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Abstract：
BACKGROUND: PALB2, 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.
METHODS: 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 PALB2 on immunotherapy.
RESULTS: Genetic 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 (PALB2 smut). 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 PALB2 wt (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).
CONCLUSIONS: These findings suggest that PALB2 may not be used as a biomarker for determining prognosis on immunotherapy in NSCLC.
METHODS: 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 PALB2 on immunotherapy.
RESULTS: Genetic 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 (PALB2 smut). 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 PALB2 wt (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).
CONCLUSIONS: These findings suggest that PALB2 may not be used as a biomarker for determining prognosis on immunotherapy in NSCLC.
摘要：
背景：PALB2，DNA损伤反应（DDR）的同源重组修复（HRR）途径中的基因，与铂类化疗的疗效有关，免疫疗法，和PARP抑制剂治疗几种肿瘤。然而,PALB2特性，它与免疫治疗生物标志物的相关性，而免疫治疗对非小细胞肺癌(NSCLC)的预后影响尚不清楚.
方法：通过下一代测序（NGS）分析来自中国晚期NSCLC患者的肿瘤组织样本（381/733基因）。肿瘤突变负荷(TMB)定义为编码区中的体细胞非同义突变的总数。通过500个已知MSI基因座的NGS评估微卫星不稳定性(MSI)。使用免疫组织化学(Dako22C3或SP263)评估程序性细胞死亡-配体1(PD-L1)表达。一个独立队列（Rizvi2018。NSCLC.240。NGS队列）包含来自240名晚期NSCLC患者的基因组和临床数据，以及包含来自429名晚期NSCLC患者的基因组和临床数据的两个队列（OAK和POPLAR研究队列）用于分析PALB2对免疫治疗的预后影响。
结果：使用NGS分析了5,227例NSCLC患者的基因突变，其中162（3.1％）带有种系PALB2突变（PALB2gmut）和87（1.66％）带有体细胞PALB2突变（PALB2黑穗病）。在PALB2gmut和PALB2smut的NSCLC患者中，最常见的突变基因是TP53(65%，64%）。与PALB野生型(PALB2wt)(6.15Muts/Mb)相比,PALB2smut(14.52Muts/Mb)与更高的TMB(p<0.001)相关。然而,PALB2gmut（6.45Muts/Mb）和PALB2wt（6.15Muts/Mb）之间的TMB没有显着差异（p=0.64）。PALB2gmut之间PD-L1表达无差异，PALB2smut，和PALB2wt。在Rizvi2018中。NSCLC.240。NGS队列,PALB2突变(3.15个月)和PALB2wt(3.17个月)的无进展生存期(PFS)(HR=1.06,p=0.93)无差异.NSCLC患者的OAK和POPLAR研究队列显示，PALB2突变（10.38个月）和PALB2wt（11.07个月）之间的总生存期（OS）（HR=1.1，p=0.75）没有差异。
结论：这些研究结果表明，PALB2可能不能用作确定NSCLC免疫治疗预后的生物标志物。
方法：通过下一代测序（NGS）分析来自中国晚期NSCLC患者的肿瘤组织样本（381/733基因）。肿瘤突变负荷(TMB)定义为编码区中的体细胞非同义突变的总数。通过500个已知MSI基因座的NGS评估微卫星不稳定性(MSI)。使用免疫组织化学(Dako22C3或SP263)评估程序性细胞死亡-配体1(PD-L1)表达。一个独立队列（Rizvi2018。NSCLC.240。NGS队列）包含来自240名晚期NSCLC患者的基因组和临床数据，以及包含来自429名晚期NSCLC患者的基因组和临床数据的两个队列（OAK和POPLAR研究队列）用于分析PALB2对免疫治疗的预后影响。
结果：使用NGS分析了5,227例NSCLC患者的基因突变，其中162（3.1％）带有种系PALB2突变（PALB2gmut）和87（1.66％）带有体细胞PALB2突变（PALB2黑穗病）。在PALB2gmut和PALB2smut的NSCLC患者中，最常见的突变基因是TP53(65%，64%）。与PALB野生型(PALB2wt)(6.15Muts/Mb)相比,PALB2smut(14.52Muts/Mb)与更高的TMB(p<0.001)相关。然而,PALB2gmut（6.45Muts/Mb）和PALB2wt（6.15Muts/Mb）之间的TMB没有显着差异（p=0.64）。PALB2gmut之间PD-L1表达无差异，PALB2smut，和PALB2wt。在Rizvi2018中。NSCLC.240。NGS队列,PALB2突变(3.15个月)和PALB2wt(3.17个月)的无进展生存期(PFS)(HR=1.06,p=0.93)无差异.NSCLC患者的OAK和POPLAR研究队列显示，PALB2突变（10.38个月）和PALB2wt（11.07个月）之间的总生存期（OS）（HR=1.1，p=0.75）没有差异。
结论：这些研究结果表明，PALB2可能不能用作确定NSCLC免疫治疗预后的生物标志物。
