Epidermal Growth Factor Receptor Pathway Mutations and Colorectal Cancer Therapy

Context.—Rational anticancer therapy is beginning to expand the practice of surgical pathology beyond a primarily morphologic and immunophenotypic analysis into the molecular arena. Molecular testing of tumors can have both diagnostic and therapeutic value, which guides treatment decisions. This is true for colorectal cancer in which mutations in signaling mediators predict resistance to anti–epidermal growth factor receptor (anti-EGFR) therapy. Objective.—To review the clinically relevant mutations that currently guide treatment decisions in metastatic colorectal cancer, summarize additional mutations that are expected to improve the prognostic sensitivity of molecular testing, and provide practical suggestions for submitting specimens for molecular analysis. Data Sources.—Peer-reviewed literature reporting pertinent clinical trial data, mutation analysis, and molecular mechanisms of drug resistance, as well as comprehensive review articles germane to the topic and published testing recommendations from the College of American Pathologists. Conclusions.—Molecular analysis of colorectal cancer is now mandated before initiation of anti-EGFR therapy and directly impacts treatment options and outcomes. Familiarity with the mutations that determine utility and efficacy of therapy, as well as the importance of careful sample selection, will facilitate appropriate testing and optimize patient care.