ASCP/CAP/AMP/ASCO Guideline on Molecular Biomarkers for Evaluation of Colorectal Cancer

As reported in the Journal of Clinical Oncology by Antonia Sepulveda, MD, PhD, of Columbia University, and colleagues, a joint guideline on the use of molecular biomarkers for evaluation of colorectal cancer has been developed by an expert panel from the American Society for Clinical Pathology (ASCP), the College of American Pathologists (CAP), the Association for Molecular Pathology (AMP), and ASCO. The guideline was informed by data derived from a comprehensive literature search including over 4,000 articles. The panel was co-chaired by Dr. Sepulveda (AMP); Stanley R. Hamilton, MD, PhD (CAP), of The University of Texas MD Anderson Cancer Center; Carmen Allegra, MD (ASCO), of the University of Florida Medical Center, Gainesville; and Wayne Grody, MD, PhD (ASCP), of the University of California Los Angeles Medical Center.

The guideline consists of 21 guideline statements, including 8 recommendations, 10 expert consensus opinions, and 3 no recommendations. The type of statement is shown in brackets.

Guideline Statements

1. Patients with colorectal cancer being considered for anti–epidermal growth factor receptor (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). [Recommendation]

2a. BRAF p.V600 (BRAF c. 1799 (p.V600) mutational analysis should be performed for prognostic stratification. [Recommendation]

2b. BRAF p.V600 mutational analysis should be performed in deficient mismatch repair tumors with loss of MLH1 to evaluate for Lynch syndrome risk. Presence of BRAF mutation strongly favors a sporadic pathogenesis. Absence of BRAF mutation does not exclude the risk for Lynch syndrome. [Recommendation]

3. Clinicians should order mismatch repair status testing for identification of patients at high risk for Lynch syndrome and/or prognostic stratification. [Recommendation]

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. [No recommendation]

5. There is insufficient evidence to recommend PIK3CA mutational analysis for therapy selection outside of a clinical trial. [No recommendation]

Note: Retrospective studies suggest improved survival with postoperative aspirin in patients with PIK3CA mutation.

6. There is insufficient evidence to recommend PTEN analysis (expression by immunohistochemistry [IHC] or deletion by fluorescence in situ hybridization [FISH]) in patients considered for therapy selection outside of a clinical trial. [No recommendation]

7. Metastatic or recurrent colorectal cancer tissues are the preferred specimens for treatment-predictive biomarker testing. In their absence, primary tumor tissue is an acceptable alternative. [Expert consensus opinion]

8. Formalin-fixed paraffin-embedded tissue is an acceptable specimen for molecular biomarker mutational testing. Use of other specimens (eg, cytology specimens) will require additional adequate validation, as would any changes in tissue-processing protocols. [Expert consensus opinion].

9. Laboratories must use validated colorectal cancer molecular biomarker testing methods with sufficient performance characteristics for the intended clinical use. Testing validation should follow accepted standards for clinical molecular diagnostics tests. [Strong recommendation]

10. Performance of molecular biomarker testing must be validated in accordance with best laboratory practices. [Strong recommendation]

11. Laboratories must validate the performance of immunohistochemical testing for molecular biomarkers (currently for MLH1, MSH2, MSH6, and PMS2) in accordance with best laboratory practices. [Strong recommendation]

12. Laboratories must provide clinically appropriate turnaround times and optimal utilization of tissue specimens by using appropriate techniques (eg, multiplexed assays) for clinically relevant molecular and immunohistochemical biomarkers. [Expert consensus opinion]

13. Molecular and immunohistochemical biomarker testing should be initiated in a timely fashion based on clinical scenario and in accordance with institutionally accepted practices. [Expert consensus opinion]

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 [Expert consensus opinion].

15. Members of the patient’s medical team, including pathologists, may initiate molecular biomarker test orders in accordance with institutionally accepted practices. [Expert consensus opinion]

16. Laboratories that must send out tests for treatment-predictive biomarkers should process and send specimens to reference molecular laboratories in a timely manner. [Expert consensus opinion]

Note: 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. [Expert consensus opinion]

18. Laboratories should use testing methods that are able to detect mutations in specimens with at least 5% mutant allele frequency, taking into account the analytic sensitivity of the assay (limit of detection) and tumor enrichment (eg, microdissection). [Expert consensus opinion]

Note: The operational minimal neoplastic carcinoma cell content tested should be set at least two times the assay limit of detection.

19. Molecular biomarker results should be made available as promptly as feasible to inform therapeutic decision-making, both prognostic and predictive. [Expert consensus opinion]

Note: A benchmark of 90% of reports should be available within 10 working days from the date of receipt in the laboratory.

20. 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. [Expert consensus opinion]

21. Laboratories must incorporate molecular biomarker testing methods into their overall 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 must participate in formal proficiency testing programs, if available, or an alternative proficiency assurance activity. [Strong recommendation]

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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