Remon Jordi, Besse Benjamin, Leary Alexandra, Bièche Ivan, Job Bastien, Lacroix Ludovic, Auguste Aurélie, Mauduit Marjorie, Audigier-Valette Clarisse, Raimbourg Judith, Madroszyk Anne, Michels Stefan, Bayar Mohammed Amine, Jimenez Marta, Soria Jean-Charles, Rouleau Etienne, Barlesi Fabrice
Cancer Medicine Department, Gustave Roussy, Villejuif, France.
University Paris-Saclay, Orsay, France.
JTO Clin Res Rep. 2020 Jun 11;1(3):100068. doi: 10.1016/j.jtocrr.2020.100068. eCollection 2020 Sep.
Molecular profiling is considered a standard of care in advanced NSCLC. A comprehensive next-generation sequencing panel can discover somatic or germline mutations that are new druggable molecular alterations. However, the phenotypic and potential therapeutic relevance of mutation in NSCLC remains poorly defined.
From April 2014 to March 2017, 600 newly diagnosed, negative patients with advanced NSCLC were enrolled in the SAFIR02-Lung trial. Molecular profiling was done at study entry on archival tissue or frozen tissue collected from a new biopsy specimen before the third cycle of platinum-based chemotherapy. The prevalence of variants and its biological relevance were assessed. A homologous recombinant deficiency (HRD) score was based on the copy number variation data, and the germline status was determined by blood analysis. The BRCA Share database and the French CGG consortium were the references for the variant classification.
Of 379 patients with a molecular profile discussed in a tumor molecular board, variants were identified in 20 patients (5.3%), including eight patients (2.1%) with a confirmed pathogenic mutation. Two patients (0.5%) harbored a germline mutation, and for six others, a somatic mutation was identified (1.6%). All were men and mainly smokers (88%). The overall response rate to chemotherapy was 13%. variants of unknown significance were detected in 12 patients (3.2%), achieving an 8.3% overall response rate with chemotherapy. One-third of tumors carrying pathogenic mutations or variants of unknown significance had biallelic inactivation and high HRD score. Overall survival of this cohort was 12.8 months.
Pathogenic mutations occur in 2.1% of patients with advanced NSCLC. The predictive role of mutation for making treatment decisions in NSCLC seems limited based on clinical response (low platinum sensitivity) and molecular features (discrepancy between biallelic inactivation and high HRD score).
分子谱分析被认为是晚期非小细胞肺癌（NSCLC）的标准治疗手段。全面的二代测序 panel 能够发现新的可靶向治疗的分子改变，包括体细胞或种系突变。然而，NSCLC 中这些突变的表型及潜在治疗相关性仍定义不清。
2014 年 4 月至 2017 年 3 月，600 例新诊断的晚期 NSCLC 阴性患者入组 SAFIR02-Lung 试验。在研究入组时，对存档组织或在铂类化疗第三个周期前从新活检标本采集的冷冻组织进行分子谱分析。评估变异的发生率及其生物学相关性。同源重组缺陷（HRD）评分基于拷贝数变异数据，种系状态通过血液分析确定。BRCA Share 数据库和法国 CGG 联盟作为变异分类的参考。
在肿瘤分子委员会讨论分子谱的 379 例患者中，20 例（5.3%）鉴定出变异，其中 8 例（2.1%）为确诊的致病性突变。2 例（0.5%）携带种系突变，另外 6 例鉴定出体细胞突变（1.6%）。所有患者均为男性，主要为吸烟者（88%）。化疗的总缓解率为 13%。12 例患者（3.2%）检测到意义未明的变异，化疗的总缓解率为 8.3%。携带致病性突变或意义未明变异的肿瘤中，三分之一具有双等位基因失活和高 HRD 评分。该队列的总生存期为 12.8 个月。
2.1%的晚期 NSCLC 患者发生致病性突变。基于临床反应（铂敏感性低）和分子特征（双等位基因失活与高 HRD 评分之间的差异），突变在 NSCLC 治疗决策中的预测作用似乎有限。
