PD-23 Comprehensive survey of AACR GENIE cBioPortal database of receptor tyrosine kinase fusion in colorectal carcinoma identified high co-occurring genomic alterations in NTRK1 & RET fusion-positive CRC

Receptor tyrosine kinase fusion (RTK+) has been identified in colorectal carcinoma (CRC). Tumor agnostic treatment has been approved in NTRK ( NTRK+ ) and RET fusion ( RET+ ) - positive solid tumor. However, ORR was the lowest among entrectinib-treated NTRK+ CRC (20%, 2/10) and selpercatinib treated RET+ CRC (20%, 2/10). It has been reported that NTRK+ and RET+ CRC have high tumor mutation burden (TMB) (mean TMB ∼ 30-50 mut/MB) and are MSI-unstable/Mismatch repair deficient. Thus, NTRK+ and RET+ CRC patients may benefit more from FDA approved immunotherapy (single agent pembrolizumab or dostarlimab) than TKIs in NTRK+ and RET+ CRC. We surveyed all 58 human RTKs to identify RTK fusions in CRC using AACR GENIE cBioPortal public version 13.0. We abstracted and compared the number of genomic co-alterations. Patient and tumor characteristics were also abstracted. Among the 14812 unique CRC patients (57.8% colon adenocarcinoma, 22.1% colorectal adenocarcinoma, 16.9% rectal adenocarcinoma, 2.3% mucinous CRC) identified in the AACR GENIE cbioportal, a total of 153 unique RTK fusions were identified (44 with known fusion partners, 109 with intragenic rearrangement) in 27 out of the total 58 human RTKs. The most common fusions were in FGFR1 (N = 23), EGFR (N = 21), ERBB2 (N = 10), NTRK1 (N = 10), RET (N = 10), FGFR2 (N = 10), FLT1 (N = 9), FLT3 (N = 9), FLT4 (N = 7), and ALK (N = 7). The mean number of genomic co-alterations were 69.9 +/- 13.2 for NTRK1+ CRC with identified fusion partner (N = 8), 72.3 +/- 24.1 co-mutations for RET+ CRC identified fusion partner (N = 4). Including intragenic rearrangement, the mean number was 67.7 +/- 13.2 for NTRK1+ CRC (N = 10) and 43.6 +/- 36.4 for RET+ CRC (N = 10). Combining NTRK1/3/RET+ CRC with known fusion partners (N = 13), the mean number of genomic co-mutations was 68.3 +/- 7.9 compared to mean number of 11.8 +/- 11.1 co-mutations for all other RTK+ CRC ( ALK, EGFR, FGFR1/2, ERBB4, FLT1/3/4, LMKT2, MET, NTRK2, PDGFR-b, ROS1 ) with known fusion partners (N = 30, one sample with no recorded genomic co-mutations, one duplicated sample). NTRK1+ CRC patients were 80% female, 100% Caucasian with mean age at sequencing of 67.9 (range: 54 – 84) years old. RET+ CRC patients were 70% female, 90% Caucasian with mean age of 72.3 (range: 64 – 88) years old. Mean age of the rest of the RTK+ CRC with fusion partners was 59.4 (range: 36 – 83), 70% female and 73.3% Caucasian. In this comprehensive survey of human RTK fusions in CRC, NRTK1+ and RET+ CRC harbor significantly higher mean co-occurring genomic alterations compared to other RTK+ CRC consistent with previous reports. Hypothesis-generating randomized trials comparing pembrolizumab versus target-specific TKIs should be performed to address optimal treatment of NTRK1/3/RET+ CRC.