ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer
Open accessAbstract
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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ROS1 fusions are rare genetic events reported in multiple solid tumors, including NSCLC, with prevalence 0.9% to 2.6%.
“These ROS1 fusions are rare genetic events reported in multiple solid tumors, including non–small cell lung cancer (NSCLC), where the prevalence is 0.9% to 2.6%.1,3-5”
From Taletrectinib in <i>ROS1</i> + Non–Small Cell Lung Cancer: TRUST (2025) · cites this paper as [5]
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- Authors
- Pietrantonio, F., Di Nicolantonio, F., Schrock, A. B., Lee, J., Tejpar, S., Sartore-Bianchi, A., Hechtman, J. F., Christiansen, J., Novara, L., Tebbutt, N., Fucà, G., Antoniotti, C., Kim, S. T., Murphy, D., Berenato, R., Morano, F., Sun, J., Min, B., Stephens, P. J., Chen, M., Lazzari, L., Miller, V. A., Shoemaker, R., Amatu, A., Milione, M., Ross, J. S., Siena, S., Bardelli, A., Ali, S. M., Falcone, A., de Braud, F., & Cremolini, C.
- Affiliations
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Department of Oncology, University of Torino, Candiolo (TO), Italy
- Foundation Medicine (United States) (US)
- Samsung Medical Center (KR)
- Universitair Ziekenhuis Leuven (BE)
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Memorial Sloan Kettering Cancer Center (US)
- Ignyta (United States) (US)
- University of Turin (IT)
- Austin Health (AU)
- University of Pisa (IT)
- Candiolo Cancer Institute (IT)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- University of Milan (IT)
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- ORCID
- Pietrantonio, Filippo
- Schrock, Alexa B
- Lee, Jeeyun
- Tejpar, Sabine
- Hechtman, Jaclyn F
- Christiansen, Jason
- Novara, Luca
- Tebbutt, Niall
- Fucà, Giovanni
- Antoniotti, Carlotta
- Kim, Seung Tae
- Murphy, Danielle
- Morano, Federica
- Sun, James
- Chen, Marissa
- Lazzari, Luca
- Miller, Vincent A
- Amatu, Alessio
- Milione, Massimo
- Ross, Jeffrey S
- Siena, Salvatore
- Bardelli, Alberto
- Ali, Siraj M
- Falcone, Alfredo
- Cremolini, Chiara
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-06-01
- Volume
- 109
- Issue
- 12
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2620839015
- Cited by
- 317
- References
- 33
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 23 · 2023: 24 · 2022: 31 · 2021: 68 · 2020: 65 · 2019: 50 · 2018: 17 · 2017: 10
- FWCI
- 17.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- Amgen
- Eli Lilly and Company
- Sanofi
- Celgene
- European Commission (635342)
- Associazione Italiana per la Ricerca sul Cancro (16788, 17707)
- Servier
- Fondazione Oncologia Niguarda Onlus
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- metastatic colorectal cancer, ALK rearrangement, ROS1 rearrangement, NTRK rearrangement, overall survival, RAS wild-type, microsatellite instability-high, RNF43 mutation, anti-EGFR resistance, right-sided tumors, elderly patients, immunophenotype
- MeSH terms
- Anaplastic Lymphoma Kinase, Adolescent, Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Liver Neoplasms, Lung Neoplasms, Lymphatic Metastasis, Male, Middle Aged, Peritoneal Neoplasms, Prognosis, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Biomarkers, Tumor, Colorectal Neoplasms, Gene Rearrangement, Gene Expression Regulation, Neoplastic, Survival Rate, Receptor, trkA, Young Adult
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