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 This is an original JCO publication from 2017. Please visit the JCO website to access the full article.


Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology


 Authors

Antonia R. Sepulveda, Stanley R. Hamilton, Carmen J. Allegra, Wayne Grody, Allison M. Cushman-Vokoun, William K. Funkhouser, Scott E. Kopetz, Christopher Lieu, Noralane M. Lindor, Bruce D. Minsky, Federico A. Monzon, Daniel J. Sargent, Veena M. Singh, Joseph Willis, Jennifer Clark, Carol Colasacco, R. Bryan Rumble, Robyn Temple-Smolkin, Christina B. Ventura, and Jan A. Nowak

THE BOTTOM LINE

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology and the American Society of Clinical Oncology

Key Guideline Questions

I. What biomarkers are useful to select patients with CRC for targeted and conventional therapies?

II. How should tissue specimens be processed for biomarker testing for CRC management?

III. How should biomarker testing for CRC management be performed?

IV. How should molecular testing of CRC be implemented and operationalized?

V. Are there emerging genes/biomarkers that should be routinely tested in CRC?

Target Population

Patients with CRC being considered for treatment with anti-EGFR inhibitors or conventional chemotherapy

Target Audience

Pathologists, laboratorians, oncologists and other clinicians, molecular diagnostics professionals, scientists, government agencies, non-profit organizations, patients and patient advocates, members of the public, and additional stakeholders as appropriate.

Methods

The American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP) and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to develop an evidence-based guideline to help establish standard molecular biomarker testing, guide targeted therapies, and advance personalized care for colorectal cancer patients.

Guideline Statements

1. 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) (Type: recommendation; Strength of Evidence: convincing/adequate, benefits outweigh harms; Quality of Evidence: high/intermediate).

2a. 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 (Type: recommendation, Strength of Evidence: adequate/ inadequate, balance of benefits and harms; Quality of Evidence: intermediate/low).

2b. 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 (Type: recommendation, Strength of Evidence: adequate/inadequate, balance of benefits and harms; Quality of Evidence: intermediate/low).

3. 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 (Type: recommendation; Strength of Evidence: adequate/inadequate, balance of benefits and harms; Quality of Evidence: intermediate/low).

4. There is insufficient evidence to recommend BRAF c.1799 p.V600 mutational status as a predictive molecular biomarker for response to anti-EGFR inhibitors (Type: no recommendation; Strength of Evidence: insufficient, benefits/harms balance unknown; Quality of Evidence: insufficient).

5. There is insufficient evidence to recommend PIK3CA mutational analysis of colorectal carcinoma tissue for therapy selection outside of a clinical trial (Type: no recommendation; Strength of Evidence: insufficient, benefits/harms balance unknown; Quality of Evidence: insufficient). Note: Retrospective studies have suggested improved survival with post-operative aspirin use in patients whose colorectal carcinoma harbors a PIK3CA mutation.

6. 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 (Type: no recommendation; Strength of Evidence: insufficient, benefits/harms balance unknown; Quality of Evidence: insufficient).

7. 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 (Type: expert consensus opinion; Strength of Evidence: inadequate/ Insufficient, benefits and harms in balance; Quality of Evidence: low).

8. 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 (Type: expert consensus opinion; Strength of Evidence: inadequate/ Insufficient, benefits and harms in balance; Quality of Evidence: low).

9. 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 (Type: strong recommendation; Strength of Evidence: Convincing/adequate, benefits outweigh harms; Quality of Evidence: high/intermediate).

10. Performance of molecular biomarker testing for colorectal carcinoma must be validated in accordance with best laboratory practices (Type: strong recommendation; Strength of Evidence: Convincing/adequate, benefits outweigh harms; Quality of Evidence: high/intermediate).

11. 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 (Type: strong recommendation; Strength of Evidence: Convincing/adequate, benefits outweigh harms; Quality of Evidence: high/ intermediate).

12. 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 (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low).

13. 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 (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low). Note: Test ordering can occur on a case-by-case basis or by policies established by the medical staff.

14. Laboratories should establish policies to ensure efficient allocation and utilization of tissue for molecular testing, particularly in small specimens (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low).

15. Members of the patient’s medical team, including pathologists, may initiate colorectal carcinoma molecular biomarker test orders in accordance with institutionally accepted practices (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low).

16. 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 (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low). Note: It is suggested that a benchmark of 90% of specimens should be sent out within 3 working days.

17. 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 (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low).

18. 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) (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low). Note: It is recommended that the operational minimal neoplastic carcinoma cell content tested should be set at least 2 times the assay’s LOD.

19. Colorectal carcinoma molecular biomarker results should be made available as promptly as feasible in order to inform therapeutic decision-making, both prognostic and predictive (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low).Note: It is suggested that a benchmark of 90% of reports available within 10 working days from date of receipt in the molecular diagnostics laboratory.

20. 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 (Type: expert consensus opinion; Strength of Evidence: inadequate/Insufficient, benefits and harms in balance; Quality of Evidence: low).

21. 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 (Type: strong recommendation; Strength of Evidence: Convincing/adequate, benefits outweigh harms; Quality of Evidence: high/intermediate).

Additional Resources:

More information, including Supplemental Digital Content (Methodology) with additional evidence tables, slide sets, and clinical tools and resources, is available at www.asco.org/CRC-markers-guideline and www.asco.org/guidelineswiki. Patient information is available at www.cancer.net

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.

SUMMARY OF RECOMMENDATIONS

RecommendationEvidence Rating
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).

Type: recommendation

Strength of Evidence: convincing/adequate, benefits outweigh harms

Quality of Evidence: high/intermediate

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.

Type: recommendation

Strength of Evidence: adequate/inadequate, balance of benefits and harms

Quality of Evidence: intermediate/low

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.

Type: recommendation

Strength of Evidence: adequate/inadequate, balance of benefits and harms

Quality of Evidence: intermediate/low

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.

Type: recommendation

Strength of Evidence: adequate/inadequate, balance of benefits and harms

Quality of Evidence: intermediate/low

There is insufficient evidence to recommend BRAF c.1799 p.V600 mutational status as a predictive molecular biomarker for response to anti-EGFR inhibitors.Type: no recommendation Strength of Evidence: insufficient, benefits/harms balance unknown Quality of Evidence: insufficient
There is insufficient evidence to recommend PIK3CA mutational analysis of colorectal carcinoma tissue for therapy selection outside of a clinical trial. Note: Retrospective studies have suggested improved survival with post-operative aspirin use in patients whose colorectal carcinoma harbors a PIK3CA mutation.

Type: no recommendation

Strength of Evidence: insufficient, benefits/harms balance unknown

Quality of Evidence: insufficient

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.

Type: no recommendation

Strength of Evidence: insufficient, benefits/harms balance unknown

Quality of Evidence: insufficient

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.

Type: expert consensus opinion

Strength of Evidence: inadequate/insufficient, benefits and harms in balance

Quality of Evidence: low

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.Type: expert consensus opinion Strength of Evidence: inadequate/insufficient, benefits and harms in balance Quality of Evidence: low
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.

Type: strong recommendation

Strength of Evidence: convincing/adequate, benefits outweigh harms

Quality of Evidence: high/intermediate

Performance of molecular biomarker testing for colorectal carcinoma must be validated in accordance with best laboratory practices.

Type: strong recommendation

Strength of Evidence: Convincing/adequate, benefits outweigh harms

Quality of Evidence: high/intermediate

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.

Type: strong recommendation

Strength of Evidence: convincing/adequate, benefits outweigh harms

Quality of Evidence: high/intermediate

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.

Type: expert consensus opinion

Strength of Evidence: inadequate/Insufficient, benefits and harms in balance

Quality of Evidence: low

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. Note: Test ordering can occur on a case-by-case basis or by policies established by the medical staff.

Type: expert consensus opinion

Strength of Evidence: inadequate/Insufficient, benefits and harms in balance

Quality of Evidence: low

Laboratories should establish policies to ensure efficient allocation and utilization of tissue for molecular testing, particularly in small specimens.

Type: expert consensus opinion

Strength of Evidence: inadequate/Insufficient, benefits and harms in balance

Quality of Evidence: low

Members of the patient’s medical team, including pathologists, may initiate colorectal carcinoma molecular biomarker test orders in accordance with institutionally accepted practices.

Type: expert consensus opinion

Strength of Evidence: inadequate/Insufficient, benefits and harms in balance

Quality of Evidence: low

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. Note: It is suggested that a benchmark of 90% of specimens should be sent out within 3 working days.

Type: expert consensus opinion

Strength of Evidence: inadequate/Insufficient, benefits and harms in balance

Quality of Evidence: low

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.

Type: expert consensus opinion

Strength of Evidence: inadequate/Insufficient, benefits and harms in balance

Quality of Evidence: low

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). Note: It is recommended that the operational minimal neoplastic carcinoma cell content tested should be set at least 2 times the assay’s LOD.

Type: expert consensus opinion

Strength of Evidence: inadequate/Insufficient, benefits and harms in balance

Quality of Evidence: low

Colorectal carcinoma molecular biomarker results should be made available as promptly as feasible in order to inform therapeutic decision-making, both prognostic and predictive Note: It is suggested that a benchmark of 90% of reports available within 10 working days from date of receipt in the molecular diagnostics laboratory.

Type: expert consensus opinion

Strength of Evidence: inadequate/Insufficient, benefits and harms in balance

Quality of Evidence: low

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.

Type: expert consensus opinion

Strength of Evidence: inadequate/insufficient, benefits and harms in balance

Quality of Evidence: low

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.

Type: strong recommendation

Strength of Evidence: convincing/adequate, benefits outweigh harms

Quality of Evidence: high/intermediate



ASCO Guideline Disclaimer: The clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (“ASCO”) to assist practitioners in clinical decision making. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating physician, as the information does not account for individual variation among patients. Recommendations reflect high, moderate or low confidence that the recommendation reflects the net effect of a given course of action.  The use of words like “must,” “must not,” “should,” and “should not” indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating physician in the context of treating the individual patient. Use of the information is voluntary.  ASCO provides this information on an “as is” basis, and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.


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