The number of molecular biomarkers to inform treatment decisions in patients with metastatic colorectal cancer (mCRC) continues to expand and with it the methodologies that can be employed to evaluate these biomarkers. Beyond standard diagnostic and prognostic biomarkers, such as those used for Lynch syndrome, mutations in KRAS exon 2 are well established as predictive for lack of response to the antiepidermal growth factor receptor therapies panitumumab and cetuximab. Recent studies have extended these findings by demonstrating that mutations in KRAS exons 3 and 4 and in NRAS exons 2, 3, and 4 (with all KRAS and NRAS mutations collectively referred to as RAS) are also predictive for treatment outcomes among patients with mCRC receiving panitumumab and cetuximab in combination with chemotherapy or as monotherapy. Consequently, evaluation of these additional loci has been incorporated into current clinical guidelines, and pathologists will need to develop testing procedures and algorithms to reliably and rapidly evaluate RAS status. With the increased number of mutations that must be examined to evaluate the status of RAS and other emerging biomarkers, next-generation sequencing technologies are likely to become increasingly important in mCRC testing. This review describes new considerations for pathologists that have arisen as a consequence of the incorporation of additional biomarker testing into clinical practice for mCRC.
*City of Hope National Medical Center, Duarte
†Cedars-Sinai Medical Center, Los Angeles
‡Amgen Inc., Thousand Oaks, CA
R.K.P. and J.R.L. contributed equally.
R.K.P. and T.S. received support by the National Cancer Institute of the National Institutes of Health under Award Number P30CA33572.
S.D.P. is currently employed at Gilead Sciences Inc., Foster City, CA. S.D.P. was an employee of and stockholder in Amgen Inc. at the time this manuscript was written. C. E. Lofton-Day is an employee of and stockholder in Amgen Inc.
Reprints: Jean R. Lopategui, MD, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, SSB, Suite 362, Los Angeles, CA 90048 (e-mail: firstname.lastname@example.org).
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