RET-fusions: a novel paradigm in colorectal cancer
Authors: C. Santos, R. Sanz-Pamplona, R. Salazar
Journal: Annals of Oncology (2018)

The development of deep sequencing assays has allowed the identification of new oncogenic alterations in solid tumours. In the last decades, multiples gene fusions produced by chromosomal rearrangements have been described, although few of them are clinically relevant [1.Schram A.M. Chang M.T. Jonsson P. Drilon A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance.Nat Rev Clin Oncol. 2017; 14: 735-748Crossref PubMed Scopus (124) Google Scholar]. Gene fusions resulting in kinase activation lead to an increased activity in downstream signalling pathways promoting tumour growth and cell survival. Moreover, these kinases represent potential targets for drug development. Kinase fusions involving ALK, ROS1, RET, NTRK1/2/3, FGFR1/2/3, BRAF, CRAF and PRKCA/B have been identified in different tumour types, although frequency and distribution differ between them [2.Stransky N. Cerami E. Schalm S. et al.The landscape of kinase fusions in cancer.Nat Commun. 2014; 5: 4846Crossref PubMed Scopus (492) Google Scholar]. In colorectal cancer (CRC) gene rearrangements have been described in <1% of cases [2.Stransky N. Cerami E. Schalm S. et al.The landscape of kinase fusions in cancer.Nat Commun. 2014; 5: 4846Crossref PubMed Scopus (492) Google Scholar, 3.Kloosterman W.P. Coebergh van den Braak R.R.J. Pieterse M. et al.A systematic analysis of oncogenic gene fusions in primary colon cancer.Cancer Res. 2017; 77: 3814-3822Crossref PubMed Scopus (48) Google Scholar]. As observed in other tumour types [4.Qi M. Li Y. Liu J. et al.Morphologic features of carcinomas with recurrent gene fusions.Adv Anat Pathol. 2012; 19: 417-424Crossref PubMed Scopus (7) Google Scholar], these gene alterations define a subtype of CRC characterised by the absence of BRAF and RAS mutations and high microsatellite instability [3.Kloosterman W.P. Coebergh van den Braak R.R.J. Pieterse M. et al.A systematic analysis of oncogenic gene fusions in primary colon cancer.Cancer Res. 2017; 77: 3814-3822Crossref PubMed Scopus (48) Google Scholar, 5.Pietrantonio F. Di Nicolantonio F. Schrock A.B. et al.ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer.J Natl Cancer Inst. 2017; 109 () doi101093/jnci/djx089)Crossref PubMed Scopus (103) Google Scholar]. ALK, ROS1, RET, NTRK3, BRAF and RSPO1 are the common gene fusions identified in CRC primary tumours [5.Pietrantonio F. Di Nicolantonio F. Schrock A.B. et al.ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer.J Natl Cancer Inst. 2017; 109 () doi101093/jnci/djx089)Crossref PubMed Scopus (103) Google Scholar, 6.Le Rolle A.F. Klempner S.J. Garrett C.R. et al.Identification and characterization of RET fusions in advanced colorectal cancer.Oncotarget. 2015; 6: 28929-28937Crossref PubMed Scopus (63) Google Scholar] and constitute a novel paradigm of oncogenic addiction. In this issue, Pietrantonio et al. report clinical, pathological and molecular characteristics of a well-documented case series of RET rearranged metastatic CRC patients [7.Pietrantonio F. Di Nicolantonio F. Schrock A.B. et al.RET fusions in a small subset of advanced colorectal cancers at risk of being neglected.Ann Oncol. 2018; 29: 1394-1401Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. Fluorescent in situ hybridisation (FISH) and immunohistochemistry analyses were used to screen RET fusions. From a total of 315 samples, 24 (7.6%) were found to harbour RET rearrangements. Interestingly, tumours with RET fusions are characterised by a right colon location, older age at diagnosis, RAS and BRAF wild-type and predominantly MSI-high, probably defining a new CRC subtype. Therefore, although RET fusions are not frequent events, they are confined in a particular group of CRC samples. Indeed, the authors point out that more than two thirds of patients with right sided, MSI-high and RAS/BRAF wild-type tumours harbour RET fusions. Moreover, RET rearrangements could be considered a new putative prognostic marker as positive-RET patients have a fourfold increased risk of death compared with negative-RET patients. To conclude, the authors suggest to test RET fusions in this specific population to identify patients who may potentially benefit from RET inhibitors and improve the poor prognosis observed with conventional therapies. RET is a proto-oncogene that encodes a transmembrane receptor with a tyrosine kinase domain. Different alterations, either mutations or rearrangements, result in kinase activation which activates downstream signalling pathways such as RAS/MAPK, PI3K/AKT or JNK leading to tumour growth and cell survival [8.Jhiang S.M. The RET proto-oncogene in human cancers.Oncogene. 2000; 19: 5590-5597Crossref PubMed Scopus (232) Google Scholar]. RET aberrations are present in <2% of solid neoplasms (mutations 38.6%, fusions 30.7%, amplifications 25% and other rearrangement 3.4%) but represent a hallmark of specific tumour types such as thyroid carcinomas, including medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC), which harbour RET alterations in up to 80% of cases [9.Kato S. Subbiah V. Marchlik E. et al.Aberrations in diverse cancers: next-generation sequencing of 4,871 Patients.Clin Cancer Res. 2017; 23: 1988-1997Crossref PubMed Scopus (90) Google Scholar, 10.Yakushina V.D. Lerner L.V. Lavrov A.V. Gene fusions in thyroid cancer.Thyroid. 2018; 28: 158-167Crossref PubMed Scopus (36) Google Scholar]. In other solid tumours the incidence of RET alterations is much lower. RET fusions and mutations have been detected in lung adenocarcinomas (5.6%), ovarian epithelial carcinoma (7.4%) or salivary gland adenocarcinomas (6.5%) [9.Kato S. Subbiah V. Marchlik E. et al.Aberrations in diverse cancers: next-generation sequencing of 4,871 Patients.Clin Cancer Res. 2017; 23: 1988-1997Crossref PubMed Scopus (90) Google Scholar]. Different RET fusion partners have been identified although CCDC6 and NCO4 are the most frequent (COSMIC database). In agreement, these are the most prevalent gene fusions reported by Pietrantonio et al. In addition, they also described two novel rearrangements, TNIP1-RET and SNRNP70-RET. The identification of these alterations is clearly relevant because several multi-tyrosine kinase (MTK) inhibitors with anti-RET activity have been developed in the last decade [11.Drilon A. Hu Z.I. Lai G.G.Y. Tan D.S.W. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes.Nat Rev Clin Oncol. 2017; 15: 150Crossref PubMed Scopus (15) Google Scholar]. Vandetanib and cabozantinib, both MTK inhibitors, have been approved by the FDA and EMA for metastatic or non resectable MTC due to the effect on progression-free survival [12.Wells S.A. Robinson B.G. Gagel R.F. et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2012; 30: 134-141Crossref PubMed Scopus (885) Google Scholar, 13.Elisei R. Schlumberger M.J. Müller S.P. et al.Cabozantinib in progressive medullary thyroid cancer.J Clin Oncol. 2013; 31: 3639-3646Crossref PubMed Scopus (645) Google Scholar]. Vandetanib—a VEGFR2, EGFR and RET inhibitor—demonstrated efficacy in terms of progression-free survival in unresectable locally advanced or metastatic MTC compared with placebo (hazard ratio = 0.46, 95% CI, 0.31–0.69) [12.Wells S.A. Robinson B.G. Gagel R.F. et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2012; 30: 134-141Crossref PubMed Scopus (885) Google Scholar]. Similar efficacy results were reported with cabozantinib—an MET, VEGFR1-2 and RET inhibitor—in the EXAM trial [13.Elisei R. Schlumberger M.J. Müller S.P. et al.Cabozantinib in progressive medullary thyroid cancer.J Clin Oncol. 2013; 31: 3639-3646Crossref PubMed Scopus (645) Google Scholar]. Cabozantinib led to a substantial improvement in progression-free survival compared with placebo (11.2 versus 4.0 months, P-value <0.001). Interestingly, vandetanib and cabozantinib benefit was more evident in patients with RET M918T-positive tumours (56.5% and 35.7% of the studies populations, respectively), with a significant improvement in both progression-free survival (13.9 versus 4.0 months, P-value <0.0001) and overall survival (44.3 versus 18.9 months, P-value = 0.03) for cabozantinib [12.Wells S.A. Robinson B.G. Gagel R.F. et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2012; 30: 134-141Crossref PubMed Scopus (885) Google Scholar, 14.Schlumberger M. Elisei R. Müller S. et al.Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma.Ann Oncol. 2017; 28: 2813-2819Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. Later on, other MTK inhibitors such as sorafenib and lenvatinib also demonstrated benefit in different phase III clinical trials in patients with radioactive iodine-refractory differentiated thyroid carcinomas, and were subsequently approved by the major agencies in this indication [15.Brose M.S. Nutting C.M. Jarzab B. et al.Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.Lancet. 2014; 384: 319-328Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar, 16.Schlumberger M. Tahara M. Wirth L.J. et al.Lenvatinib in radioiodine-refractory thyroid cancer.N Engl J Med. 2015; 372: 621Crossref PubMed Scopus (689) Google Scholar]. The prolonged progression-free survival with MTK inhibitors observed in tumours enriched with RET aberrations, such as thyroid cancers, led to investigate the role of these target agents in a subset of lung carcinomas harbouring RET alterations [11.Drilon A. Hu Z.I. Lai G.G.Y. Tan D.S.W. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes.Nat Rev Clin Oncol. 2017; 15: 150Crossref PubMed Scopus (15) Google Scholar]. Different phase II clinical trials have evaluated the role of cabozantinib or vandetanib in NSCLC, showing median overall response rates up to 47% [17.Drilon A. Rekhtman N. Arcila M. et al.Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.Lancet Oncol. 2016; 17: 1653-1660Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 18.Yoh K. Seto T. Satouchi M. et al.Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.Lancet Respir Med. 2017; 5: 42-50Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar]. RET aberrations are frequent oncogenic events only in thyroid carcinomas (MTC and PCT). Thus, in this tumour type it is cost-efficient to run RET molecular test (not only mutational analysis), and its evaluation is recommended in the routine clinical practice [19.Wells S.A. Asa S.L. Dralle H. et al.Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma.Thyroid. 2015; 25: 567-610Crossref PubMed Scopus (901) Google Scholar]. However, RET analysis in other tumour types could be no cost-effective due to its low frequency of alterations. In these settings, it would be helpful to predefine a subset of patients with a potentially higher rate of RET alterations. In this sense, Pietrantonio et al have characterised a subgroup of CRC patients, defined by RAS/BRAF wild-type and MSI-high tumours located in right colon, enriched in RET fusions. Previously, the authors reported the clinicopathological and molecular characteristics of ALK/ROS1/NTRK1 rearranged metastatic CRC [5.Pietrantonio F. Di Nicolantonio F. Schrock A.B. et al.ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer.J Natl Cancer Inst. 2017; 109 () doi101093/jnci/djx089)Crossref PubMed Scopus (103) Google Scholar]. Fusions in these genes defined a subgroup of patients with tumours characterised by right-sided, high microsatellite instability and RAS wild-type. It is noteworthy that genes fusions in CRC confer poor prognosis and could be also a new mechanism of treatment resistance [5.Pietrantonio F. Di Nicolantonio F. Schrock A.B. et al.ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer.J Natl Cancer Inst. 2017; 109 () doi101093/jnci/djx089)Crossref PubMed Scopus (103) Google Scholar]. In other tumour types, such as lung carcinomas, positive-RET tumours also constitute a different cancer subtype [20.Drilon A. Wang L. Hasanovic A. et al.Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas.Cancer Discov. 2013; 3: 630-635Crossref PubMed Scopus (377) Google Scholar, 21.Tsuta K. Kohno T. Yoshida A. et al.RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis.Br J Cancer. 2014; 110: 1571-1578Crossref PubMed Scopus (90) Google Scholar]. Additionally, other noncolorectal tumour types with high microsatellite instability, such as gastric or endometrial cancers, warrant further investigations to check out for these gene rearrangements, which could also be game changing. From a therapeutic point of view, since the results reported from phase II and III clinical trials in thyroid and lung cancers are so positive, it is expected that other positive-RET tumours could benefit from anti-RET drugs. However, due to its rarity, it is not feasible to conduct clinical trials in specific diseases and data of antitumour activity derived from early trials, real world data (RWD) [22.Gautschi O. Milia J. Filleron T. et al.Targeting RET in patients with RET-rearranged lung cancers: results from the global, Multicenter RET Registry.J Clin Oncol. 2017; 35: 1403-1410Crossref PubMed Scopus (178) Google Scholar] or case reports. In this sense, a number of basket clinical trials including solid tumours with RET aberrations are ongoing (NCT02272998, NCT03157128, NCT03194893, NCT02450123, NCT03037385, NCT01877811) and may elucidate the therapeutic activity in patients with positive-RET tumours beyond thyroid and lung cancers. In conclusion, deep sequencing techniques (RNA-seq and next generation sequencing assays) have allowed the identification of recurrent gene fusions as relevant events in CRC, as well as in other tumour types. Therefore, we should consider to evaluate gene rearrangements, including RET fusions, in a specific CRC population defined by MSI-high tumours with nondriver mutations, because up to two-thirds of these tumours could be addicted to these genomic aberrations (Figure 1). These patients could benefit from different therapeutic strategies that include tyrosine kinase inhibitors, although this warrants further investigation under currently ongoing clinical trials or RWD studies. None declared.