Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Department of Oncology, University of Torino, Candiolo, Italy.
J Natl Cancer Inst. 2017 Dec 1;109(12). doi: 10.1093/jnci/djx089.
ALK, ROS1, and NTRK fusions occur in 0.2% to 2.4% of colorectal cancers. Pioneer cases of metastatic colorectal cancer (mCRC) patients bearing rearrangements who benefited from anti-ALK, ROS, and TrkA-B-C therapies have been reported previously. Here we aimed at characterizing the clinical and molecular landscape of ALK, ROS1, and NTRK rearranged mCRC.
Clinical features and molecular characteristics of 27 mCRC patients bearing ALK, ROS1, and NTRK rearranged tumors were compared with those of a cohort of 319 patients not bearing rearrangements by means of Fisher's exact, χ2 test, or Mann-Whitney test as appropriate. Overall survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was adopted in the multivariable analysis. Deep molecular and immunophenotypic characterizations of rearranged cases, including those described in The Cancer Genome Atlas database, were performed. All statistical tests were two-sided.
Closely recalling the "BRAF history," ALK, ROS1, and NTRK rearrangements more frequently occurred in elderly patients (P = .02) with right-sided tumors (P < .001) and node-spreading (P = .03), RAS wild-type (P < .001), and MSI-high (P < .001) cancers. All patients bearing ALK, ROS1, and NTRK fusions had shorter overall survival (15.6 months, 95% confidence interval [CI] = 0.0 to 20.4 months) than negative patients (33.7 months, 95% CI = 28.3 to 42.1 months), both in the univariate (hazard ratio [HR] = 2.17, 95% CI = 1.03 to 4.57, P < .001) and multivariable models (HR = 2.33, 95% CI = 1.10 to 4.95, P = .02). All four evaluable patients with rearrangements showed primary resistance to anti-epidermal growth factor receptor agents. Frequent association with potentially targetable RNF43 mutations was observed in MSI-high rearranged tumors.
ALK, ROS1, and NTRK rearrangements define a new rare subtype of mCRC with extremely poor prognosis. Primary tumor site, MSI-high, and RAS and BRAF wild-type status may help to identify patients bearing these alterations. While sensitivity to available treatments is limited, targeted strategies inhibiting ALK, ROS, and TrkA-B-C provided encouraging results.
ALK、ROS1 和 NTRK 融合在 0.2%至 2.4%的结直肠癌中发生。先前已有报道称，患有转移性结直肠癌（mCRC）的先驱病例，这些病例携带可从抗 ALK、ROS 和 TrkA-B-C 治疗中获益的重排。在这里，我们旨在描述 ALK、ROS1 和 NTRK 重排 mCRC 的临床和分子特征。
通过 Fisher 精确检验、χ2 检验或适当的 Mann-Whitney 检验，比较 27 例携带 ALK、ROS1 和 NTRK 重排肿瘤的 mCRC 患者与 319 例未携带重排的患者的临床特征和分子特征。采用 Kaplan-Meier 法估计总生存期曲线，并采用对数秩检验进行比较。采用 Cox 比例风险模型进行多变量分析。对重排病例进行深入的分子和免疫表型特征分析，包括在癌症基因组图谱数据库中描述的特征。所有统计检验均为双侧。
与“BRAF 病史”密切相关，ALK、ROS1 和 NTRK 重排更常发生于老年患者（P =.02）、右侧肿瘤（P <.001）、淋巴结扩散（P =.03）、RAS 野生型（P <.001）和 MSI 高（P <.001）的癌症中。所有携带 ALK、ROS1 和 NTRK 融合的患者的总生存期均短于阴性患者（15.6 个月，95%置信区间 [CI] = 0.0 至 20.4 个月），无论在单变量（风险比 [HR] = 2.17，95%CI = 1.03 至 4.57，P <.001）还是多变量模型（HR = 2.33，95%CI = 1.10 至 4.95，P =.02）中均如此。所有 4 例可评估的重排患者对表皮生长因子受体抑制剂均表现出原发性耐药。在 MSI 高重排肿瘤中观察到与潜在靶向 RNF43 突变的频繁关联。
ALK、ROS1 和 NTRK 重排定义了一种具有极差预后的 mCRC 的新罕见亚型。原发肿瘤部位、MSI 高、RAS 和 BRAF 野生型状态可能有助于识别携带这些改变的患者。尽管对现有治疗的敏感性有限，但针对 ALK、ROS 和 TrkA-B-C 的靶向策略提供了令人鼓舞的结果。
