Journal Article

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 Fucà, 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 Chiu, M 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 and C Cremolini

in Annals of Oncology

Published on behalf of European Society Medical Oncology

Volume 29, issue 6, pages 1394-1401
Published in print June 2018 | ISSN: 0923-7534
Published online March 2018 | e-ISSN: 1569-8041 | DOI: https://dx.doi.org/10.1093/annonc/mdy090
RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

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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.

Keywords: RET; colorectal cancer; gene fusions; targeted therapy; MSI-high; prognosis

Journal Article.  2850 words.  Illustrated.

Subjects: Medical Oncology

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