Comprehensive Genomic Profiling Identifies Novel Genetic Predictors of Response to Anti-PD-(L)1 Therapies in Non-Small Cell Lung Cancer
Comprehensive Genomic Profiling Identifies Novel Genetic Predictors of Response to Anti-PD-(L)1 Therapies in Non-Small Cell Lung Cancer
复制标题
全面的基因组分析确定了非小细胞肺癌抗 PD-(L)1 疗法反应的新型遗传预测因子
DOI：
10.1158/1078-0432.ccr-19-0585
复制
发表时间：
2019-08-15
影响因子：
11.5
通讯作者：
Zhang, Li
中科院分区：
文献类型：
--
作者：
Fang, Wenfeng;Ma, Yuxiang;Zhang, Li
目的：免疫检查点抑制剂(ICI)使癌症治疗发生了革命性的变化。实验设计：我们通过全外显子组和靶向下一代测序(422个肿瘤基因小组)对78例接受抗PD-(L)1治疗的非小细胞肺癌患者进行了基因组图谱分析，以探索ICI反应的预测生物标志物。我们评估了肿瘤突变负荷(TMB)、特异性体细胞突变和拷贝数改变(CNA)与免疫治疗反应的关系。结果：我们证实高TMB与改善临床预后有关，基因小组定量的TMB与WES结果密切相关(Spearman‘s r=0.81)。与野生型相比，FAT1突变患者具有更高的持久临床受益(DCB，71.4%比22.7%，P=0.01)和客观有效率(ORR，57.1%比15.2%，P=0.02)。另一方面，有EGFR/ERBB2激活突变的患者与其他患者相比，中位无进展生存期(MPFS)降低[51.0vs.70.5d，P=0.0037，HR，2.47；95%可信区间(CI)，1.32~4.62]。此外，包含肿瘤抑制基因ITGA9和几个趋化因子受体途径基因的特定染色体3p片段的拷贝数丢失高度预测了不良的临床结果(6个月存活率，0%vs.31%，P=0.012，HR，2.08；95%CI，1.09-4.00)。我们的发现在两个独立发表的包含多种癌症类型的数据集中得到了进一步的验证。结论：我们发现了新的基因组生物标记物，可以预测抗PD-(L)1治疗的反应。我们的发现表明，对TMB和前述分子标志物的综合分析可以导致对非小细胞肺癌患者ICI治疗反应的更大预测能力。
Purpose: Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood.Experimental Design: We performed genomic profiling of 78 patients with non-small cell lung cancer (NSCLC) who underwent anti-PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response.Results: We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's r = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32-4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09-4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types.Conclusions: We identified novel genomic biomarkers that were predictive of response to anti-PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.