4.7 Article

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions

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CLINICAL CANCER RESEARCH
卷 27, 期 6, 页码 1695-1705

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-4073

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  1. Grateful Foundation
  2. Jacqueline Fish Memorial Fund
  3. NIH [P50CA127003]
  4. Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Research
  5. Stand Up To Cancer
  6. Lustgarten Foundation
  7. Damon Runyon Cancer Research Foundation [PST-15-18]
  8. Douglas Gray Woodruff Chair fund
  9. Guo Shu Shi Fund
  10. Anonymous Family Fund for Innovations in Colorectal Cancer
  11. Project P fund
  12. George Stone Family Foundation
  13. SteveO'Connor Memorial Fund

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RTK fusions in colorectal cancer are rare but enrich in right-sided and MMR-D colorectal cancers. They occur in RAS and BRAF wild-type tumors, providing an important therapeutic target for MSS colorectal cancer.
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 wildtype 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.

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