Woo et al have comprehensively reviewed controversies surrounding anti–epidermal growth factor receptor (anti-EGFR) treatment in metastatic colon cancer, specifically the unresolved issue of anti-EGFR therapy in patients with colorectal carcinomas (CRC) harboring KRAS Gly13Asp (G13D) mutation. Even before the report by De Roock et al on the potential benefit of cetuximab in CRC with KRAS p.G13D, there were contradicting data on the prognostic significance of this mutation (reviewed in Hartman et al). The apparently discrepant clinical and cell line data may be reconciled by taking into account the phenomenon of mutant allele–specific imbalance (MASI).
Introduced by Soh et al, the term “MASI” summarizes a variety of mechanisms that may lead to the predominance of the mutated allele over the wild-type allele. Such an allelic imbalance favoring the mutant allele may result from the deletion of the wild-type allele, and/or copy number gain of the mutant allele. It was shown that KRAS MASI is associated with increased ras guanine triphosphatase activity in cell lines and worse outcome in KRAS-mutated CRC. In a study of 394 patients with KRAS-mutated CRC, KRAS MASI developed by chromosome 12 hyperploidy or KRAS amplification, most frequently in cases with KRAS codon 13 mutations. In a multivariate analysis, KRAS codon 13 MASI represented an adverse prognostic factor independent of clinical stage and tumor site.
We would like to suggest for future reports on anti-EGFR therapy in KRAS p.G13D-mutated CRC to explicitly control for KRAS MASI. Two scenarios are likely. First, the presence or absence of KRAS MASI may correlate with response to anti-EGFR treatment. Alternatively, anti-EGFR treatment may have no therapeutic effect and the outcome differences attributed to anti-EGFR therapy in some studies may merely reflect the unaccounted effect of KRAS MASI. Practically, KRAS MASI can be estimated from a semiquantitative review of routine sequencing electropherograms or by more sophisticated methods aimed at detecting KRAS allelic imbalances, chromosome 12 hyperploidy, or KRAS amplification.
Douglas J. Hartman, MD
Simion I. Chiosea, MD
Department of Pathology
University of Pittsburgh Medical Center