Prognostic and predictive implications of tumor suppressor gene alterations in non-small cell lung cancer

: In addition to identifying alterations suitable for molecularly targeted therapy (TT), comprehensive genomic profiling (CGP) may convey prognostic/predictive information in advanced non-small-cell lung cancer (aNSCLC). We investigated the impact of tumor suppressor gene alterations (TSGAs) on aNSCLC patients' outcome in a real-world setting. The IMMINENT clinical-genomic database, which provides data on molecular and clinico-pathological features, treatment history, and patients' outcomes of aNSCLC patients who underwent CGP using tissue- or blood-based next-generation sequencing (NGS) between May 2019 and November 2022 was interrogated to assess overall (OS) and progression-free survival (PFS). The Cox proportional hazard model was used to assess the prognostic and predictive role of genomic features. Two hundred and one patients were included in the analysis. Genomic alterations in STK11, KEAP1, and MYC were associated with poorer OS, while ALK alterations were associated with better OS; after adjustment, STK11 and KEAP1 alterations retained their independent negative prognostic impact. Moreover, KRAS:STK11 and KRAS:KEAP1 co-mutations cooperated to negatively influence OS. In terms of predictive performance, CDKN2A/B alterations predicted worse PFS on chemotherapy (CT) and TP53 alterations predicted worse PFS on TT, while both CDKN2A/B and TP53, as well as KRAS, alterations predicted better PFS on immunotherapy (IO). Extended CGP, encompassing TSGAs, provides valuable prognostic and predictive insights for aNSCLC, thereby adding to the mere identification of potential targets for TT. Our findings also underline the complexity of the lung cancer molecular landscape and suggest the need for studying a personalized therapeutic approach in patients with TSGAs.