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

Ann Oncol. 2018 Jun 1;29(6):1394-1401. doi: 10.1093/annonc/mdy090.


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: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) 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 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 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 versus 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology*
  • Female
  • Follow-Up Studies
  • Gene Rearrangement*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Oncogene Proteins, Fusion / genetics*
  • Prognosis
  • Proto-Oncogene Proteins c-ret / genetics*
  • Survival Rate
  • Young Adult


  • Biomarkers, Tumor
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Associated data