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

F Pietrantonio, F Di Nicolantonio, A B Schrock, J Lee, F Morano, G Fuca, P Nikolinakos, A Drilon, J F Hechtman, J Christiansen, K Gowen, G M Frampton, P Gasparini, D Rossini, C Gigliotti, S T Kim, M Prisciandaro, J Hodgson, A Zaniboni, V K ChiuM Milione, R Patel, V Miller, A Bardelli, L Novara, L Wang, S M Pupa, G Sozzi, J Ross, M Di Bartolomeo, A Bertotti, S Ali, L Trusolino, A Falcone, F de Braud, C Cremolini

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1394-1401
Number of pages8
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume29
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

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