1. Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions
- Author
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Kimmie Ng, Aaron R. Thorner, George D. Demetri, Lauren K. Brais, Emma Reilly, Jeffrey A. Meyerhardt, Atul B. Shinagare, Cheta Siletti, Geoffrey I. Shapiro, Jason L. Hornick, Jessica J. Lin, Matthew D. Ducar, Anna F. Farago, Ewa Sicinska, Liam F. Spurr, Andrew D. Cherniack, Laura E. MacConaill, Rachel B. Keller, Brian M. Wolpin, Azra H. Ligon, Rahul Gujrathi, Matthew Meyerson, Marios Giannakis, Ritika Abhyankar, James M. Cleary, Jeffrey W. Clark, Harshabad Singh, Anwesha Nag, Yvonne Y. Li, and Matthew H. Kulke
- Subjects
0301 basic medicine ,Alectinib ,Adult ,Male ,Cancer Research ,Oncogene Proteins, Fusion ,Colorectal cancer ,Entrectinib ,MLH1 ,Receptor tyrosine kinase ,Article ,03 medical and health sciences ,0302 clinical medicine ,Biomarkers, Tumor ,Medicine ,Humans ,Molecular Targeted Therapy ,neoplasms ,Protein Kinase Inhibitors ,Aged ,biology ,Crizotinib ,business.industry ,Cancer ,Receptor Protein-Tyrosine Kinases ,Middle Aged ,medicine.disease ,Prognosis ,Lynch syndrome ,digestive system diseases ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,business ,Colorectal Neoplasms ,medicine.drug ,Follow-Up Studies - Abstract
Purpose: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion–associated colorectal cancer. Experimental Design: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results. Results: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair–deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E–mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy. Conclusions: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
- Published
- 2020