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Ref Type Journal Article
PMID (33414136)
Authors Singh H, Li YY, Spurr LF, Shinagare AB, Abhyankar R, Reilly E, Brais LK, Nag A, Ducar MD, Thorner AR, Shapiro GI, Keller RB, Siletti C, Clark JW, Farago AF, Lin JJ, Demetri GD, Gujrathi R, Kulke MH, MacConaill LE, Ligon AH, Sicinska E, Meyerson ML, Meyerhardt JA, Cherniack AD, Wolpin BM, Ng K, Giannakis M, Hornick JL, Cleary JM
Title Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 27
Issue 6
Date 2021 Mar 15
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ROS1 - GOPC rectosigmoid cancer predicted - sensitive Entrectinib Case Reports/Case Series Actionable In a clinical case study, Rozlytrek (entrectinib) treatment resulted in a 16% reduction of tumor burden in a patient with advanced rectosigmoid adenocarcinoma harboring ROS1-GOPC who enrolled in a Phase II trial, and the patient remained on treatment after 9 months (PMID: 33414136; NCT02568267). 33414136