RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

BACKGROUND: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: 1) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811); 2) cohorts screened at two Italian and one South Korean Institutions; 3) Foundation Medicine Inc. database. Next generation sequencing data were analyzed for RET rearranged cases. RESULTS: RET fusions were more frequent in older patients (median age of 66 vs. 60 years, p = 0.052), with ECOG PS 1-2 (90% vs. 50%, p = 0.02), right-sided (55% vs. 32%, P=0.013), previously unresected primary tumors (58% vs. 21%, P<0.001), RAS and BRAF wild-type (100% vs. 40%, p < 0.001) and MSI-high (48% vs. 7%, P<0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 vs. 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P<0.001). In the multivariable model, RET rearrangements were still associated with shorter OS [HR: 2.97; 95% CI, 1.25-7.07; P=0.014], while primary tumor location, RAS and BRAF mutations and MSI status were not. CONCLUSIONS: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.