Association between somatic RET mutations and clinical and genetic characteristics in patients with metastatic colorectal cancer

Abstract Background Rearranged during transfection (RET) is a targetable oncogene. RET fusions have been reported in patients with metastatic colorectal cancer (mCRC). However, RET mutations in mCRC are less studied. Here, we aimed to characterize the clinical, pathological, and molecular landscape of RET-mutated mCRC. Methods Five hundred and eighty-two patients were included in this study. Next-generation sequencing was performed to detect RET mutations and calculate tumor mutation burden (TMB). We compared the clinical, pathological, and molecular characteristics of mCRC cases with tumors that harbored somatic RET mutations (N = 16, 2.7%) or had wild-type RET (N = 566, 97.3%). Results Males comprised the absolute majority of cases with RET mutations (15/16 [93.8%]) compared to their fraction among cases with wild-type RET (339/566 [59.9%]). Furthermore, all patients with RET mutations were younger than 60 years (16/16 [100%]), whereas such patients were less predominant in the group with wild-type RET (379/566 [67.0%]). Individuals with tumors positive for RET mutations more frequently exhibited mucinous histology (5/16 [31.2%] versus 55/566 [9.7%]), exhibited a lower incidence of liver metastasis (4/16 [25.0%] versus 335/566 [59.2%]) and higher incidence of peritoneal metastasis (9/16 [56.2%] versus 161/566 [28.4%]), expressed wild-type TP53 (8/16 [50.0%] versus 120/566 [21.2%]), and showed an increased frequency of MSI-high (6/16 [37.5%] versus 18/566 [3.2%]). In those with microsatellite-stable mCRC, patients with RET mutations had a higher median TMB than patients with wild-type RET (9.4 versus 6.7 mutations/Mb, respectively, P = 0.001). The median progression-free survival was similar in individuals with mutated and wild-type RET on the oxaliplatin-based regimen (7.1 versus 8.7 months, P = 0.516). Conclusions Our study suggests that cases with RET mutations represent a separate mCRC subtype. Further studies are needed to evaluate the efficacy of RET inhibitors in mCRC patients with RET mutations.