Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer
Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer
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DOI：
10.1200/jco.18.00177
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发表时间：
2019-04-10
影响因子：
45.3
通讯作者：
Tan, Daniel S. W.
中科院分区：
文献类型：
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作者：
Lai, Gillianne Gy;Lim, Tse Hui;Tan, Daniel S. W.
间充质上皮转化因子（MET）激活已被认为是表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）的一个致癌驱动因素，并可介导对EGFR酪氨酸激酶抑制剂（TKI）的原发性和继发性耐药。高拷贝数阈值被认为可以增强对MET抑制剂的反应。我们研究了MET拷贝数增益（CNG）在治疗初期转移性egfr突变阳性NSCLC中的临床相关性。患者和方法对200名连续确诊为转移性治疗初始egfr突变阳性的患者进行MET荧光原位杂交。我们将MET-high定义为CNG大于或等于5，并附加了7号染色体MET/着丝粒部分比率大于或等于2的标准进行扩增。通过Kaplan-Meier法估计met高和met低患者的治疗失败时间（TTF）到EGFR TKI，并使用log-rank检验进行比较。研究人员对13例早期切除的59个部门的egfr突变阳性NSCLC进行了多区域单核苷酸多态性阵列分析，以研究MET CNG的瘤内异质性。结果200例转移性队列患者中有52例（26%）在诊断时met -高；46例（23%）有多体，6例（3%）有扩增。met -高和低的中位TTF分别为12.2个月（95% CI， 5.7至22.6个月）和13.1个月（95% CI， 10.6至15.0个月）（P = 0.566），无论拷贝数阈值如何，缓解率均无显著差异。在接受进展后活检的6例MET高患者中，有3例观察到MET丢失，这与早期肿瘤中观察到的MET CNG的显着肿瘤内异质性一致。同时存在MET扩增的患者（154例中有5例[3.2%]）对EGFR TKI反应不佳（TTF， 1.0至6.4个月）。尽管荧光原位杂交显示高达26%的TKI初始egfr突变阳性NSCLC具有高MET CNG，但这并未显著影响对TKI的反应，除了被鉴定为MET扩增的患者。我们的数据强调了采用任意拷贝数阈值的局限性，以及在egfr突变阳性的非小细胞肺癌中定义治疗上可处理的MET通路失调需要进行交叉分析验证。(C) 2019由美国临床肿瘤学会批准
PURPOSE Mesenchymal epithelial transition factor (MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC.PATIENTS AND METHODS MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naive EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 rati greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG.RESULTS Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively (P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154).CONCLUSION Although up to 26% of TKI-naive EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC. (C) 2019 by American Society of Clinical Oncology