Molecular Biomarkers for the Evaluation of Colorectal Cancer
Publication Date: February 6, 2017
Last Updated: March 27, 2023
Diagnosis
Colorectal carcinoma patients being considered for anti-EGFR therapy must receive RAS mutational testing. Mutational analysis should include KRAS and NRAS codons 12, 13 of exon 2; 59, 61 of exon 3; and 117 and 146 of exon 4 (“expanded” or “extended” RAS). ( R , C , B , H )
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BRAF p.V600 (BRAF c. 1799 (p.V600) mutational analysis should be performed in colorectal cancer tissue in patients with colorectal carcinoma for prognostic stratification.
( R , A , B/H , I )616
BRAF p.V600 mutational analysis should be performed in deficient MMR tumors with loss of MLH1 to evaluate for Lynch Syndrome risk. Presence of a BRAF mutation strongly favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome. ( R , A , B/H , I )
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Clinicians should order mismatch repair status testing in patients with colorectal cancers for the identification of patients at high risk for Lynch syndrome and/or prognostic stratification. ( R , A , B/H , I )
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There is insufficient evidence to recommend BRAF c.1799 p.V600 mutational status as a predictive molecular biomarker for response to anti-EGFR inhibitors. ( NR , Ins , U , Ins )
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There is insufficient evidence to recommend PIK3CA mutational analysis of colorectal carcinoma tissue for therapy selection outside of a clinical trial. ( NR , Ins , U , Ins )
Note: Retrospective studies have suggested improved survival with post-operative aspirin use in patients whose colorectal carcinoma harbors a PIK3CA mutation.
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There is insufficient evidence to recommend PTEN analysis [expression by immunohistochemistry (IHC) or deletion by fluorescence in situ hybridization (FISH)] in colorectal carcinoma tissue for patients who are being considered for therapy selection outside of a clinical trial. ( NR , Ins , U , Ins )
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Metastatic or recurrent colorectal carcinoma tissues are the preferred specimens for treatment predictive biomarker testing and should be used if such specimens are available and adequate. In their absence, primary tumor tissue is an acceptable alternative, and should be used. ( EC , Ina , B/H , L )
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Formalin fixed paraffin embedded tissue is an acceptable specimen for molecular biomarker mutational testing in colorectal carcinoma. Use of other specimens (e.g. cytology specimens) will require additional adequate validation, as would any changes in tissue processing protocols.
( EC , Ina , B/H , L )616
Laboratories must use validated colorectal carcinoma molecular biomarker testing methods with sufficient performance characteristics for the intended clinical use. Colorectal carcinoma molecular biomarker testing validation should follow accepted standards for clinical molecular diagnostics tests. ( S , C , B , H )
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Performance of molecular biomarker testing for colorectal carcinoma must be validated in accordance with best laboratory practices. ( S , C , B , H )
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Laboratories must validate the performance of IHC testing for colorectal carcinoma molecular biomarkers (currently IHC testing for MLH1, MSH2, MSH6, and PMS2) in accordance with best laboratory practices. ( S , C , B , H )
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Laboratories must provide clinically appropriate turnaround times and optimal utilization of tissue specimens by using appropriate techniques (e.g. multiplexed assays) for clinically relevant molecular and immunohistochemical biomarkers of colorectal cancer. ( EC , Ina , B/H , L )
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Molecular and IHC biomarker testing in colorectal carcinoma should be initiated in a timely fashion based upon the clinical scenario and in accordance with institutionally accepted practices. ( EC , Ina , B/H , L )
Note: Test ordering can occur on a case-by-case basis or by policies established by the medical staff.
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Laboratories should establish policies to ensure efficient allocation and utilization of tissue for molecular testing, particularly in small specimens. ( EC , Ina , B/H , L )
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Members of the patient’s medical team, including pathologists, may initiate colorectal carcinoma molecular biomarker test orders in accordance with institutionally accepted practices. ( EC , Ina , B/H , L )
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Laboratories that require send out of tests for treatment predictive biomarkers should process and send colorectal carcinoma specimens to reference molecular laboratories in a timely manner. ( EC , Ina , B/H , L )
Note: It is suggested that a benchmark of 90% of specimens should be sent out within 3 working days.
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Pathologists must evaluate candidate specimens for biomarker testing to ensure specimen adequacy taking into account tissue quality, quantity, and malignant tumor cell fraction. Specimen adequacy findings should be documented in the patient report. ( EC , Ina , B/H , L )
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Laboratories should use colorectal carcinoma molecular biomarker testing methods that are able to detect mutations in specimens with at least 5% mutant allele frequency, taking into account the analytical sensitivity of the assay (limit of detection or LOD) and tumor enrichment (e.g. microdissection). ( EC , Ina , B/H , L )
Note: It is recommended that the operational minimal neoplastic carcinoma cell content tested should be set at least 2 times the assay’s LOD.
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Colorectal carcinoma molecular biomarker results should be made available as promptly as feasible in order to inform therapeutic decision-making, both prognostic and predictive.
( EC , Ina , B/H , L )Note: It is suggested that a benchmark of 90% of reports be available within 10 working days from date of receipt in the molecular diagnostics laboratory.
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Colorectal carcinoma molecular biomarker testing reports should include a results and interpretation section readily understandable by oncologists and pathologists. Appropriate Human Genome Variation Society (HGVS) and Human Genome Organisation (HUGO) nomenclature must be used in conjunction with any historical genetic designations. ( EC , Ina , B/H , L )
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Laboratories must incorporate colorectal carcinoma molecular biomarker testing methods into their overall laboratory quality improvement program, establishing appropriate quality improvement monitors as needed to assure consistent performance in all steps of the testing and reporting process. In particular, laboratories performing colorectal carcinoma molecular biomarker testing must participate in formal proficiency testing programs, if available, or an alternative proficiency assurance activity. ( S , C , B , H )
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Recommendation Grading
Disclaimer
The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.
Overview
Title
Molecular Biomarkers for the Evaluation of Colorectal Cancer
Authoring Organizations
American Society for Clinical Pathology
American Society of Clinical Oncology
Association for Molecular Pathology
College of American Pathologists
Publication Month/Year
February 6, 2017
Last Updated Month/Year
October 2, 2024
Supplemental Implementation Tools
Document Type
Guideline
External Publication Status
Published
Country of Publication
US
Document Objectives
The scope of the project was to develop an evidence-based guideline to help establish standard molecular biomarker testing, guide targeted therapies, and advance personalized care for patients with CRC.
Target Patient Population
Patients with CRC being considered for treatment with anti-EGFR inhibitors or conventional chemotherapy
Target Provider Population
Pathologists, laboratorians, oncologists and other clinicians, molecular diagnostics professionals, scientists
PICO Questions
What biomarkers are useful to select patients with CRC for targeted and conventional therapies?
How should tissue specimens be processed for biomarker testing for CRC management?
How should biomarker testing for CRC management be performed?
How should molecular testing of CRC be implemented and operationalized?
Are there emerging genes/biomarkers that should be routinely tested in CRC?
Inclusion Criteria
Male, Female, Adult, Older adult
Health Care Settings
Ambulatory, Hospital, Laboratory services, Outpatient
Intended Users
Nurse, nurse practitioner, physician, physician assistant
Scope
Diagnosis, Assessment and screening
Keywords
biomarkers, colorectal cancer, CRC, Molecular Biomarkers, anti-EGFR
Source Citation
DOI: 10.1200/JCO.2016.71.9807 Journal of Clinical Oncology 35, no. 13 (May 01, 2017) 1453-1486.
Supplemental Methodology Resources
Methodology
Number of Source Documents
123
Literature Search Start Date
July 27, 2013
Literature Search End Date
September 24, 2015
Description of External Review Process
ASCO has a rigorous review process for guidelines. After the draft has been approved by the Expert Panel, the guideline is independently reviewed and approved by the Clinical Practice Guideline Oversight Committee (CPGC). Select members of the CPGC are asked to critically review the guideline prior to the next scheduled CPGC meeting. The CPGC members then present the results of their reviews to the full committee, discuss the review with the full committee, and the CPGC votes on whether to approve the guideline (with recusals from members who have relationships with affected companies). Approved ASCO Guidelines are then submitted to the Society’s journal for consideration of publication.
Description of Public Comment Process
ASCO has a rigorous review process for guidelines. After the draft has been approved by the Expert Panel, the guideline is independently reviewed and approved by the Clinical Practice Guideline Oversight Committee (CPGC). Select members of the CPGC are asked to critically review the guideline prior to the next scheduled CPGC meeting. The CPGC members then present the results of their reviews to the full committee, discuss the review with the full committee, and the CPGC votes on whether to approve the guideline (with recusals from members who have relationships with affected companies). Approved ASCO Guidelines are then submitted to the Society’s journal for consideration of publication.
Specialties Involved
Gastroenterology, Medical Genetics And Genomics, Oncology, Pathology, Clinical Pathology, Medical Oncology, Pathology, Oncology
Description of Systematic Review
The Protocol specifies the purpose of the guideline product, target patient population, clinical outcomes of interest, key features of the systematic literature review, and a proposed timeline for completion. ASCO staff, the Expert Panel Co‐Chairs, and possibly other panel members selected by the Co‐Chairs (the Expert Panel Steering Committee), will typically draft the protocol for full panel review. A standard protocol worksheet is used for consistency.
Once the Co‐Chairs have approved a first draft of the Protocol, the Protocol will be shared with the full Expert Panel. At the discretion of the Guidelines Director, the CPGC leadership and/or the CPGC Methodology Subcommittee may review the Protocol to make suggestions for revision intended to clarify aspects of the plan for developing the guideline. These suggestions are sent to the Expert Panel Co‐Chairs. Work on the systematic literature review can proceed upon the sign‐off of the Protocol by the Expert Panel.
List of Questions
See full text
Description of Study Criteria
See supplement
Description of Search Strategy
Upon approval of the Protocol, a systematic review of the medical literature is conducted. ASCO staff use the information entered into the Protocol, including the clinical questions, inclusion/exclusion criteria for qualified studies, search terms/phrases, and range of study dates, to perform the systematic review. Literature searches of selected databases, including The Cochrane Library and Medline (via PubMed) are performed. Working with the Expert Panel, ASCO staff complete screening of the abstracts and full text articles to determine
eligibility for inclusion in the systematic review of the evidence.
Unpublished data from meeting abstracts are not generally used as part of normal ASCO guideline development (“Meeting Data”). However, abstract data from reputable scientific meetings and congresses may be included on a case‐by‐case basis after review by the CPGC leadership. Expert Panels should present a rationale to support integration of abstract data into a guideline. The CPGC leadership will consider the following inclusion criteria for the unpublished scientific meeting data: 1) whether the data were independently peer reviewed in connection with a reputable scientific meeting or congress; 2) the potential clinical impact of the unpublished data; 3) the methodological quality and validity of the associated study; 3) the potential harms of not including the data; and 4) the availability of other published data to inform the guideline recommendations.
Description of Study Selection
Literature search results were reviewed and deemed appropriate for full text review by two ASCO staff reviewers in consultation with the Expert Panel Co-Chairs. Data were extracted by two staff reviewers and subsequently checked for accuracy through an audit of the data by another ASCO staff member. Disagreements were resolved through discussion and consultation with the Co-Chairs if necessary. Evidence tables are provided in the manuscript and/or in Data Supplement.
Description of Evidence Analysis Methods
ASCO guideline recommendations are crafted, in part, using the GuideLines Into DEcision Support (GLIDES) methodology. ASCO adopted a five‐step approach to carry out quality appraisal, strength of evidence ratings and strength of recommendations ratings. The ASCO approach was primarily adapted from those developed by the AHRQ,, USPSTF, and GRADE, however with the validation of the GRADE methodology, the sole use of GRADE is being evaluated by the Clinical Practice Guidelines Committee.
Description of Evidence Grading
High: High confidence that the available evidence reflects the true magnitude and direction of the net effect (i.e., balance of benefits v harms) and that further research is very unlikely to change either the magnitude or direction of this net effect.
Intermediate: Moderate confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research is unlikely to alter the direction of the net effect; however, it might alter the magnitude of the net effect.
Low: Low confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research may change either the magnitude and/or direction this net effect.
Insufficient: Evidence is insufficient to discern the true magnitude and direction of the net effect. Further research may better inform the topic. The use of the consensus opinion of experts is reasonable to inform outcomes related to the topic.
Description of Recommendation Grading
ASCO uses a formal consensus methodology based on the modified Delphi technique in clinically important areas where there is limited evidence or a lack of high‐quality evidence to inform clinical guidance recommendations.
Evidence Based: There was sufficient evidence from published studies to inform a recommendation to guide clinical practice.
Formal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. Therefore, the Expert Panel used a formal consensus process to reach this recommendation, which is considered the best current guidance for practice. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak"). The results of the formal consensus process are summarized in the guideline and reported in the Data Supplement (see the Supporting Documents" field).
Informal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. The recommendation is considered the best current guidance for practice, based on informal consensus of the Expert Panel. The Panel agreed that a formal consensus process was not necessary for reasons described in the literature review and discussion. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak").
No recommendation: There is insufficient evidence, confidence, or agreement to provide a recommendation to guide clinical practice at this time. The Panel deemed the available evidence as insufficient and concluded it was unlikely that a formal consensus process would achieve the level of agreement needed for a recommendation.
Description of Funding Source
ASCO provides funding for Guideline Development.
Company/Author Disclosures
ASCO Conflict of Interest Policy complies with the CMSS Code for Interactions with Companies. ASCO requires disclosure by individuals involved in drafting, reviewing, and approving guideline recommendations.
Percentage of Authors Reporting COI
100