Work

Tumor Mutation Burden Survey of AACR GENIE Database Revealed NTRK ( NTRK +) and RET ( RET +) Fusions Positive Colorectal Carcinoma (CRC) as Distinct Subsets

Year: 2025

Type: article

Abstract: BACKGROUND: Receptor tyrosine kinase (RTK) inhibitors have been approved for the treatment of NTRK fusion (NTRK+) and RET fusion (RET+) positive solid tumors in a tumor-agnostic manner. However, the objective response rate was the lowest among entrectinib-treated NTRK+ colorectal cancer (CRC) (20%) and selpercatinib-treated RET+ CRC (20%) among all NTRK+, and RET+ solid tumors, respectively. METHODS: We compared tumor mutation burden (TMB) in NTRK+/RET+ CRC with all other NTRK+ and RET+ solid tumors using the American Association for Cancer Research (AACR) GENIE database (Version 13.0). RESULTS: We identified 14,812 unique CRC patients. Considering only samples with identified fusion partners, the mean TMB was 66.6 ± 15.8 (mt/MB) for NTRK+ CRC (N = 9) and 35 ± 11.5 for RET+ CRC (N = 4), which were significantly higher when compared to the mean number of 6.2 ± 5.4 of TMB for all other RTK+ CRC (N = 30, p < 0.05). Furthermore, NTRK+ CRC harbored significantly higher TMB than RET+ CRC (p = 0.003). In comparison, the mean TMB was 4.0 ± 1.9 for RET+ NSCLC (N = 65) and 2.6 ± 1.6 for RET+ Thyroid cancer (N = 52). Mean TMB for all other NTRK+ solid tumors was < 11 and significantly lower than the mean TMB of NTRK+ CRC. 1482 (10.0%) CRC patients had their MSI status reported. Three out of three NTRK+ CRC patients with known MSI status were all dMMR (100%). 0 out of 12 non-NTRK/non-RET RTK+ CRC patients were dMMR (0%). CONCLUSIONS: NRTK+ and RET+ CRC possess significantly higher TMB than other RTK+ CRC or NTRK+/RET+ non-CRC solid tumors. TMB testing should be routinely done in MSI-H CRC, and TMB ≥ 35 mut/MB samples should be screened for NTRK and RET fusions as an enrichment strategy to provide additional treatment for NTRK+ and RET+ CRC patients.

Source: Cancer Medicine

DOI: 10.1002/cam4.70665

Authors: Zhaohui Liao Arter, Alexandria T. M. Lee, Misako Nagasaka, Sai‐Hong Ignatius Ou

Institutions: University of California, Irvine, UC Irvine Chao Family Comprehensive Cancer Center

Language: English

Topic: Colorectal Cancer Treatments and Studies

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,700