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

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.