Michels Sebastian, Heydt Carina, van Veggel Bianca, Deschler-Baier Barbara, Pardo Nuria, Monkhorst Kim, Rüsseler Vanessa, Stratmann Jan, Griesinger Frank, Steinhauser Susanne, Kostenko Anna, Diebold Joachim, Fassunke Jana, Fischer Rieke, Engel-Riedel Walburga, Gautschi Oliver, Geissinger Eva, Haneder Stefan, Ihle Michaela A, Kopp Hans-Georg, de Langen Adrianus J, Martinez-Marti Alex, Nogova Lucia, Persigehl Thorsten, Plenker Dennis, Puesken Michael, Rodermann Ernst, Rosenwald Andreas, Scheel Andreas H, Scheffler Matthias, Spengler Werner, Seggewiss-Bernhardt Ruth, Brägelmann Johannes, Sebastian Martin, Vrugt Bart, Hellmich Martin, Sos Martin L, Heukamp Lukas C, Felip Enriqueta, Merkelbach-Bruse Sabine, Smit Egbert F, Büttner Reinhard, Wolf Jürgen
University Hospital of Cologne, Cologne, Germany.
Netherlands Cancer Institute, Amsterdam, the Netherlands.
JCO Precis Oncol. 2019 Mar 27;3. doi: 10.1200/PO.18.00210. eCollection 2019.
Third-generation epidermal growth factor receptor () tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes.
Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs.
Co-occurring genetic aberrations were found in 74.4% of p.T790-positive samples (n = 124). Mutations in were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor () amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 8.2 months; 95% CI, 1.69 to 14.77 months; ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, amplification, mutations).
Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.
第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）对EGFR突变型肺癌中第一代EGFR TKIs的获得性耐药（AR）有效。然而，疗效存在个体间异质性。我们展示了接受第三代EGFR TKIs治疗患者治疗前和治疗后样本的分子特征及其对治疗结果的影响。
利用两个肺癌网络和两个肺癌中心的数据库，我们对124例对第一代EGFR TKIs呈p.T790M阳性AR的患者进行了分子特征分析。在56例患者中，对第三代EGFR TKI治疗结果与分子特征进行相关性分析是可行的。此外，收集了29例对第三代EGFR TKIs治疗进展患者的配对治疗后活检样本。
在74.4%的p.T790阳性样本（n = 124）中发现了共发基因畸变。检测到的最常见畸变是KRAS突变（44.5%；n = 53），且对第三代EGFR TKI治疗无显著影响。在5%的样本（n = 6）中发现间充质-上皮转化因子（MET）扩增，显著降低了第三代EGFR TKIs的疗效（例如，无进展生存期的中位数，1.0个月；95%置信区间，0.37至1.72对8.2个月；95%置信区间，1.69至14.77个月；P≤.001）。在对第三代EGFR TKIs呈AR的29个样本中，发现了EGFR（例如，p.T790M缺失、获得p.C797S或p.G724S）或其他基因（例如，MET扩增、KRAS突变）的基因变化。
EGFR突变型肺癌中额外的基因畸变很常见，可能介导对第三代EGFR TKIs的固有耐药和获得性耐药。MET扩增与初始治疗失败密切相关，是对第三代EGFR TKIs获得性耐药的常见机制。因此，将EGFR抑制剂与针对常见耐药机制的TKIs联合使用可能会延迟获得性耐药。
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