AUTHOR=Zhang Jiexia , Tang Shuangfeng , Zhang Chunning , Li Mingyao , Zheng Yating , Hu Xue , Huang Mengli , Cheng Xiangyang 

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

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.742833

DOI=10.3389/fonc.2021.742833

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p><italic>PALB2</italic>, 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 <italic>PARP</italic> inhibitor therapy in several tumors. However, the <italic>PALB2</italic> characteristics, its correlation with immunotherapy biomarker, and the prognostic effect of immunotherapy in non-small cell lung cancer (NSCLC) were unknown.</p></sec><sec><title>Methods</title><p>Tumor 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 <italic>PALB2</italic> on immunotherapy.</p></sec><sec><title>Results</title><p>Genetic mutation of 5,227 NSCLC patients were analyzed using NGS, of which 162 (3.1%) harbored germline <italic>PALB2</italic> mutation (<italic>PALB2<sup>gmut</sup></italic>) and 87 (1.66%) harbored somatic <italic>PALB2</italic> mutation (<italic>PALB2</italic><sup>smut</sup>). In NSCLC patients with <italic>PALB2<sup>gmut</sup></italic> and <italic>PALB2<sup>smut</sup></italic>, the most frequently mutated gene was <italic>TP53</italic> (65%, 64%). <italic>PALB2<sup>smut</sup></italic> (14.52 Muts/Mb) was associated with higher TMB (<italic>p</italic> &lt; 0.001) than <italic>PALB</italic> wild-type (<italic>PALB2<sup>wt</sup></italic>) (6.15 Muts/Mb). However, there was no significant difference in TMB between <italic>PALB2<sup>gmut</sup></italic> (6.45 Muts/Mb) and <italic>PALB2</italic><sup>wt</sup> (6.15 Muts/Mb) (<italic>p</italic> = 0.64). There was no difference in PD-L1 expression among <italic>PALB2<sup>gmut</sup></italic>, <italic>PALB2<sup>smut</sup></italic>, and <italic>PALB2<sup>wt</sup></italic>. In the Rizvi2018.NSCLC.240.NGS cohort, there was no difference in progression-free survival (PFS) (HR =1.06, <italic>p</italic> = 0.93) between <italic>PALB2</italic> mutation (3.15 months) and <italic>PALB2<sup>wt</sup></italic> (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, <italic>p</italic> = 0.75) between <italic>PALB2</italic> mutation (10.38 months) and <italic>PALB2<sup>wt</sup></italic> (11.07 months).</p></sec><sec><title>Conclusions</title><p>These findings suggest that <italic>PALB2</italic> may not be used as a biomarker for determining prognosis on immunotherapy in NSCLC.</p></sec>