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American Society of Clinical Oncology Provisional ClinicalOpinion: Testing for KRAS Gene Mutations in PatientsWith Metastatic Colorectal Carcinoma to Predict Responseto Anti–Epidermal Growth Factor Receptor MonoclonalAntibody TherapyCarmen J. Allegra, J. Milburn Jessup, Mark R. Somerfield, Stanley R. Hamilton, Elizabeth H. Hammond,Daniel F. Hayes, Pamela K. McAllister, Roscoe F. Morton, and Richard L. Schilsky 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).
cal Affairs, American Society of Clinical 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 ofthe 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 physicianin light of each patient’s individual circumstances. ASCO PCOs describe the use of procedures andtherapies in clinical practice and cannot be assumed to apply to the use of these interventions in thecontext of clinical trials. ASCO assumes no responsibility for any injury or damage to persons orproperty arising out of or related to any use of ASCO’s PCOs, or for any errors or omissions.
J Clin Oncol 27:2091-2096. 2009 by American Society of Clinical Oncology 2009 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at F. Hoffmann-La Roche Ltd. on October 26, 2011 from Copyright 2009 American Society of Clinical Oncology. All rights reserved.
Allegra et al
with respect to KRAS mutational status. The TEC also included INTRODUCTION
phase II and III randomized clinical trials from the 2008 ASCO The American Society of Clinical Oncology (ASCO) has established a Annual Meeting if the full presentation slides were available online.
rigorous, evidence-based approach—the provisional clinical opinion The TEC review identified post hoc analyses on subsets from (PCO)—to offer a rapid response to emerging data in clinical oncol- five randomized, controlled trials (RCTs) of cetuximab or panitu- ogy. The PCO is intended to offer timely clinical direction to ASCO’s mumab that evaluated outcomes for patients with metastatic colo- oncologists following publication or presentation of potentially rectal cancer in relation to KRAS mutational status (Table 1); and practice-changing data from major studies (Appendix).
five single-arm studies that retrospectively evaluated treatment This PCO addresses only the utility of testing for mutations in response according to KRAS status (Table 2). Two broad findings codons 12 or 13 of the KRAS gene in patients with metastatic colorec- emerged from the TEC assessment of these studies: (1) a consistent tal carcinoma to predict response to anti– epidermal growth factor correlation between presence of a KRAS mutation in codon 12 or receptor (anti-EGFR) monoclonal antibody (MoAb) therapy, that is, 13 and lack of response to anti-EGFR MoAb therapy in patients with metastatic colorectal cancer; and (2) evidence of improvedtumor response, progression-free, and/or overall survival in re-sponse to anti-EGFR MoAb therapy only in those patients with no STATEMENT OF THE CLINICAL ISSUE
mutation in codon 12 or 13 (wild type) versus abnormal (mutated)KRAS tumors in analyses from four of five RCTs.
Results from phase II and III clinical trials of the anti-EGFR MoAbs Oncologists should understand that both the PCO and the cetuximab and panitumumab when used either as monotherapy or in TEC review are based on assays that detect mutations in codons 12 combination with chemotherapy, have shown that patients with met- and 13 of KRAS only. Mutations also occur, although uncom- astatic colorectal carcinoma may benefit from these therapies and monly, at codons 61 and 146, and these also activate KRAS. In both agents are approved by the US Food and Drug Administration addition, the PCO and the TEC review do not evaluate the differ- (FDA) for treatment of metastatic colorectal cancer. Stratified analyses ences in sensitivity and specificity among the various assays that are of data from these trials by KRAS mutational status—not detected available for KRAS mutation testing. (See excerpt from the College (“wild type”) or abnormal (mutated)—indicated that patients with of American Pathologists [CAP] Perspectives on Emerging Tech- KRAS mutation in codon 12 or 13 did not derive benefit from treat- nology [POET] Report on KRAS mutation testing, next para- graph.) The oncologist is encouraged to discuss these issues withthe Director of his/her clinical laboratory. Finally, this PCO islimited to the current state of knowledge about the treatment of ASCO’S PROVISIONAL CLINICAL OPINION
metastatic colorectal carcinoma and does not address the use ofanti-EGFR MoAbs for adjuvant therapy in colorectal carcinoma,the use of small molecule tyrosine kinase inhibitors in metastatic Based on a systematic review of the relevant literature, all patients
colorectal carcinoma, or assays for other alterations that have been with metastatic colorectal carcinoma who are candidates for
reported to affect response to anti-EGFR MoAbs (eg, mutation in anti-EGFR monoclonal antibody therapy should have their tumor
BRAF,2,12,13 PI3K,14,15 or PTEN15 genes and loss of expression of tested for KRAS mutations in a CLIA-accredited laboratory. If
KRAS mutation in codon 12 or 13 is detected, then patients with
PTEN16 that may indicate resistance; amplification of EGFR,17 lack metastatic colorectal carcinoma should not receive anti-EGFR
of amplification of PTEN,18 and expression of epiregulin or am- monoclonal antibody therapy as part of their treatment.
phiregulin7 that may indicate response). These subjects are eitherthe focus of current research, or there are insufficient data to justifyan opinion at present.19 LITERATURE REVIEW AND ANALYSIS
SUMMARY OF THE COLLEGE OF AMERICAN PATHOLOGISTS
The review of the evidence on which this PCO is based consists pri- POET REPORT ON KRAS MUTATION TESTING
marily of the rigorous systematic review of the literature conductedby the Blue Cross and Blue Shield Association (BCBSA) Technol- Under a reciprocal arrangement with the CAP, ASCO is reprinting ogy Evaluation Center (TEC).1-10 Details of the BCBSA TEC assess- key elements of a CAP POET report on KRAS mutation testing for ment can be found in the full TEC report, which is available at www colorectal cancer as a service to the ASCO membership. The CAP .bcbs.com/blueresources/tec/press/KRAS-mutations-epidermal.html.
POET report was developed by an ad hoc panel and offers state-of- In summary, the TEC searched MEDLINE through October 2008 the-art information on KRAS testing for the CAP membership. The to identify all relevant articles on anti-EGFR MoAb therapy and full CAP document can be found at http://www.cap.org/POET.
KRAS mutation analysis. The TEC supplemented its review bysearching for relevant abstracts from the ASCO 2008 Annual Meet-ing via the online database (www.asco.org/vm). Studies were CAP KRAS Specimen and Test Information
included in the TEC assessment if they were peer-reviewed, full- Acceptable sample types. The samples should be specifically cho- length, English-language articles and investigated response to anti- sen by a pathologist to include predominantly tumor cells without EGFR MoAbs among patients with metastatic colorectal cancer significant necrosis or inflammation.
2009 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at F. Hoffmann-La Roche Ltd. on October 26, 2011 from Copyright 2009 American Society of Clinical Oncology. All rights reserved.
ASCO Provisional Clinical Opinion
Table 1. Randomized Clinical Trial Evidence on Relationship of KRAS Mutation Status to Efficacy of Anti-EGFR Monoclonal Antibodies in Patients
.01 (for interaction, KRAS mutation status ϫ treatment arm) Abbreviations: EGFR, epidermal growth factor receptor; WT, wild type; HR, hazard ratio; OR, odds ratio; PFS, progression-free survival; FOLFIRI, folinic acid, fluorouracil, and irinotecan; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; CRYSTAL, Cetuximab Combined With Irinotecan in First-Line Therapy for MetastaticColorectal Cancer; OPUS, Oxaliplatin and Cetuximab in First-Line Treatment of mCRC; CAIRO2, Capecitabine, Irinotecan, and Oxaliplatin in Advanced ColorectalCancer (2).
Adapted with permission11: BlueCross BlueShield Association. Technology Evaluation Center. KRAS Mutations and Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer TEC Assessments 2008; volume 23, tab 6. Copyright 2008, BlueCross BlueShield Association.
● Freshly extracted from patient, provided fresh or in RNA Acceptable assay types. In all cases, DNA is first extracted by preservation solution such as RNAlater laboratory specific and standardized protocols that incorporate stan- ● Freshly extracted from patient and rapidly frozen and dards to assure adequate and specific extraction.
● Real-time polymerase chain reaction. In real-time poly- ● Neutral buffered formalin fixed and paraffin embedded, area merase chain reaction, fluorescent probes specific for the of interest selected specifically by the pathologist most common mutations in codons 12 and 13 are utilized.
2009 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at F. Hoffmann-La Roche Ltd. on October 26, 2011 from Copyright 2009 American Society of Clinical Oncology. All rights reserved.
Allegra et al
Table 2. Single-Arm Studies of Treatment of Metastatic CRC With Anti-EGFR Monoclonal Antibodies and KRAS Mutational Status
Abbreviations: EGFR, epidermal growth factor receptor; CRC, colorectal cancer; WT, wild type; PFS, progression-free survival; OS, overall survival.
Adapted with permission11: BlueCross BlueShield Association. Technology Evaluation Center. KRAS Mutations and Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer TEC Assessments 2008; volume 23, tab 6. Copyright 2008, BlueCross BlueShield Association.
When a mutation is present, the probe binds and fluores- KRAS abnormal. Treatment with anti-EGFR monoclonal anti- body therapy is not recommended based on the ASCO PCO. Muta- ● Direct sequencing analysis. KRAS mutations can also be iden- tion was found. Report will specify what mutation was found, what tified using a direct sequencing method of exon 1 in the KRAS assay was done, and what controls were used.
gene. This technique identifies all possible mutations inthe exon.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
● At this time, there are no FDA-approved tests for KRAS test- OF INTEREST
ing, but KRAS testing can be performed using laboratory-developed tests. Outside the United States, a United Although all authors completed the disclosure declaration, the following Kingdom-based company, DxS, offers a kit (TheraScreen) for author(s) indicated a financial or other interest that is relevant to the its KRAS mutations assay. DxS and other vendors are ex- subject matter under consideration in this article. Certain relationships pected to seek US Food and Drug Administration approval for marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed ● Choice of assay defined by which assay the laboratory has description of the disclosure categories, or for more information about validated and routinely uses. Oncologist should consult with ASCO’s conflict of interest policy, please refer to the Author Disclosure laboratory about specific test name to order.
Declaration and the Disclosures of Potential Conflicts of Interest section
in Information for Contributors.
Employment or Leadership Position: Daniel F. Hayes, Eli Lilly & Co
Assay Reporting
Consultant or Advisory Role: None Stock Ownership: None
KRAS normal. No mutation was identified. Report will specify Honoraria: None Research Funding: None Expert Testimony: None
Other Remuneration: None
2009 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at F. Hoffmann-La Roche Ltd. on October 26, 2011 from Copyright 2009 American Society of Clinical Oncology. All rights reserved.
ASCO Provisional Clinical Opinion
AUTHOR CONTRIBUTIONS
Pamela K. McAllister, Roscoe F. Morton, Richard L. Schilsky
Final approval of manuscript: Carmen J. Allegra, J. Milburn Jessup,
Manuscript writing: Carmen J. Allegra, J. Milburn Jessup, Mark R.
Stanley R. Hamilton, Daniel F. Hayes, Pamela K. McAllister, Roscoe F.
Somerfield, Stanley R. Hamilton, Elizabeth H. Hammond, Daniel F. Hayes, 7. Khambata-Ford S, Garrett CR, Meropol
EGFR FISH-positive colorectal cancer patients. Br J REFERENCES
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control in metastatic colorectal cancer patients Wild-type BRAF is required for response to panitu- type KRAS is required for panitumumab efficacy in treated with cetuximab. J Clin Oncol 25:3230-3237, mumab or cetuximab in metastatic colorectal can- patients with metastatic colorectal cancer. J Clin 8. Lie`vre A, Bachet JB, Boige V, et al: KRAS
14. Jhawer M, Goel S, Wilson AJ, et al: PIK3CA
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FOLFOX with or without cetuximab: The OPUS experi- loss of expression predicts cetuximab efficacy in ence. J Clin Oncol 26:178s, 2008 (suppl; abstr 4000) 10. Van Cutsem E, Lang I, D’haens G, et al: KRAS
metastatic colorectal cancer patients. Br J Cancer 4. De Roock W, Piessevaux H, De Schutter J, et
status and efficacy in the first-line treatment of al: KRAS wild-type state predicts survival and is patients with metastatic colorectal cancer (meta- 17. Moroni M, Sartore-Bianchi A, Veronese S, et
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6. Karapetis CS, Khambata-Ford S, Jonker DJ, et
23, tab 6). Chicago, IL, BlueCross BlueShield Asso- KRAS mutations and sensitivity to epidermal growth al: K-ras mutations and benefit from cetuximab in factor receptor inhibitors in colorectal cancer: Prac- advanced colorectal cancer. N Engl J Med 359:1757- 12. Cappuzzo F, Varella-Garcia M, Finocchiaro G,
tical application of patient selection. J Clin Oncol et al: Primary resistance to cetuximab therapy in Acknowledgment
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 ofDirectors and Health Services Committee; to Kaitlin Einhaus, Karen Hagerty, Shauniece Morris, Jerome Seidenfeld, and Sarah Temin for theirassistance in manuscript preparation; to the BlueCross and BlueShield Association Technology Evaluation Center’s Heather Brown, NaomiAronson, and other staff; and to the College of American Pathologists’ Saeed Ahmad and Noel Adachi, other staff, and physician volunteers fortheir collaboration.
Appendix
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 selectionof 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 practiceguidelines (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’sEditorial Boards are comprised of content experts in oncology and related specialties. On request from ASCO, the relevant PDQ Editorial Boardwill 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 KRASmutations and anti-EGFR monoclonal antibody in metastatic colorectal cancer. BCBSA TEC made the technology assessment available to ASCOfor 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 accordancewith ASCO’s Conflict of Interest Management Procedures for Clinical Practice Guidelines (“COI Procedures”). The COI Procedures call for the 2009 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at F. Hoffmann-La Roche Ltd. on October 26, 2011 from Copyright 2009 American Society of Clinical Oncology. All rights reserved.
Allegra et al
majority of ad hoc panel members to have no relationships with companies potentially affected by the PCO, and generally require ad hoc panelcochairs 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 ofthe ASCO Board (Past-President, President, President-Elect) and selected content experts drawn from the Board membership and appointed atthe discretion of the President.
2009 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at F. Hoffmann-La Roche Ltd. on October 26, 2011 from Copyright 2009 American Society of Clinical Oncology. All rights reserved.

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