The landscape of NTRK fusions in Chinese patients with solid tumor

Abstract

Background: NTRK gene fusions resulting in the elevated expression of TRK kinases were discovered in a wide variety of tumor types but generally at a low frequency. TRK inhibitors such as LOXO-101 and entrectinib had remarkable and durable antitumor activities in patients (pts) with TRK fusion-positive cancers, regardless of age or tumor type. Methods: FFPE tumor samples of over 3700 Chinese solid tumor pts were collected for NGS-based assay. We measured the gene fusions, mutations, and copy number alterations in tumor tissue against matched blood. Pan-Trk IHC testing was performed on five NTRK1 fusions. Results: 12 pts were idendified as NTRK fusion positive, which accounted to approximately 0.3% of the Chinese solid tumor pts in our cohort. Seven out of 12 pts harbored NTRK1 fusions with 6 partners, and the remaining ones were NTRK3 fusions with 2 partners. The half fusions with novel partner genes or breakpoints were defined as likely fusions. The tumor types of pts with NTRK fusions included NSCLC, colorectal cancer (CRC), prostate cancer and fibrosarcoma. NTRK fusions were more likely t occur in NSCLC and CRC, which accouted for 0.3% and 1.4%, respectively. Three predicted likely fusions and two known fusions were selected to perform pan-Trk IHC assay, and four were IHC positive. One known TPR-NTRK1 fusion not detected by IHC, which highlighted the necessity to use NGS to detect NTRK fusions due to higher sensitivity and capability. NTRK fusions were not always mutually exclusive with driver mutations. Three lung cancer pts with NTRK fusions also harbored EGFR-sensitive mutations. Conclusions: This study revealed NTRK fuisons in approximately 0.3% of Chinese solid tumor pts for the first time. The NTRK gene fusions more commonly occurred in NSCLC (0.3%) and CRC (1.4%), but may occur with other targetable alterations such as EGFR-activating mutations. NGS panel sequencing showed the advantage of detecting NTRK fusion and providing structure information of partners which could potentially guide more precise treatment options. (Table Presented) .