Genomic scarring score as a criterion for PARP inhibitor administration in early-stage NSCLC

BackgroundPARP inhibitors (PARPi) have shown clinical efficacy in tumors, germline or/and somatic BRCA1/2 mutations being valid biomarkers for patient selection. Although homologous recombination (HR) gene mutations have been described in NSCLC, the use of PARPi has not shown clinical benefit. However, patients with homologous recombination deficiency (HRD) could still be suitable candidates for PARPi.MethodsThe HR status of 136 early-stage NSCLC patients was assessed based on the genomic scarring score and mutation profile of HR genes (GSS; AmoyDx® HRD Complete Panel). The HR status was confirmed functionally by RAD51 staining of both primary tumor and patient-derived xenografts (PDX). The effect of CDDP and PARPi was assessed in high (h-GSS) and low (l-GSS) GSS PDXs.Results39/136 (28.7%) patients had GSS>50 (h-GSS) and were classified as HRD. Of the 8/136 (5.9%) with germ-line pathogenic/likely pathogenic (P/LP) HR gene mutations, only 3 were h-GSS. Conversely, somatic P/LP HR mutations were enriched in the h-GSS group compared to the n low GSS (l-GSS) group (14/39 vs 19/97, p=0.045). However, 9/19 (47.4%) HR gene-mutated l-GSS tumours scored <10, indicating the absence of any correlation between genomic instability and the HR gene mutational status. The prevalence of TP53 mutations was 94.9% and 51.5% in the h-GSS and l-GSS group, respectively (p<0.001), while the GSS was significantly (p<0.0001) associated with TP53 variant allele frequency (VAF). CDDP-induced DNA damage in h-GSS PDXs failed to increase the frequency of RAD51 foci in contrast to l-GSS PDXs. Consistently, CDDP-based adjuvant therapy resulted in a significantly better disease-free interval (DFI) in patients with h-GSS/TP53mut but not l-GSS/TP53wt tumors (p=0.012). Finally, h-GSS but not l-GSS PDXs responded to PARPi monotherapy as assessed by tumor growth inhibition.ConclusionsOur data indicate that a substantial portion of patients with NSCLC have HRD tumors, supporting the use of PARPi alone or in combination with other drugs, provided patients are selected on the basis of GSS rather than the presence of HR gene mutations.Legal entity responsible for the studyBiomedical Research Foundation of the Academy of Athens.FundingHorizon 2020, Grant agreement ID: 953234.DisclosureAll authors have declared no conflicts of interest.