therapeutic option. With this study, patients with BRCA1/2 and HR mutations will then potentially be directed to study protocols investigating PARPi activity or to compassionate drug administration.

A second aim is to investigate primary and acquired resistance mechanisms to PARPi by profiling BRCA genes in plasma samples prospectively collected from patients with BRCA-mutant metastatic ovarian cancer treated with PARPi. To date, in fact, resistance mutations have been characterized in heterogeneous clinical settings, but their actual prevalence and evolution in patients undergoing standard platinum-based adjuvant chemotherapy + PARPi maintenance is still unknown. In this scenario, primary (before PARPi) and acquired (post-maintenance therapy) PARPi resistance mutations can be identified. This comparison will push us to adopt circulating tumor DNA (ctDNA) analysis in our routine clinical practice and potentially extended to other tumor types, such as prostate and pancreatic cancer, for which BRCA1/2 assessment is often based on original surgical specimens, due to the impossibility of obtaining additional recent tissue exposed to previous lines of systemic therapy.