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. 2017 Dec 1;109(12).
doi: 10.1093/jnci/djx089.

ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer

Filippo Pietrantonio  1 , Federica Di Nicolantonio  2   3 , Alexa B Schrock  4 , Jeeyun Lee  5 , Sabine Tejpar  6 , Andrea Sartore-Bianchi  7 , Jaclyn F Hechtman  8 , Jason Christiansen  9 , Luca Novara  2 , Niall Tebbutt  10 , Giovanni Fucà  1 , Carlotta Antoniotti  11   12 , Seung Tae Kim  5 , Danielle Murphy  9 , Rosa Berenato  1 , Federica Morano  1 , James Sun  4 , Bosun Min  9 , Philip J Stephens  4 , Marissa Chen  9 , Luca Lazzari  1 , Vincent A Miller  1 , Robert Shoemaker  1 , Alessio Amatu  1 , Massimo Milione  1 , Jeffrey S Ross  1 , Salvatore Siena  1 , Alberto Bardelli  1 , Siraj M Ali  1 , Alfredo Falcone  1 , Filippo de Braud  1 , Chiara Cremolini  11   12
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Free article

ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer

Filippo Pietrantonio et al. J Natl Cancer Inst. .
Free article

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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