Mandatory Extended RAS Testing for mCRC

Alok A. Khorana, MD


September 19, 2014

Extended RAS Mutations and Anti-EGFR Monoclonal Antibody Survival Benefit in Metastatic Colorectal Cancer: a Meta-analysis of Randomized Controlled Trials

Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS
Ann Oncol. 2014 Aug 12. [Epub ahead of print]

Study Summary

Multiple subgroup analyses of randomized trials[1,2,3,4,5] have suggested that patients who have "extended RAS" mutations (in exons 3 and 4 of KRAS and exons 2, 3, and 4 of NRAS) not only may not benefit from anti-epidermal growth factor receptor (EGFR) therapy but may potentially be harmed. Sorich and colleagues conducted a systematic review and meta-analysis of such reported trials. Overall, nine trials of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria.

Approximately 20% of KRAS exon 2 wild-type tumors were found to have one of the extended RAS mutations. "True" wild-type RAS mutations (either KRAS exon 2 or new RAS mutations) had significantly superior progression-free survival (PFS) (P < .001) and overall survival (OS) (P = .008) with use of anti-EGFR monoclonal antibodies (mAbs). Benefits were consistent across anti-EGFR agents, variations in chemotherapy backbone, and lines of therapy. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > .05).


This study confirms emerging data from a variety of subgroup analyses of previously conducted randomized controlled trials that extended RAS mutations should properly be classified alongside KRAS and be considered a contraindication to treatment with anti-EGFR therapy. Altogether, approximately 55% of all metastatic colorectal patients are now considered to be RAS-mutant. Continuing to treat these patients with anti-EGFR therapy exposes them to significant additional toxicity without likelihood of benefit; in addition, this approach also costs the health system significant financial resources.

Although there was significant treatment-effect heterogeneity across studies in the mutant population, it is worthwhile to note that some subgroup analyses suggested worsened median survival in RAS-mutant patients. At the time of treatment decision, extended RAS testing (as opposed to only KRAS) should therefore be mandatory. Pathology departments and treating clinicians will need to ensure that testing on clinical specimens can be coordinated in a timely fashion to prevent patients from receiving potentially harm-inducing regimens.


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