晚期非小细胞肺癌患者肿瘤突变负荷与靶向治疗疗效相关性
Relationship between tumor mutational burden and efficacy of targeted therapies in patients with advanced nonsmall cell lung cancer
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摘要: 目的：探讨晚期非小细胞肺癌肿瘤突变负荷（TMB）与肿瘤靶向治疗疗效的相关性。方法：纳入2016年1月至2018年1月在复旦大学附属中山医院行靶向治疗的51例晚期非小细胞肺癌患者，采用靶向二代测序技术检测其肿瘤组织标本的TMB水平，并分析TMB与靶向治疗疗效的相关性。结果：51例非小细胞肺癌患者的中位TMB水平为6.2个突变/Mb，其中吸烟患者的TMB水平较不吸烟患者升高（P=0.046）。将所有入组患者分为高TMB组和中低TMB组，生存分析显示：与高TMB组相比，中低TMB组患者的无进展生存期（PFS）更长（410 d vs 217 d, HR=0.331, 95% CI 0.165~0.665, P=0.001 2）。亚组分析显示：在男女性、有无吸烟史、合并TP53基因突变与否患者中，中低TMB组者的中位PFS均长于高TMB组患者（P＜0.05）；在腺癌、表皮生长因子受体（EGFR）突变、EGFR 19外显子缺失、EGFR L858R患者中，中低TMB组患者的中位PFS也长于高TMB组患者（P＜0.05）。结论：对于具有驱动突变的晚期非小细胞肺癌患者，肿瘤组织TMB水平对靶向治疗疗效具有预测作用，高TMB水平提示靶向治疗患者的PFS更短。Abstract: Objective：To explore the relationship between tumor mutational burden (TMB) and efficacy of targeted therapies in patients with advanced nonsmall cell lung cancer (NSCLC).Methods：Between Jan. 2016 and Jan. 2018, fiftyone NSCLC patients receiving targeted therapy were enrolled in Zhongshan Hospital, Fudan University. TMB levels in tumor tissue samples from these patients were examined using targeted nextgeneration sequencing.Results：The median TMB level of NSCLC patients with driver mutations and receiving targeted therapy was 6.2 mutations/Mb, with TMB levels in smokers significantly higher than nonsmokers (P=0.046). All enrolled patients were divided into high TMB and moderate/low TMB groups. Survival analysis showed that patients with moderate/low TMB had longer progressionfree survival (PFS) compared with patients with high TMB (410 d vs 217 d, HR= 0.331, 95% CI 0.1650.665, P=0.001 2). Subgroup analysis showed that the median PFS was longer in the moderate/low TMB group than that in the high TMB group among the subgroups of gender, whether smoking, and TP53 gene mutation status. In the subgroups of adenocarcinoma who harbor epidermal growth factor receptor (EGFR) mutations, EGFR exon 19 deletion, and EGFR L858R, the median PFS was also longer in the moderate/low TMB group than that in the high TMB group (P＜0.05).Conclusions：For advanced NSCLC patients with driver mutations, the TMB level of tumor tissue is a predictor of the efficacy of targeted therapy. High TMB level suggests that PFS is shorter in patients receiving targeted therapy.
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