Clinical outcome of patients with early stage and metastatic non-small cell lung cancer (NSCLCa) harboring high genomic scarring score (GSS)

Background: DNA damage and genomic instability represent hallmarks of cancer. Tumors with defects in repairing double strand breaks have been shown to respond to platinum compounds, immune checkpoint inhibitors (ICI) and PARP inhibitors. We have previously reported that 28% of early-stage Non-Small Cell Lung Cancer (NSCLC) patients present high Genomic Scarring Score (h-GSS), an indicator of genomic instability, while patient-derived xenografts from those patients respond favorably to olaparib. The aim of this study was to investigate the immune landscape of h-GSS early-stage and metastatic NSCLC patients, and to assess their clinical outcome. Material and Methods: Sixty-seven (early stage I-III) and 52 (stage IV) patients with no actionable genomic alteration were enrolled in the study. Their GSS was assessed using a commercial panel (AmoyDx® HRD Complete), which also identifies mutations in 20 homologous recombination repair (HRR) genes. PD-L1 expression (tumor proportion score-TPS) and early and late exhausted (TCF1 + PD1 + and TCF1 - PD1+, respectively) CD8 + cells were assessed using immunohistochemistry. All patients with early-stage disease received platinum-based adjuvant chemotherapy while stage IV patients received immunotherapy-based regimens. Results: h-GSS was detected in tumors from 28/67 (41.8%) patients with stage I-III NSCLC and in 16/52 (30.8%) with stage IV. TP53 mutations ( TP53mut) were observed in 27/28 (96.4%) and 22/39 (56.4%) of stage I-III h-GSS and l-GSS tumors, respectively (p<0.001), and in 12/16 (75.0%) and 15/34 (44.1%) of h-GSS and l-GSS tumors stage IV tumors, respectively (p=0.067). Early-stage but not stage IV TP53 mut patients presented a better DFI and OS, compared to wild-type TP53 tumors (p=0.002 and 0.026, respectively). Early-stage h-GSS/TP53mut and l-GSS/TP53mut patients had better DFI (p=0.012 and p=0.002, respectively) compared to l-GSS/ TP53 wt counterparts, whereas only the h-GSS/ TP53 mut status was associated with a better OS (p=0.031). PD-L1 expression in l-GSS but not in h-GSS stage IV tumors was associated with a significantly better OS (HR=0.2, 95%CI: 0.1-0.6, p=0.009). Finally, there was a statistical trend towards an increased density of both PD1+TCF1+ (0.067) and PD1+TCF1- (0.054) exhausted tumor-infiltrating lymphocytes in h-GSS compared to l-GSS tumors in patients with stage IV disease. Conclusions: The findings of this study clearly suggest that genomic instability in NSCLC, as assessed by GSS, could become an important tool for better stratification of patients regarding prognosis and treatment choice.