4P Mutational landscape of ovarian cancer patients (pts) by homologous recombination deficiency (HRD) status

Concomitant assessment of HRD and BRCA1/2 status provides critical information on platinum and poly-ADP ribose polymerase inhibitors (PARPi) sensitivity. HRD tests, in addition to evaluating genomic scars, can provide information on potential targetable genes. We included 75 pts with high-grade serous ovarian cancer from Area Vasta Romagna (AVR). The DNA obtained from FFPE tissue samples of patients were processed using the SOPHiA HRD Solutionenrichment protocol (SOPHiA GENETICS, Saint-Sulpice, Switzerland). Sequencing was performed through the NextSeq500/550 sequencer platform (Illumina) and output files (FASTQ) were uploaded on the SOPHiA DDM Platform for the analysis. Sequencing results included SNP/INDEL and gene amplifications of 28 targeted genes, BRCA status and a HRD value, obtained by combining BRCA status with genomic integrity (GI) index. Among our 75 patients (median age 67, range 36-88), 6 pts were BRCA1 mutated (7.9%) and 9 pts were BRCA2 mutated (11.8%). BRCA variants with uncertain significance (VUS) were found in 14 pts, 7 for both BRCA1 and BRCA2 (9.2% for each). Of these, 3 pts (21.4%) were HRD positive, 5 pts (35.7%) were HRD negative, and 5 pts (35.7%) were HRD indeterminate. Among 47 (61.8%) BRCA WT pts, 15 pts (20%) were HRD positive, 34 pts (45.3%) were HRD negative and for 10 pts (13.3%) HRD status was not evaluable. In the BRCA WT HRD negative group, 14 pts (41.2%) harbored at least one other mutation, with the most frequent alteration in PIK3CA (20.6%), BARD1 (17.7%), RAD51B (11.8%) and FANCA (8.8%). In the BRCA WT HRD positive group, 8 pts (44.4%) had at least one other mutation, most frequently BRIP1 (25%) and RAD51B (25%). In the BRCA mutated group, 6 pts (40%) harbored at least one other mutation, most frequently RAD51B (26.7%), FANCD2 (20%) and BARD1 (13.3%). Our test is able to discriminate HRD status in the vast majority of our patients with low number of indeterminate pts. BRCA1/2 VUS does not correlate with HRD status. Interestingly, PIK3CA mutations were found only in the HRD negative group, given the rationale for considering PIK3CA inhibitors (alone or in combination) as an investigational therapy for this population.