Investigation of PALB2 Mutation and Correlation With Immunotherapy Biomarker in Chinese Non-Small Cell Lung Cancer Patients

Abstract

BackgroundPALB2, a gene in the homologous recombination repair (HRR) pathway of the DNA damage response (DDR), is associated with the efficacy of platinum-based chemotherapy, immunotherapy, and PARP inhibitor therapy in several tumors. However, the PALB2 characteristics, its correlation with immunotherapy biomarker, and the prognostic effect of immunotherapy in non-small cell lung cancer (NSCLC) were unknown.MethodsTumor tissue samples from advanced Chinese NSCLC patients were analyzed by next-generation sequencing (NGS) (panel on 381/733-gene). Tumor mutation burden (TMB) is defined as the total number of somatic non-synonymous mutations in the coding region. Microsatellite instability (MSI) was evaluated by NGS of 500 known MSI loci. Programmed Cell Death-Ligand 1 (PD-L1) expression was evaluated using immunohistochemistry (Dako 22C3 or SP263). One independent cohort (Rizvi2018.NSCLC.240.NGS cohort) containing genomic and clinical data from 240 patients with advanced NSCLC and two cohorts (the OAK and POPLAR study cohort) containing genomic and clinical data from 429 patients with advanced NSCLC were used to analyze the prognostic effect of PALB2 on immunotherapy.ResultsGenetic mutation of 5,227 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 and PALB2smut, the most frequently mutated gene was TP53 (65%, 64%). PALB2smut (14.52 Muts/Mb) was associated with higher TMB (p < 0.001) than PALB wild-type (PALB2wt) (6.15 Muts/Mb). However, there was no significant difference in 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. In the Rizvi2018.NSCLC.240.NGS cohort, there was no difference in 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 in overall survival (OS) (HR =1.1, p = 0.75) between PALB2 mutation (10.38 months) and PALB2wt (11.07 months).ConclusionsThese findings suggest that PALB2 may not be used as a biomarker for determining prognosis on immunotherapy in NSCLC.

DNA damage response and repair gene mutations are associated with tumor mutational burden and outcomes to platinum-based chemotherapy/immunotherapy in advanced NSCLC patients

“…PALB2 is a gene in the homologous recombination repair (HRR) pathway. Jiexia Zhang et al showed that it may not be a promising prognosis predicator on immunotherapy [20]. DDR pathway alterations in SCLC had limited predictive value for platinum efficacy [21].…”

Biomarkers for Immunotherapy in Driver-Gene-Negative Advanced NSCLC

“…In patients with STK11 or KEAP1 mutations, atezolizumab yielded benefits in mOS compared to docetaxel (7.3 vs. 5.8 mo, adjusted HR 0.70; 95% CI 0.49-0.99), especially in SKmut (STK11-or KEAP1-mutated) patients with FAT3 mutation (HR = 0.06, 95% CI 0.01-0.60) [74]. EPHA mutation was significantly correlated with worse efficacy (p = 0.0186) [75], while PALB2 mutation did not correlate with efficacy of immunotherapy (HR = 1.1, p = 0.75) in the POPLAR and OAK cohorts [76]. Consistent with previous findings, a 5-genomic mutation signature composed of CREBBP, KEAP1, RAF1, STK11, and TP53 mutations was discovered to be more significantly correlated with OS than bTMB score and PD-L1 [77].…”

miR-140-3p enhances the sensitivity of LUAD cells to antitumor agents by targeting the ADAM10/Notch pathway

“…Furthermore, NSCLC is the most important type of lung adenocarcinoma, making lung adenocarcinomarelated research important [3][4][5][6]. Currently, antitumor drug treatments for lung adenocarcinoma mainly include various small molecule protein kinase inhibitors and cytotoxic chemotherapeutics [7][8][9][10][11][12].…”

“…Furthermore, NSCLC is the most important type of lung adenocarcinoma, making lung adenocarcinoma-related research important 3 - 6 . Currently, antitumor drug treatments for lung adenocarcinoma mainly include various small molecule protein kinase inhibitors and cytotoxic chemotherapeutics 7 - 12 . Although these drugs or drug combinations are believed to prolong the lives of patients and improve their quality of life, there are still many shortcomings: (1) the sensitivity of patients to these antitumor drugs is purely individual 13 - 15 ; (2) antitumor drug treatment is prone to drug resistance 13 - 15 ; and (3) the side effects of antitumor drug treatment are very serious 16 .…”