Title | TRK Fusions Are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Rosen EY, Goldman DA, Hechtman JF, Benayed R, Schram AM, Cocco E, Shifman S, Gong Y, Kundra R, Solomon JP, Bardelli A, Scaltriti M, Drilon A, Iasonos A, Taylor BS, Hyman DM |
Journal | Clin Cancer Res |
Volume | 26 |
Issue | 7 |
Pagination | 1624-1632 |
Date Published | 2020 04 01 |
ISSN | 1557-3265 |
Keywords | Adolescent, Adult, Aged, Biomarkers, Tumor, Child, Child, Preschool, Female, Genomics, Humans, Infant, Infant, Newborn, Male, Membrane Glycoproteins, Microsatellite Instability, Middle Aged, Molecular Targeted Therapy, Mutation, Neoplasms, Protein Kinase Inhibitors, Proteins, Receptor, trkA, Receptor, trkB, Receptor, trkC, Young Adult |
Abstract | PURPOSE: TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers. EXPERIMENTAL DESIGN: Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes. RESULTS: We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers ( < 0.001) and lower tumor mutation burden ( < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8-13.2]. The best overall response rate achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI, 41-81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response. CONCLUSIONS: TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors. |
DOI | 10.1158/1078-0432.CCR-19-3165 |
Alternate Journal | Clin Cancer Res |
PubMed ID | 31871300 |
PubMed Central ID | PMC7124988 |
Grant List | T32 CA160001 / CA / NCI NIH HHS / United States R01 CA226864 / CA / NCI NIH HHS / United States R25 CA020449 / CA / NCI NIH HHS / United States T32 CA009512 / CA / NCI NIH HHS / United States T32 CA009207 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States KL2 TR002385 / TR / NCATS NIH HHS / United States |
Related Faculty:
James Solomon, M.D., Ph.D.