Abstract 1765P
Background
The prevalence of NTRK fusion in colorectal cancer (CRC) was very low (about 0.35%), and a majority of them happened in MSI-H CRC. As MSI-H was a well-known predictor of immune-checkpoint inhibitor (ICI) therapy, whether NTRK fusion has synergistic or antagonistic effect on MSI-H was unknown.
Methods
Tumor tissue and paired white blood cells from more than 20000 patients with solid tumor were collected and somatic variation and MSI status were analyzed by 74 cancer-related genes and 500 MSI loci in a CLIA-certified laboratory (3Medicine Inc.).
Results
Totally, 46 patients harbored one or more NTRK fusions, including 14 CRCs, 15 lung cancers, and 17 other cancer-types. In NTRK fusion-positive CRC patients, 78.57% (11/14) were MSI-H. Importantly, none of MSI-H CRC patients with NTRK fusion harbored KRAS variation. However, among 299 MSI-H CRC patients without NTRK fusion, 50.17% (150/299) harbored KRAS variation, which was significantly higher than the former (adjusted p-value = 0.03). KRAS variation was known as a negative predictor of ICI therapy in MSI-H CRC, which suggested that MSI-H patients with NTRK fusion may be more likely to benefit from ICI therapy. Besides KRAS, NRAS and TSC2 variations were also undetected in the NTRK fusion-positive and MSI-H CRC patients, and the frequency of TSC2 variation was higher in MSI-H patients without NTRK fusion (p-value = 0.04). Furthermore, in NTRK fusion-positive lung cancers (LC), the most frequently mutated genes were TP53 and EGFR, similar to that in LC without NTRK fusion. And no gene having significantly different variation frequency between NTRK fusion-positive and -negative LC was detected. In NTRK fusion-positive patients of various cancer types other than CRC and LC, the only frequently mutated gene was TP53. However, key driver genes like EGFR, PIK3CA, ROS1, APC, and CTNNB1 were detected in a few patients. Together, the previous report that NTRK fusion-positive patients were generally lack of driver gene variation may be inaccurate.
Conclusions
NTRK fusion and KRAS variation may be mutually exclusive in MSI-H CRC. And MSI-H CRC with NTRK fusion-positive patients may be more likely to benefit from ICI therapy, which worth further validating in clinical trial.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.