Posted March 2, 2009
Mark D. Pool, MD, FCAP
CAP Molecular Oncology Committee
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Retrospective analyses from several recent large clinical trials in metastatic colorectal cancer (mCRC) have examined the role of mutations in the KRAS gene with the response to treatment using the epidermal growth factor receptor (EGFR) monoclonal antibody inhibitors cetuximab and panitumumab.1-8 These data show that both of these agents are ineffective in patients with KRAS mutation. Recently published guidelines from the National Comprehensive Cancer Network9 and the American Society of Clinical Oncology10 recommend KRAS mutation testing as part of the evaluation of mCRC patients who are being considered for anti-EGFR therapy.
EGFR is overexpressed in a large majority of colon cancers, yet there has been poor correlation between EGFR expression by immunohistochemistry and treatment response. This lack of correlation suggests that downstream effectors may be as important as EGFR expression for treatment response. Activation of EGFR triggers multiple signaling pathways resulting in promotion of tumor growth, inhibition of apoptosis, vascular proliferation, invasion, and metastasis. The most important of these pathways for CRC appears to be the Ras signaling pathway.11 Ras proteins are small GTPases, and activated Ras interacts with more than 20 different effectors. KRAS has been long known to be involved in the development and progression of CRC12 and is mutated in about 40% of CRC. The KRAS mutations most commonly found in CRC are at codons 12 and 13 and prevent dephosphorylation and inactivation of the protein, causing it to be permanently switched on, independent of EGFR-mediated signaling. Thus, a mutated KRAS protein would not likely be affected by inhibition of EGFR.
Although there is currently no FDA-approved test for the detection of KRAS mutations, several tests are commercially available. A recently presented abstract that examined 40 formalin-fixed paraffin embedded (FFPE) CRC tissues showed that, despite different methodologies, these four tests yielded comparable results,13 although allele-specific hybridization methods (HistoGeneX and Genzyme) had the highest correlation with the reference methodology of direct sequencing. The KRAS mutation test may be performed on fresh, frozen, or FFPE tissue. In contrast to HER2 expression in breast cancer, KRAS mutation occurs early in CRC carcinogenesis and is unlikely to change during disease progression. Thus, although not confirmed by prospective studies, current practice is not to re-biopsy a tumor recurrence for KRAS testing if there is sufficient material available from the previous biopsy or resection.
Pathologists play an essential role in KRAS testing, whether or not testing is performed in their own laboratory. First, specimens must be handled with careful attention to fixation in anticipation of potential genetic testing. Second, appropriate tumor tissue for testing must be selected. Third, pathologists must be aware of which KRAS mutation detection methodology is utilized in their reference laboratories and evaluate the quality processes that are used to ensure reliable results. Finally, pathologists can consult with oncologists in the appropriate use of this test and interpretation of the results.
Retrospective analyses of clinical trials have consistently demonstrated that patients with mCRC and mutant KRAS are unlikely to benefit from the addition of cetuximab or panitumumab to a chemotherapy regimen. Testing for KRAS mutation in this setting is now recommended and marks a paradigm shift in the management of these patients.
- Lièvre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992-3995.
- Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007;25(22):3230-3237.
- Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626-1634.
- Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. In: Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, IL. Abstract 4000.
- Van Cutsem E, Lang I, D’haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. In: Program and abstracts of the 44rd American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2008; Chicago, IL. Abstract 2.
- Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-time treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. In: Program and abstracts of the 44rd American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2008; Chicago, IL. Abstract 4000.
- Punt CJ, Tol J, Rodenburg CJ, et al. Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). In: Program and abstracts of the 44rd American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2008; Chicago, IL. Abstract LBA4011.
- Hecht JR, Mitchell E, Chidiac T, et al. An updated analysis of safety and efficacy of oxaliplatin (Ox)/bevacizumab (bev) +/- panitumumab (pmab) for first-line treatment (tx) of metastatic colorectal cancer (mCRC) from a randomized controlled trial (PACCE). In: Program and abstracts of the 2008 Gastrointestinal Cancers Symposium; January 25-27, 2008; Orlando, FL. Abstract 273.
- NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, v.2.2009. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Date accessed 1/20/2009.
- Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients with Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy. http://www.asco.org/ASCO/Quality+Care+%26+Guidelines/Practice+Guidelines/Provisional+Clinical+Opinion. Date accessed 1/20/2009.
- Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nature Rev Cancer. 2007;7(4):295-308.
- Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-767.
- Juan T, Suggs S, Wolf M, et al. Novel biomarkers for tumor detection and progression. In: Program and abstracts of the 2008 American Association for Cancer Research 2008 Annual Meeting; April 12-16, 2008; San Diego, CA. Abstract 1181.
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