Abstract 2061: Investigation of PALB2 mutation & correlation with immunotherapy biomarker in Chinese non-small cell lung cancer patients

Abstract

Abstract Background: PALB2, a gene in the homologous recombination repair (HRR) pathway, has been shown to be associated with the efficacy of platinum based chemotherapy, immunotherapy and PARP inhibitor therapy in several tumors. In addition, the role of germline PALB2 pathogenic variants as a major susceptibility gene has been reported in breast, ovarian, and pancreatic cancers. However, the PALB2 characteristics, its correlation with immunogenic marker, and the predictive value of immunotherapy in non-small cell lung cancer (NSCLC) was unknown. Methods: Tumor tissue samples from Chinese NSCLC were analyzed using next generation sequencing (NGS) (panel on 381/733-gene). TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Two independent cohorts (the OAK and POPLAR study cohort) with data from 429 patients, and one cohort (Rizvi2018.NSCLC.240.NGS cohort) with data from 240 patients with advanced NSCLC, were used to analyze the prognostic effect of PALB2 on immunotherapy. Result: Genetic mutation of 5227 NSCLC patients were analyzed using NGS, of which 162 (3.1%) harbored germline PALB2 mutation (PALB2gmut) and 87 (1.66%) harbored somatic PALB2 mutation (PALB2smut). In NSCLC patients with PALB2gmut, the most frequently mutated genes were TP53 (65%), followed by CYP2C19 (51%), DPYD (45%), RAC1 (45%), VEGFA (44%), EGFR (43%), MGMT (42%) and CD74 (40%). The mutation frequency of TP53 was highest in NSCLC with PALB2smut (64%), followed by CYP2C19 (47%), UGT1A1 (38%), RAC1 (36%), VEGFA (36%), CD74 (36%), EGFR (30%), and LRP1B (30%). PALB2smut (14.52 Muts/Mb) was associated with higher TMB (P < 0.001) than PALB wild-type (PALB2wt) (6.15 Muts/Mb). But there was no significant difference on TMB between PALB2gmut (6.45 Muts/Mb) and PALB2wt (6.15 Muts/Mb) (P=0.64). There was no difference in PD-L1 expression among PALB2gmut, PALB2smut, and PALB2wt. No correlation was found with PD-L1 expression. In Rizvi2018.NSCLC.240.NGS cohort, there was no difference on progression-free survival (PFS) (HR =1.06, P=0.93) between PALB2 mutation (3.15 months) and PALB2wt (3.17 months). The OAK and POPLAR study cohort of NSCLC patients showed that there was no difference on overall survival (OS) (HR =1.1, P=0.75) between PALB2 mutation (10.38 months) and PALB2wt (11.07 months). Conclusions: These findings suggest that PALB2 may not be used as a biomarker for determining prognosis on immunotherapy in NSCLC. Citation Format: Xiangyang Cheng, Yating Zheng, Wenzhuan Xie, Mengli Huang. Investigation of PALB2 mutation & correlation with immunotherapy biomarker in Chinese non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2061.