Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials
Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials
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DOI：
10.1158/1535-7163.mct-12-0290
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发表时间：
2012-09-01
影响因子：
5.7
通讯作者：
Tabernero, Josep
中科院分区：
文献类型：
--
作者：
Dienstmann, Rodrigo;Serpico, Danila;Tabernero, Josep
临床经验越来越多地表明，在靶向治疗的I期试验中，分子预筛选和生物标志物富集策略将改善癌症患者的预后。为了符合个性化肿瘤学计划的要求，分析了晚期化学难治性结直肠癌患者的肿瘤的特异性畸变（KRAS/BRAF/PIK 3CA突变，PTEN和pMET表达）。患者随后提供了I期试验与匹配的靶向药物（MTA）针对所确定的异常。在2010年和2011年期间，对254例患者进行了肿瘤分子分析：KRAS突变（80/254，31.5%），BRAF突变（24/196，12.2%），PIK 3CA突变（114例中的15例，13.2%）、KRAS和PIK 3CA突变（114例中的9例，7.9%）、低PTEN表达（183例中的97例，53.0%）和高pMET表达（64例中的38例，59.4%）。总共有68名患者接受了82种不同的MTA：磷脂酰肌醇3-激酶（PI 3 K）通路抑制剂（如果PIK 3CA突变，n = 10;或低PTEN，n = 32），PI 3 K通路抑制剂加MEK抑制剂（如果KRAS突变，n = 10;或BRAF突变，n = 1），第二代抗EGF受体单克隆抗体（如果是野生型KRAS，n = 11），抗肝细胞生长因子单克隆抗体（如果pMET高，n = 10），mTOR抑制剂加抗胰岛素样生长因子-1受体单克隆抗体（如果低PTEN，n = 5）和BRAF抑制剂（如果BRAF突变，n = 3）。MTA治疗失败的中位时间为7.9周，而既往全身抗肿瘤治疗失败的中位时间为16.3周（P < 0.001）。在1例患者中观察到部分缓解[1.2%，具有PIK 3CA突变的PI 3 K抑制剂]，在10例病例中观察到稳定疾病> 16周（12.2%）。这些结果表明，匹配化疗难治性结直肠癌患者与靶向药物在I期试验的基础上，目前的分子概况并没有赋予显着的临床效益。Mol Cancer Ther; 11（9）; 2062-71. (C)2012年AACR。
Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n = 10; or low PTEN, n = 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n = 10; or BRAF mutation, n = 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n = 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n = 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n = 5), and BRAF inhibitor (if BRAF mutation, n = 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease > 16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. Mol Cancer Ther; 11(9); 2062-71. (C) 2012 AACR.