Can Molecular Testing Indicate Optimal Treatment in Metastatic Colorectal Cancer?

Making Sense of Evidence

Centers for Disease Control and Prevention, Office of Public Health Genomics


July 01, 2013

Evidence and Recommendations for Genetic Marker Testing

The EWG found enough evidence on the analytic and clinical validity, as well as clinical utility, to support their recommendation for clinical use of KRAS mutation analysis for mCRC patients who are being considered for therapy with cetuximab or panitumumab. For all other markers considered in the recommendation, they reported "insufficient evidence to recommend for or against" use of the tests in this clinical scenario.[1] Basic findings and characteristics of the evidence are summarized in the Table .

EWG evaluation methods are built upon the ACCE model process -- the acronym representing components of evaluation: Analytic validity; Clinical validity; Clinical utility; and Ethical, legal, social implications (ELSI).[2,3] In the EGAPP recommendation considered here, analytic validity referred to accurate and reliable detection of selected mutations in KRAS, BRAF, NRAS, and PIK3CA and loss of expression of PTEN and AKT proteins. Clinical validity included such outcomes as response rates and survival, whereas clinical utility focused on the balance of benefits vs harms, and usefulness in terms of avoiding side effects and ineffective therapy.[1]

Clinical Benefit: Are We There Yet?

In the discussion of research gaps relevant to KRAS testing, the EWG presented emerging evidence suggesting that a particular codon 13 mutation (p.G13D) may actually be associated with response to anti-EGFR therapy; however, prospective studies are needed in support. With respect to BRAF, the EWG noted that "[i]t remains unclear whether there is additional benefit of pharmacogenetic testing for BRAF with respect to ability to predict poor prognosis independent of treatment effects." For the other tests considered, the EWG noted the need for supporting studies of "good" quality (as characterized in published EGAPP methods, and based upon assessment of hierarchies of data source and assessment of internal validity).[1]

The EWG has issued 8 recommendation statements since 2007.[4] In all but 1 previous EWG statement, the available evidence has been insufficient to support a recommendation for or against the use of the test under consideration. KRAS mutation analysis is only the second instance among the tests considered by EGAPP where enough evidence was available to support recommending its use (testing all newly diagnosed CRC patients for Lynch syndrome to benefit family members was the first[5]). Although there are existing guidelines supporting the use of KRAS testing to predict nonresponse to anti-EGFR therapy in mCRC, this is the first time a US-based evidence group has addressed testing for BRAF, NRAS, and PIK3CA mutations and PTEN and AKT protein expression in this clinical scenario.[1]