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Originally published as JCO Early Release 10.1200/JCO.2009.21.9170 on February 2 2009 © 2009 American Society of Clinical Oncology.
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 TherapyFrom the Division of Hematology/Oncology, Department of Medicine, University of Florida Shands Cancer Center, Gainesville, FL; Diagnostics Evaluation Branch, Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD; Cancer Policy and Clinical Affairs, American Society of Clinical Oncology; Colorectal Cancer Coalition, Alexandria, VA; Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX; Intermountain Healthcare, University of Utah School of Medicine, Salt Lake City, UT; University of Michigan Medical Center, Ann Arbor, MI; Medical Oncology and Hematology Associates, Des Moines, IA; and Biological Sciences Division, Pritzker School of Medicine, University of Chicago, Chicago, IL. Corresponding author: American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; e-mail: guidelines{at}asco.org.
Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO), offers timely clinical direction to ASCO's oncologists following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the utility of KRAS gene mutation testing in patients with metastatic colorectal carcinoma to predict response to anti–epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy with cetuximab or panitumumab (see Note). Clinical Context Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with monoclonal antibodies directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy. Recent Data Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status. Provisional Clinical Opinion Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.
The American Society of Clinical Oncology (ASCO) has established a rigorous, evidence-based approach—the provisional clinical opinion (PCO)—to offer a rapid response to emerging data in clinical oncology. The PCO is intended to offer timely clinical direction to ASCO's oncologists following publication or presentation of potentially practice-changing data from major studies (Appendix). This PCO addresses only the utility of testing for mutations in codons 12 or 13 of the KRAS gene in patients with metastatic colorectal carcinoma to predict response to anti–epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy, that is, cetuximab or panitumumab.
Results from phase II and III clinical trials of the anti-EGFR MoAbs cetuximab and panitumumab when used either as monotherapy or in combination with chemotherapy, have shown that patients with metastatic colorectal carcinoma may benefit from these therapies and both agents are approved by the US Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer. Stratified analyses of data from these trials by KRAS mutational status—not detected ("wild type") or abnormal (mutated)—indicated that patients with KRAS mutation in codon 12 or 13 did not derive benefit from treatment with cetuximab or panitumumab.
Based on a systematic review of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR monoclonal antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR monoclonal antibody therapy as part of their treatment.
The review of the evidence on which this PCO is based consists primarily of the rigorous systematic review of the literature conducted by the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center (TEC).1–10 Details of the BCBSA TEC assessment can be found in the full TEC report, which is available at www.bcbs.com/blueresources/tec/press/KRAS-mutations-epidermal.html. In summary, the TEC searched MEDLINE through October 2008 to identify all relevant articles on anti-EGFR MoAb therapy and KRAS mutation analysis. The TEC supplemented its review by searching for relevant abstracts from the ASCO 2008 Annual Meeting via the online database (www.asco.org/vm). Studies were included in the TEC assessment if they were peer-reviewed, full-length, English-language articles and investigated response to anti-EGFR MoAbs among patients with metastatic colorectal cancer with respect to KRAS mutational status. The TEC also included phase II and III randomized clinical trials from the 2008 ASCO Annual Meeting if the full presentation slides were available online. The TEC review identified post hoc analyses on subsets from five randomized, controlled trials (RCTs) of cetuximab or panitumumab that evaluated outcomes for patients with metastatic colorectal cancer in relation to KRAS mutational status (Table 1); and five single-arm studies that retrospectively evaluated treatment response according to KRAS status (Table 2). Two broad findings emerged from the TEC assessment of these studies: (1) a consistent correlation between presence of a KRAS mutation in codon 12 or 13 and lack of response to anti-EGFR MoAb therapy in patients with metastatic colorectal cancer; and (2) evidence of improved tumor response, progression-free, and/or overall survival in response to anti-EGFR MoAb therapy only in those patients with no mutation in codon 12 or 13 (wild type) versus abnormal (mutated) KRAS tumors in analyses from four of five RCTs.
Oncologists should understand that both the PCO and the TEC review are based on assays that detect mutations in codons 12 and 13 of KRAS only. Mutations also occur, although uncommonly, at codons 61 and 146, and these also activate KRAS. In addition, the PCO and the TEC review do not evaluate the differences in sensitivity and specificity among the various assays that are available for KRAS mutation testing. (See excerpt from the College of American Pathologists [CAP] Perspectives on Emerging Technology [POET] Report on KRAS mutation testing, next paragraph.) The oncologist is encouraged to discuss these issues with the Director of his/her clinical laboratory. Finally, this PCO is limited to the current state of knowledge about the treatment of metastatic colorectal carcinoma and does not address the use of anti-EGFR MoAbs for adjuvant therapy in colorectal carcinoma, the use of small molecule tyrosine kinase inhibitors in metastatic colorectal carcinoma, or assays for other alterations that have been reported to affect response to anti-EGFR MoAbs (eg, mutation in BRAF,2,12,13 PI3K,14,15 or PTEN15 genes and loss of expression of PTEN16 that may indicate resistance; amplification of EGFR,17 lack of amplification of PTEN,18 and expression of epiregulin or amphiregulin7 that may indicate response). These subjects are either the focus of current research, or there are insufficient data to justify an opinion at present.19
Under a reciprocal arrangement with the CAP, ASCO is reprinting key elements of a CAP POET report on KRAS mutation testing for colorectal cancer as a service to the ASCO membership. The CAP POET report was developed by an ad hoc panel and offers state-of-the-art information on KRAS testing for the CAP membership. The full CAP document can be found at http://www.cap.org/POET.
CAP KRAS Specimen and Test Information
Acceptable assay types. In all cases, DNA is first extracted by laboratory specific and standardized protocols that incorporate standards to assure adequate and specific extraction.
Assay Reporting KRAS abnormal. Treatment with anti-EGFR monoclonal antibody therapy is not recommended based on the ASCO PCO. Mutation was found. Report will specify what mutation was found, what assay was done, and what controls were used.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Daniel F. Hayes, Eli Lilly & Co Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
Manuscript writing: Carmen J. Allegra, J. Milburn Jessup, Mark R. Somerfield, Stanley R. Hamilton, Elizabeth H. Hammond, Daniel F. Hayes, Pamela K. McAllister, Roscoe F. Morton, Richard L. Schilsky Final approval of manuscript: Carmen J. Allegra, J. Milburn Jessup, Stanley R. Hamilton, Daniel F. Hayes, Pamela K. McAllister, Roscoe F. Morton, Richard L. Schilsky
Overview of the Provisional Clinical Opinion Development Process PCO topic selection. The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC) leadership is responsible for accepting, reviewing, and approving proposed provisional clinical opinion (PCO) topics on behalf of the ASCO Board of Directors. The selection of this PCO topic was guided by the Topic Selection Algorithm that is used by the HSC to guide selection of topics for ASCO's clinical practice guidelines (www.asco.org/guidelines/manual). PCO evidentiary basis. Provisional clinical opinions are informed by expeditious methodological assessments of the data in question. To this end, ASCO has established a relationship with the National Cancer Institute's Physician Data Query (PDQ) Editorial Boards. The PDQ's Editorial Boards are comprised of content experts in oncology and related specialties. On request from ASCO, the relevant PDQ Editorial Board will provide a written assessment of the new data. For the present PCO, however, ASCO learned that the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) was conducting a technology assessment, including a comprehensive systematic review of the available evidence, on the topic of KRAS mutations and anti-EGFR monoclonal antibody in metastatic colorectal cancer. BCBSA TEC made the technology assessment available to ASCO for use in developing this PCO. Ad hoc PCO panel. The BCBSA TEC Assessment was forwarded to an ad hoc panel that was selected and charged by the HSC to draft the PCO. The ad hoc panel includes six content experts and a patient representative. The membership of the ad hoc panel was chosen in accordance with ASCO's Conflict of Interest Management Procedures for Clinical Practice Guidelines ("COI Procedures"). The COI Procedures call for the majority of ad hoc panel members to have no relationships with companies potentially affected by the PCO, and generally require ad hoc panel cochairs to be free from relationships with affected companies. PCO review and approval. The PCO was approved by a unanimous vote of (1) the ad hoc panel members (2); the HSC leadership (Past-Chair, Chair, Chair-Elect, and selected content experts) and selected content experts drawn from the HSC membership; and (3) a subset of the ASCO Board (Past-President, President, President-Elect) and selected content experts drawn from the Board membership and appointed at the discretion of the President.
The ad hoc panel is grateful to Monica Bertagnolli, MD, Douglas Blayney, MD, Nancy Davidson, MD, Jeffrey Meyerhardt, MD, Lisa Newman, MD, Richard Theriault, DO, and Sandra Wong, MD, for reviewing earlier drafts of the manuscript on behalf of the ASCO Board of Directors and Health Services Committee; to Kaitlin Einhaus, Karen Hagerty, Shauniece Morris, Jerome Seidenfeld, and Sarah Temin for their assistance in manuscript preparation; to the BlueCross and BlueShield Association Technology Evaluation Center's Heather Brown, Naomi Aronson, and other staff; and to the College of American Pathologists' Saeed Ahmad and Noel Adachi, other staff, and physician volunteers for their collaboration.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. 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 26:1626–1634, 2008. 2. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643–2648, 2007. 3. Bokemeyer C, Bondarenko I, Hartmann JT, et al: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal (metastatic CRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26:178s; 2008 (suppl) abstr 4000. 4. De Roock W, Piessevaux H, De Schutter J, et al: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19:508–515, 2008. 5. Di Fiore F, Blanchard F, Charbonnier F, et al: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96:1166–1169, 2007.[CrossRef][Medline] 6. Karapetis CS, Khambata-Ford S, Jonker DJ, et al: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765, 2008. 7. 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 25:3230–3237, 2007. 8. Lièvre A, Bachet JB, Boige V, et al: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379, 2008. 9. 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). J Clin Oncol 26:180s; 2008 (suppl) abstr LBA4011. 10. 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 (metastatic CRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 26:5s; 2008 (suppl) abstr 2.[CrossRef] 11. BlueCross BlueShield Association. Technology Evaluation Center: KRAS Mutations and Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer TEC Assessments (vol 23, tab 6). Chicago, IL: BlueCross BlueShield Association, 2008. 12. Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al: Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 99:83–89, 2008.[CrossRef][Medline] 13. Di Nicolantonio F, Martini M, Molinari F, et al: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712, 2008. 14. Jhawer M, Goel S, Wilson AJ, et al: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953–1961, 2008. 15. Perrone F, Lampis A, Orsenigo M, et al: PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 20:84–90, 2009. 16. Frattini M, Saletti P, Romagnani E, et al: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139–1145, 2007.[CrossRef][Medline] 17. Moroni M, Sartore-Bianchi A, Veronese S, et al: EGFR FISH in colorectal cancer: What is the current reality? Lancet Oncol 9:402–403, 2008.[CrossRef][Medline] 18. Razis E, Briasoulis E, Vrettou E, et al: Potential value of PTEN in predicting cetuximab response in colorectal cancer: An exploratory study. BMC Cancer 8:234; 2008.[CrossRef][Medline] 19. Jimeno A, Messersmith WA, Hirsch FR, et al: KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: Practical application of patient selection. J Clin Oncol 27:1130–1136, 2009. Submitted January 9, 2009; accepted January 9, 2009.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
