Colorectal cancer (CRC) is the second leading cause of cancer death in the U.S. [1
]. Despite improvements in CRC screening rates, an unfortunately large percentage of patients present with locally advanced or metastatic disease at the time of diagnosis [1
]. Over the last decade, the development of novel therapeutics, including biologic agents such as antibodies that target the epidermal growth factor receptor (EGFR), has improved the prognosis for metastatic CRC (mCRC) patients. Recently, advances in our understanding of the EGFR pathway have led to the routine use of Kirsten-ras (KRAS
) mutational status as a predictive marker of response to anti-EGFR therapy.
Although EGFR is overexpressed in the majority (50%–80%) of colorectal tumors, it is clear that EGFR-targeted therapies are effective in only a subset of these patients. To use targeted drugs most effectively, it is important to identify rational molecular markers of response or lack of response to the therapy; such an approach optimizes the use of financial resources and prevents patients from receiving ineffective drugs. A well-known example of drug development paralleling discovery of rational molecular targets is trastuzumab, an anti–human epidermal growth factor receptor (HER)-2 monoclonal antibody. HER-2 is overexpressed in 10%–30% of malignant breast cancers, and overexpression of HER-2 is a strong predictor of response to trastuzumab therapy [2
]. Since its approval by the U.S. Food and Drug Administration (FDA), trastuzumab use has been limited to patients whose tumors overexpress HER-2.
Like HER-2 overexpression in breast cancer, KRAS mutational status has emerged as a predictive molecular marker in CRC. Rigorous data have now clearly shown that activating KRAS mutations predict lack of response to anti-EGFR therapy. In fact, KRAS mutational status has also been shown to play a prognostic and predictive role in other tumor types, including lung cancer. This review highlights the major studies that have shown this correlation as well as the resulting changes to clinical guidelines and the FDA labeling for cetuximab and panitumumab. Further, the potential role of mutations at other points in the EGFR signaling pathway [including mutations in BRAF, loss of phosphatase and tensin homologue deleted on chromosome ten (PTEN) expression, and mutations in the phosphatidylinositol-3-kinase (PI3K)–AKT pathway] in predicting response to anti-EGFR therapy is discussed.