ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer.

Filippo Pietrantonio, Federica Di Nicolantonio, Alexa B. Schrock, Jeeyun Lee, Sabine Tejpar, Andrea Sartore-Bianchi, Jaclyn F. Hechtman, Jason Christiansen, Luca Novara, Niall Tebbutt, Giovanni Fuca, Carlotta Antoniotti, Seung Tae Kim, Danielle Murphy, Rosa Berenato, Federica Morano, James Sun, Bosun Min, Philip J. Stephens, Marissa Chen & 1 others Chiara Cremolini

Research output: Contribution to journalArticle

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, chi2 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.
Original languageEnglish
JournalJournal of the National Cancer Institute
Volume109
Publication statusPublished - Dec 1 2017

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Colorectal Neoplasms
Confidence Intervals
Neoplasms
Proportional Hazards Models
Survival
Atlases
Epidermal Growth Factor Receptor
History
Genome
Databases
Mutation
Therapeutics
N-methylsuccinimide

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Pietrantonio, F., Di Nicolantonio, F., Schrock, A. B., Lee, J., Tejpar, S., Sartore-Bianchi, A., ... Cremolini, C. (2017). ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer. Journal of the National Cancer Institute, 109.

ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer. / Pietrantonio, Filippo; Di Nicolantonio, Federica; Schrock, Alexa B.; Lee, Jeeyun; Tejpar, Sabine; Sartore-Bianchi, Andrea; Hechtman, Jaclyn F.; Christiansen, Jason; Novara, Luca; Tebbutt, Niall; Fuca, Giovanni; Antoniotti, Carlotta; Kim, Seung Tae; Murphy, Danielle; Berenato, Rosa; Morano, Federica; Sun, James; Min, Bosun; Stephens, Philip J.; Chen, Marissa; Cremolini, Chiara.

In: Journal of the National Cancer Institute, Vol. 109, 01.12.2017.

Research output: Contribution to journalArticle

Pietrantonio, F, Di Nicolantonio, F, Schrock, AB, Lee, J, Tejpar, S, Sartore-Bianchi, A, Hechtman, JF, Christiansen, J, Novara, L, Tebbutt, N, Fuca, G, Antoniotti, C, Kim, ST, Murphy, D, Berenato, R, Morano, F, Sun, J, Min, B, Stephens, PJ, Chen, M & Cremolini, C 2017, 'ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer.', Journal of the National Cancer Institute, vol. 109.
Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Tejpar S, Sartore-Bianchi A et al. ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer. Journal of the National Cancer Institute. 2017 Dec 1;109.
Pietrantonio, Filippo ; Di Nicolantonio, Federica ; Schrock, Alexa B. ; Lee, Jeeyun ; Tejpar, Sabine ; Sartore-Bianchi, Andrea ; Hechtman, Jaclyn F. ; Christiansen, Jason ; Novara, Luca ; Tebbutt, Niall ; Fuca, Giovanni ; Antoniotti, Carlotta ; Kim, Seung Tae ; Murphy, Danielle ; Berenato, Rosa ; Morano, Federica ; Sun, James ; Min, Bosun ; Stephens, Philip J. ; Chen, Marissa ; Cremolini, Chiara. / ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer. In: Journal of the National Cancer Institute. 2017 ; Vol. 109.
@article{6f243843798a4a1bb792a9b090153236,
title = "ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer.",
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, chi2 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.",
author = "Filippo Pietrantonio and {Di Nicolantonio}, Federica and Schrock, {Alexa B.} and Jeeyun Lee and Sabine Tejpar and Andrea Sartore-Bianchi and Hechtman, {Jaclyn F.} and Jason Christiansen and Luca Novara and Niall Tebbutt and Giovanni Fuca and Carlotta Antoniotti and Kim, {Seung Tae} and Danielle Murphy and Rosa Berenato and Federica Morano and James Sun and Bosun Min and Stephens, {Philip J.} and Marissa Chen and Chiara Cremolini",
year = "2017",
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day = "1",
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volume = "109",
journal = "Journal of the National Cancer Institute",
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TY - JOUR

T1 - ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer.

AU - Pietrantonio, Filippo

AU - Di Nicolantonio, Federica

AU - Schrock, Alexa B.

AU - Lee, Jeeyun

AU - Tejpar, Sabine

AU - Sartore-Bianchi, Andrea

AU - Hechtman, Jaclyn F.

AU - Christiansen, Jason

AU - Novara, Luca

AU - Tebbutt, Niall

AU - Fuca, Giovanni

AU - Antoniotti, Carlotta

AU - Kim, Seung Tae

AU - Murphy, Danielle

AU - Berenato, Rosa

AU - Morano, Federica

AU - Sun, James

AU - Min, Bosun

AU - Stephens, Philip J.

AU - Chen, Marissa

AU - Cremolini, Chiara

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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, chi2 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.

AB - 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, chi2 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.

M3 - Article

VL - 109

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

ER -