Metastatic Colorectal Cancer: Beyond RAS and BRAF

Elucidating molecular landscape of mCRC in term of rare molecular alterations

Dr Filippo Pietrantonio of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy said in an oral presentation at the ESMO World Congress on Gastrointestinal Cancer 2017 (28 June – 1 July, Barcelona, Spain) that RET rearrangements define a new and rare molecular subtype of metastatic colorectal cancer (mCRC) associated with unfavourable prognosis and specific clinicopathological and molecular features.

RET fusions occur in less than 1% of CRCs, and may represent new therapeutic targets, as indicated by earlier promising reports of individual patients treated with tyrosine kinase inhibitors. However, the clinical and molecular landscape of RET rearranged mCRC is still largely unknown, explained Dr Pietrantonio in study background.

The study team identified patients worldwide with mCRC harboring RET fusions taking advantage of 1) previously published molecular case reports; 2) Italian and Korean screening collaboration; 3) phase I trial of RXDX-105 (NCT01877811); 4) Foundation Medicine Clinical Database.

Clinicopathological and molecular characteristics of RET rearranged cases were compared with those of non-rearranged cases screened at 3 referral centres in Milan, Pisa and Seoul.

In total 17 RET rearranged (including 10 NCOA4-RET, 6 CCDC6-RET and 1 TRIM24-RET fusions) and 189 not rearranged mCRCs were included in the report.

Rearrangements were more frequent in older patients (p = 0.016), RAS wild-type (p < 0.001), BRAF wild-type (p = 0.079) and MSI-high (p < 0.002). All RET fusions were found in RAS and BRAF wild-type (wt) tumours and, in 56% of cases, in MSI-high ones. No significant association with primary tumour location was found (p = 0.147).

At a median follow-up of 28.5 months, patients bearing RET rearranged tumours had a shorter overall survival (OS) when compared to non-rearranged (HR: 3.28, 95% CI 2.32-3.29; p < 0.001). In the multivariable model including other significant prognostic variables (primary tumour resection, RAS and MMR status), rearrangements were the only factor with retained borderline association with shorter OS (HR: 2.41, 95% CI 0.91 - 6.34; p = 0.077). A patient receiving FOLFOX-panitumumab experienced disease progression as best response, while treatments with unselective RETinhibitors such as regorafenib or sunitinib achieved short-lasting clinical benefit.

Data on preclinical activity of unselective and selective inhibitors in RET fusion positive patient-derived xenograft along with extended next generation sequencing molecular data were underway at time of the abstract submission.

Except for lack of significant association with right sidedness, the present findings in RET rearranged mCRC resemble those previously reported for ALK, ROS1 and NTRK positive cases. Since sensitivity to available treatment options, including anti-EGFR monoclonal antibodies (mAbs), may be very limited, targeted approaches with RET specific inhibitors, such as RXDX-105, should be a priority for future research.

Dr Pietrantonio was also a part of the study team who presented data from a case-control study of dissecting primary resistance to anti-EGFR mAbs in RAS and BRAF wt mCRC at ASCO 2017 Annual Meeting.

Only 40-50% of patients with RAS and BRAF wt CRC tumours achieve response to single agent anti-EGFR therapy. Different molecular alterations have been suggested as genomic predictors of primary resistance to anti-EGFR mAbs: 1. Alterations leading to the hyperactivation of tyrosine kinase receptors other than EGFR (HER2, MET, TrkA-C, ROS1, ALK, RET); 2. Mutations constitutively activating downstream signalling pathways (RAS/RAF/MAPKs, PI3K/PTEN7Akt). However, these different molecular alterations suggested as predictors of resistance have not been validated.

The investigators conducted a case-control study to prospectively demonstrate the negative predictive impact of HER2 amplification or mutations (mut), MET amplification, NTRK/ROS1/ALK/RET rearrangements, and mut activating MAPKs or PI3K/Akt axis. Patients with RAS and BRAF wt mCRC clearly resistant (cases) or clearly sensitive (controls) to anti-EGFR mAbs were selected.

Hypothesizing a prevalence of candidate alterations of 0% and 15% among controls and cases, 47 cases and 47 controls were needed to be able to reject the null hypothesis of equally prevalent alterations, with a- and b- error 0.05 and 0.20.

Since hypermutated tumours may hardly rely on a single pathway for their growth, the researchers also evaluated the impact of microsatellite instability (MSI).

In total 47 cases and 47 controls were included. Primary endpoint was met: mentioned alterations were reported in 20 (42.6%) cases and 1 (2.1%) control (p<0.001). MSI-high was significantly more frequent among resistant than sensitive tumours (15% vs 0%, p<0.001).

HER2 amplification was found in 7 resistant patients, HER2 mut (G776V, exon 20) in one patient with resistant disease, MET amplification in 5 patients with resistant mCRC, HER2 and MET co-amplification were found in one resistant patient, NTRK rearrangements were found in two cases with resistant mCRC (SCYL3-NTRK1 and TPM3-NTRK1), RET rearrangement in one case with resistant disease (CCDC6-RET), PIK3CA exon 20 mut (A1035V) was found in one resistant case while H1047R in one sensitive patient, AKT1 mut in one case of resistant disease (R25C, exon 2), and PTEN mut in 3 cases of resistant disease (L247S, R233stop and del P248, exon 7). 

RAS mut at low allele fraction by Hotspot Cancer Panel v2 was found in 3 cases and new RAS mut as well in 3 cases of resistant disease.

The study team concluded that it is the first prospective demonstration that the combined assessment of these rare alterations allows to better select patients for anti-EGFR mAbs, while opening the way to other tailored therapies.


  1. Pietrantonio F, Schrock A, Lee J, et al. RET rearrangements define a new and rare molecular subtype of metastatic colorectal cancer (mCRC); abstract O-011. Ann Oncol (2017) 28 (suppl_3): mdx262.010. DOI:
  2. Cremolini C, Morano F, Moretto R, et al. Dissecting primary resistance to anti-EGFRs in RAS and BRAF wt metastatic colorectal cancer (mCRC): A case-control study. J Clin Oncol 35, 2017 (suppl; abstr 11508)