ESMO E-Learning: Validated and Promising Predictive Factors in mCRC: Recent Updates on RAS Testing

Learning Objectives

  • To understand why and how recommendations for molecular testing have been changed recently in metastatic colorectal cancer  
  • To understand implications for Ras testing in clinical practice
  • To understand new perspectives for RAS testing in metastatic colorectal cancer 
Title Duration Content CME Points CME Test
Validated and Promising Predictive Factors in mCRC: Recent Updates on RAS Testing 31 min. 46 slides 1 Take Test
Fotios Loupakis
Fotios Loupakis
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The Epidermal growth factor receptor (EGFR) Antibody cetuximab was first approved a decade ago for use with FOLFIRI chemotherapy in metastatic colorectal cancer (mCRC). Another EGFR antibody, panitumumab, was approved for use with FOLFOX in a similar patient population. After these drug approvals, the data suggested that the most common activating mutations in KRAS, at codons 12 and 13 in Exon 2, were negative predictors for treatment benefit from EGFR antibodies. It was followed by regulatory agencies restricting cetuximab and panitumumab to the patients without KRAS exon 2 Mutations.

After no definitive predictive roles were identified for activating BRAF and PIK3CA mutations or for loss of PTEN expression, the focus shifted back to Ras. KRAS exon 3 and 4 mutations have been found as oncogenic and associated with resistance to EGFR-targeted agents in preclinical models. These findings have yielded interest in secondary analyses of numerous phase II and III clinical trials to investigate the effect of expanded RAS mutations.

Currently, the definition of expanded RAS has foreseen testing of KRAS and NRAS codons 12 and 13 (exon 2), 59 and 61 (exon 3), and 117 and 146 (exon 4). Mutations in KRAS and NRAS are typically mutually exclusive. Current evidence suggests routine testing for expanded RAS mutations in all patients with mCRC. Based on the European Medicines Agency recommendation, the European Commission has updated prescribing indications for panitumumab and cetuximab, restricting their use to patients with RAS Wild-type mCRC.

In this E-learning module, the author elaborates an extensive body of knowledge from various clinical trials on expanded RAS testing in mCRC. He encourages expanded RAS mutation testing as part of the initial work-up for mCRC, because it will identify an additional pool of patients who are unlikely to benefit from EGFR antibodies.

Furthermore, activating BRAF Codon 600 (exon 15) mutations occur in 5-10% of CRCs and are mutually exclusive from RAS mutations, with rare exceptions. BRAF V600–mutant CRCs have a poor prognosis and do not respond well to standard therapies. BRAF testing may be useful as ongoing BRAF-directed clinical trials offer a promise to this subgroup of patients.

Liquid biopsies may be a new reliable tool to track the dynamism of tumour progression and to clarify mechanisms of acquired resistance.

Last update: 16 June 2015

The author has reported no conflict of interest