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.
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.
Authors: Alexa B Schrock; Dean Pavlick; Samuel J Klempner; Jon H Chung; Brady Forcier; Allison Welsh; Lauren Young; Bryan Leyland-Jones; Rodolfo Bordoni; Richard D Carvajal; Joseph Chao; Razelle Kurzrock; Jason K Sicklick; Jeffrey S Ross; Philip J Stephens; Craig Devoe; Fadi Braiteh; Siraj M Ali; Vincent A Miller Journal: Clin Cancer Res Date: 2018-01-23 Impact factor: 12.531
Authors: Vivy T Cusumano; Anthony Myint; Edgar Corona; Liu Yang; Jennifer Bocek; Antonio G Lopez; Marcela Zhou Huang; Naveen Raja; Anna Dermenchyan; Lily Roh; Maria Han; Daniel Croymans; Folasade P May Journal: Dig Dis Sci Date: 2021-02-20 Impact factor: 3.199
Authors: Christopher H Lieu; Erica A Golemis; Ilya G Serebriiskii; Justin Newberg; Amanda Hemmerich; Caitlin Connelly; Wells A Messersmith; Cathy Eng; S Gail Eckhardt; Garrett Frampton; Matthew Cooke; Joshua E Meyer Journal: Clin Cancer Res Date: 2019-06-26 Impact factor: 12.531
Authors: Sally R Williams; Tareq A Juratli; Brandyn A Castro; Tyler T Lazaro; Corey M Gill; Naema Nayyar; Matthew R Strickland; Melanie Babinski; Sarah E Johnstone; Matthew P Frosch; Ian M Silverman; Heather A Ely; Alexander B Kaplan; Megan R D'Andrea; Ivanna V Bihun; Kaitlin Hoang; Emily Batchelor; Jason Christiansen; Daniel P Cahill; Frederick G Barker; Priscilla K Brastianos Journal: J Neurol Surg B Skull Base Date: 2019-01-10
Authors: Matthew Clarke; Alan Mackay; Britta Ismer; Jessica C Pickles; Ruth G Tatevossian; Scott Newman; Tejus A Bale; Iris Stoler; Elisa Izquierdo; Sara Temelso; Diana M Carvalho; Valeria Molinari; Anna Burford; Louise Howell; Alex Virasami; Amy R Fairchild; Aimee Avery; Jane Chalker; Mark Kristiansen; Kelly Haupfear; James D Dalton; Wilda Orisme; Ji Wen; Michael Hubank; Kathreena M Kurian; Catherine Rowe; Mellissa Maybury; Stephen Crosier; Jeffrey Knipstein; Ulrich Schüller; Uwe Kordes; David E Kram; Matija Snuderl; Leslie Bridges; Andrew J Martin; Lawrence J Doey; Safa Al-Sarraj; Christopher Chandler; Bassel Zebian; Claire Cairns; Rachael Natrajan; Jessica K R Boult; Simon P Robinson; Martin Sill; Ira J Dunkel; Stephen W Gilheeney; Marc K Rosenblum; Debbie Hughes; Paula Z Proszek; Tobey J Macdonald; Matthias Preusser; Christine Haberler; Irene Slavc; Roger Packer; Ho-Keung Ng; Shani Caspi; Mara Popović; Barbara Faganel Kotnik; Matthew D Wood; Lissa Baird; Monika Ashok Davare; David A Solomon; Thale Kristin Olsen; Petter Brandal; Michael Farrell; Jane B Cryan; Michael Capra; Michael Karremann; Jens Schittenhelm; Martin U Schuhmann; Martin Ebinger; Winand N M Dinjens; Kornelius Kerl; Simone Hettmer; Torsten Pietsch; Felipe Andreiuolo; Pablo Hernáiz Driever; Andrey Korshunov; Lotte Hiddingh; Barbara C Worst; Dominik Sturm; Marc Zuckermann; Olaf Witt; Tabitha Bloom; Clare Mitchell; Evelina Miele; Giovanna Stefania Colafati; Francesca Diomedi-Camassei; Simon Bailey; Andrew S Moore; Timothy E G Hassall; Stephen P Lowis; Maria Tsoli; Mark J Cowley; David S Ziegler; Matthias A Karajannis; Kristian Aquilina; Darren R Hargrave; Fernando Carceller; Lynley V Marshall; Andreas von Deimling; Christof M Kramm; Stefan M Pfister; Felix Sahm; Suzanne J Baker; Angela Mastronuzzi; Andrea Carai; Maria Vinci; David Capper; Sergey Popov; David W Ellison; Thomas S Jacques; David T W Jones; Chris Jones Journal: Cancer Discov Date: 2020-04-01 Impact factor: 39.397