Ross, Jeffrey S.

PURPOSE We sought to characterize outcome associations of poly ADP-ribose polymerase inhibitors (PARPi) in patients with ovarian cancer (OVCA) whose cancers contain homozygous loss (deletions) of homologous recombination repair (HRR) pathway genes, an alteration class not uniformly reported on clinical testing and not susceptible to acquired resistance via secondary reversion mutations. METHODS This study used US-based deidentified Flatiron Health-Foundation Medicine OVCA Clinico-Genomic Database. Patients with advanced OVCA and genomic profiling by Foundation Medicine were assembled into cohorts evaluating PARPi monotherapy use, and separately, PARPi maintenance therapy use, with outcomes associated with HRR gene alterations: BRCA1 / 2 , PALB2 , RAD51B/C/D , BARD1 , and BRIP1 . RESULTS 1.5% (82/5,404) had HRR gene homozygous loss, with BRCA1 and BRCA2 loss being most common. Among all OVCAs with BRCA1/2 alterations, 7.5% (63/836) were homozygous losses. Most BRCA1 (34/38, 89%) and BRCA2 (18/25, 72%) homozygous losses were intragenic, with breakpoints not spanning entire gene. Maintenance cohort: 22 patients had HRR gene homozygous loss, with strongly improved progression-free survival (PFS) for PARPi versus no PARPi use (HR, 0.06, 95% CI, 0.01 to 0.37). Monotherapy cohort: patients without HRR alterations (n = 198), HRR mutations or rearrangements (n = 93), and HRR homozygous loss (n = 8) had median PFS of 4.9, 10.6, and 25.4 months, and median overall survival of 18.5, 22.5, and 51.8 months, respectively. CONCLUSION We observe durable PARPi effectiveness for patients with OVCA and HRR gene homozygous loss in routine practice. We demonstrate the importance of detecting and reporting homozygous loss in HRR genes, an aspect not standard to all sequencing assays.

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is largely considered a nonimmunogenic malignancy; however, approximately 1%, of patients may have tumors with deficient mismatch repair, high microsatellite instability, or high tumor mutational burden (TMB ≥10 mutations/Mb), which may be predictive of response to immune checkpoint inhibitor (ICI) therapy. We sought to analyze outcomes of patients with high-TMB and pathogenic genomic alterations observed in this population. METHODS This study included patients with PDAC who underwent comprehensive genomic profiling (CGP) at Foundation Medicine (Cambridge, MA). Clinical data were obtained from a US-wide real-world clinicogenomic pancreatic database. We report genomic alterations in those with high and low TMB, and compare outcomes on the basis of receipt of single-agent ICI or therapy regimens not containing ICI. RESULTS We evaluated 21,932 patients with PDAC who had tissue CGP data available, including 21,639 (98.7%) with low-TMB and 293 (1.3%) with high-TMB. Among patients with high-TMB, a greater number of alterations were observed in BRCA2, BRAF, PALB2, and genes of the mismatch repair pathway, whereas fewer alterations were observed in KRAS. Among patients who received an ICI (n = 51), those with high-TMB had more favorable median overall survival when compared with the low-TMB subset (25.7 v 5.2 months; hazard ratio, 0.32; 95% CI, 0.11 to 0.91; P = .034). CONCLUSION Longer survival was observed in patients with high-TMB receiving ICI compared with those with low-TMB. This supports the role of high-TMB as a predictive biomarker for efficacy of ICI therapy in PDAC. Additionally, we report higher rates of BRAF and BRCA2 mutations and lower rates of KRAS mutation among patients with PDAC and high-TMB, which to our knowledge, is a novel finding.