VanderLaan Paul A, Rangachari Deepa, Mockus Susan M, Spotlow Vanessa, Reddi Honey V, Malcolm Joan, Huberman Mark S, Joseph Loren J, Kobayashi Susumu S, Costa Daniel B
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
Lung Cancer. 2017 Apr;106:17-21. doi: 10.1016/j.lungcan.2017.01.011. Epub 2017 Jan 25.
The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance.
We retrospectively probed our institutional lung cancer database for tumors with EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and evaluated tumor response to EGFR tyrosine kinase inhibitors (TKIs).
Out of 171 EGFR mutated tumor-patient cases, 20 were sequenced using at least a limited comprehensive genomic profiling platform. 50% harbored concurrent TP53 mutation, 10% PIK3CA mutation, 5% PTEN mutation, among others. The response rate to EGFR TKIs, the median progression-free survival (PFS) to TKIs, the percentage of EGFR-T790M TKI resistance and survival had higher trends in EGFR mutant/TP53 wild-type cases when compared to EGFR mutant/TP53 mutant tumors (all p >0.05 without statistical significance); with a significantly longer median PFS in EGFR-exon 19 deletion mutant/TP53 wild-type cancers treated with 1st generation EGFR TKIs (p=0.035).
Concurrent mutations, specifically TP53, are common in EGFR mutated lung cancer and may alter clinical outcomes. Additional cohorts will be needed to determine if comprehensive molecular profiling adds clinically relevant information to single gene assay identification in oncogene-driven lung cancers.
表皮生长因子受体（EGFR）突变的肺癌对EGFR抑制剂的反应程度和持续时间存在异质性。我们推测，鉴于临床实践中普遍采用的单基因检测诊断模式，目前尚不清楚这些肿瘤的并发基因组格局可能在临床结局和/或耐药机制中发挥作用。
我们回顾性地在机构肺癌数据库中搜索具有EGFR激酶结构域突变的肿瘤，这些肿瘤也通过更全面的分子谱分析进行了评估，并评估了肿瘤对EGFR酪氨酸激酶抑制剂（TKIs）的反应。
在171例EGFR突变的肿瘤患者病例中，20例使用了至少一个有限的综合基因组谱分析平台进行测序。其中50%存在并发TP53突变，10%存在PIK3CA突变，5%存在PTEN突变等。与EGFR突变/TP53突变肿瘤相比，EGFR突变/TP53野生型病例对EGFR TKIs的反应率、对TKIs的无进展生存期（PFS）中位数、EGFR-T790M TKI耐药百分比和生存率有更高的趋势（所有p>0.05，无统计学意义）；第一代EGFR TKIs治疗的EGFR外显子19缺失突变/TP53野生型癌症的PFS中位数显著更长（p=0.035）。
并发突变，特别是TP53突变，在EGFR突变的肺癌中很常见，可能会改变临床结局。需要更多队列来确定综合分子谱分析是否能为致癌基因驱动的肺癌单基因检测识别增加临床相关信息。
