eMedicine Specialties > Genomic Medicine > Oncology

Colorectal Cancer and KRAS

Author: Maurie Markman, MD,, Vice President for Clinical Research, Professor of Cancer Medicine, University of Texas M D Anderson Cancer Center
Contributor Information and Disclosures

Updated: Jun 30, 2009

Overview

One actively investigated approach in the management of advanced and metastatic colorectal cancer (CRC) has been the delivery of agents whose primary purpose is to interfere with the biological activity of the epidermal growth factor receptor (EGFR).
 
However, it is well-recognized that only a subset of patients whose colorectal tumors have been demonstrated to overexpress the EGFR receptor on their cell surfaces will actually exhibit a favorable biological and clinical response to anti-EGFR antibody therapy. Both the costs and potential toxicities associated with this management paradigm add to the relevance of efforts to more critically define particular patient populations that would be most likely to respond to treatment with this class of agents, or, conversely, that would be highly unlikely to exhibit clinical benefit.
 
Randomized trials in patients with metastatic CRC that included anti-EGFR antibody therapy have specifically evaluated the impact of the mutational status of KRAS (wild-type [normal] versus mutated [abnormal]) on patient outcome. Notably, the presence of a KRAS mutation was found to be associated with the absence of biological and clinical activity for the anti-EGFR antibody treatment.1,2 Approximately 30% to 50% of colorectal tumors are known to have a mutated (abnormal) KRAS.

Clinical Implications of the Genetic Mutation

Several phase 3 randomized trials have revealed the favorable impact on survival associated with the administration of one of two currently available anti-EGFR antibodies (cetuximab [Erbitux], panitumumab [Vectibix]) in patients with KRAS wild type.1,2,3
 
Analysis of tumor samples obtained from 394 patients with metastatic CRC who were randomly assigned in a phase III trial to receive cetuximab plus best supportive care or best supportive care alone demonstrated improved overall survival (median, 9.5 vs. 4.8 months; P < 0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; P < 0.001) in those in the cetuximab arm who had KRAS wild type.  By contrast, patients with mutated KRAS showed no significant benefit from cetuximab vs. best supportive care alone.1 Similarly, a significantly greater response rate (61% v 37%; P = 0.011) and a significantly lower risk of disease progression (hazard ratio = 0.57; P = 0.0163) was seen in patients with KRAS wild type being treated with cetuximab and FOLFOX (fluorouracil + leucovorin + oxaliplatin) vs. patients withmutated KRAS receiving the same treatment.3
 
Using tissue from 427 patients with metastatic CRC enrolled in a phase III trial comparing panitumumab plus best supportive care or best supportive care alone demonstrated significantly greater progression-free survival (median, 12.3 weeks vs. 7.3 weeks; P < 0.0001) in patients with KRAS wild type treated with panitumumab, while no difference was seen in patients with mutated KRAS treated with the same regimen (median, 7.4 weeks vs. 7.3 weeks). Although there was no significant overall survival difference between the groups, multivariate analysis showed that KRAS wild type status independently predicted overall survival in both the panitumumab (hazard ratio, 0.64; P = 0004) and best supportive care (HR, 0.68; P = 0.007) arms.2   
 
A careful read of the data from these and other trials clearly demonstrates that patients with mutated KRAS are unlikely to benefit from anti-EGFR antibody therapy. However, it is not clear that patients with KRAS wild type will definitely respond, only that they have a reasonable opportunity to derive clinical benefit from the therapy. For example, in the panitumumab trial, there were no responders in the mutated KRAS group randomized to the therapy and only a 17% partial response rate was noted in the KRAS wild type group.2
 
Based on these observations, it is strongly recommended that patients with metastatic CRC who are being considered for treatment with anti-EGFR antibody therapy should be tested for the presence of a KRAS mutation prior to the administration of therapy. This will ensure that the therapy is not administered to patients who are unlikely to obtain benefit.
 
Accordingly, NCCN Clinical Practice Guidelines as well as a Provisional Clinical Opinion from the American Society of Clinical Oncology recommend initiating use of anti-EGFR therapy in patients with KRAS wild type only.4,5

Testing for the Genetic Mutation

KRAS status is determined via PCR analysis of formalin-fixed, paraffin-embedded block, unstained slides, or fresh snap frozen biopsy tissue for the presence of a mutation in codons 12, 13, or 61 of the KRAS gene on chromosome 12.

The following companies are currently offering KRAS mutation status testing:

Clarient, Inc. (http://www.clarientinc.com)
Caris Diagnostics (http://www.carisdx.com)
DxS (http://www.dxsdiagnostics.com)
Genzyme Genetics (http://www.genzymegenetics.com)
LabCorp (http://www.labcorp.com)
Response Genetics (http://responsegenetics.com)
Targeted Molecular Diagnostics (http://www.tmdlab.com)

Resources

More information about colorectal cancer, KRAS, and targeted treatments for KRAS wild type colorectal cancer can be found in Medscape's Colorectal Cancer Resource Center and the Cancer: Biologic Therapies Resource Center as well as in the eMedicine article on Colon Cancer.

Keywords

Metastatic colorectal cancer, epidermal growth factor receptor, EGFR, KRAS, cetuximab, panitumumab

 


More on Colorectal Cancer and KRAS

References

References

  1. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. Oct 23 2008;359(17):1757-65. [Medline].

  2. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. Apr 1 2008;26(10):1626-34. [Medline].

  3. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. Feb 10 2009;27(5):663-71. [Medline].

  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Colon Cancer v.2.200. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed June 2, 2009.

  5. [Best Evidence] Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF. 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. J Clin Oncol. Apr 20 2009;27(12):2091-6. [Medline].

Further Reading

Keywords

Metastatic colorectal cancer, epidermal growth factor receptor, EGFR, KRAS, cetuximab, panitumumab

Contributor Information and Disclosures

Author

Maurie Markman, MD,, Vice President for Clinical Research, Professor of Cancer Medicine, University of Texas M D Anderson Cancer Center
Maurie Markman, MD, is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Eli Lilly Honoraria Speaking and teaching; Genentech Consulting fee Consulting; Cellgene Consulting fee Consulting; Hana Pharmaceuticals Consulting fee Consulting; Boehringer Ingelheim Consulting fee Consulting; Ortho Biotech Consulting fee Consulting; Pfizer  Speaking and teaching

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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