F Pietrantonio1, F Di Nicolantonio2, A B Schrock3, J Lee4, F Morano5, G Fucà5, P Nikolinakos6, A Drilon7, J F Hechtman8, J Christiansen9, K Gowen3, G M Frampton3, P Gasparini10, D Rossini11, C Gigliotti2, S T Kim4, M Prisciandaro5, J Hodgson6, A Zaniboni12, V K Chiu13, M Milione14, R Patel9, V Miller3, A Bardelli2, L Novara15, L Wang16, S M Pupa10, G Sozzi10, J Ross3, M Di Bartolomeo5, A Bertotti2, S Ali3, L Trusolino2, A Falcone11, F de Braud17, C Cremolini11. 1. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy. Electronic address: filippo.pietrantonio@istitutotumori.mi.it. 2. Department of Oncology, University of Torino, Candiolo, Italy; ECMO, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy. 3. Clinical Development, Foundation Medicine, Inc., Cambridge, USA. 4. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 5. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 6. Medical Oncology, University Cancer & Blood Center, Athens. 7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. 8. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. 9. Department of Diagnostics, Ignyta, Inc., San Diego, USA. 10. Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 11. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. 12. Department of Medical Oncology, Fondazione Poliambulanza, Brescia, Italy. 13. Department of Internal Medicine, University of New Mexico, Albuquerque, USA. 14. Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 15. ECMO, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy. 16. Department of Pathology, St Jude Children's Research Hospital, Memphis, USA. 17. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
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.
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.
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