Colorectal cancer with gene fusions: Navigating the genomic landscape and treatment selection in a phase I unit.
Authors: Camila Braganca Xavier, Lei Kang, Hung Le, Michael Kahle, Apostolia Maria Tsimberidou, Aung Naing, Ecaterina Elena Dumbrava, Jordi Rodon Ahnert, Paula R. Pohlmann, Sarina A. Piha-Paul, Siqing Fu, Stephane Champiat, Timothy A. Yap, Tin-Yun Tang, Scott Kopetz, Funda Meric-Bernstam, David S. Hong
Journal: Journal of Clinical Oncology (2025)

3558 Background: Gene fusions are rare genomic events in colorectal cancer (CRC) and can co-occur with other potentially actionable alterations. Navigating early-phase trial selection in this scenario can be challenging. Objectives: To evaluate the genomic landscape, treatment selection, and clinical outcomes of patients (pts) with CRC harboring gene fusions enrolled in at least one clinical trial in the Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center. Methods: We used a computerized data extraction tool to review clinical and genomic data of pts with CRC harboring gene fusions between June 2011 and June 2024. The actionability of the genomic alterations was classified by the Precision Oncology Decision Support team. Median overall survival (mOS) was defined as the time from consent to the date of death or last follow up. Kaplan-Meier method was used to estimate survival and the Cox proportional hazards model to evaluate the impact of multiple variables. Results: 56 pts were included (28 female; 28 male) with a median age of 50.5 years (range 25-84). Colon was the most frequent tumor location (n=29, 51.8%) followed by rectal (n=15, 26.8%), small bowel (n=8, 14.3%), and appendiceal (n=3, 5.3%). Most cases had adenocarcinoma histology (n=54, 96.4%). The median time from diagnosis to completion of the molecular test identifying the gene fusion was 3 mo (range 0-36) for pts whose tumors were diagnosed in the metastatic setting. A total of 65 fusions were identified (range 1-3 per pt); 48 of them occurring in actionable or potentially actionable genes (78.8%) and 17 in non-actionable genes (26.2%). RAS alterations were present in 27 cases (48.2%) and BRAF alterations in 10 cases (17.9%). 8 patients had alterations in ERBB2 (14.3%) and 32 in genes related to DNA damage repair (DDR; 57.1%). In total, patients were enrolled in 91 trials (range 1-7 per pt). Target therapy (TT) was offered to 33 pts (58.9%) while the remaining were offered non-TT (n=23, 41.1%). Treatment selection was fusion-driven in 10 cases (17.9%; 4 NTRK, 3 FGFR, 1 RET, 1 ROS1, and 1 ALK). Notably, one pt with a ETV6-NTRK fusion was enrolled sequentially in 4 immunotherapy (IO) and TT trials, surviving on-trial for over 3.5 years. 3 patients received TT for KRAS (5.4%), 4 for BRAF (7.1%), 4 for ERBB2 (7.1%), and 8 for DDR alterations (14.3%). The mOS was 10.0 mo (95% CI, 5-NR) for pts receiving non-TT and 11 mo (95% CI, 3-21) for patients receiving TT (p 0.985). Age group (cutoff 50 years), gender, cancer stage at diagnosis, RAS, BRAF and DDR alterations, and treatment type (TT vs. non-TT or IO) were not related to survival in the multivariate level (p=0.9). Conclusions: A comprehensive genomic evaluation of pts with CRC harboring gene fusions can expand early-phase treatment possibilities. DDR alterations are more frequent in this group than in unselected CRC cohorts and can represent an additional target for TT.