NEW GUIDELINES FOR MOLECULAR TESTING FOR COLORECTAL CANCER

A group of professional societies has released a draft of a clinical practice guideline on the use of molecular marker testing for patients with primary or metastatic colorectal carcinoma.

This new evidence-based guideline will help establish standard molecular marker testing, guide targeted therapies, and advance personalized care for these patients, according to the American Society for Clinical Pathology, the College of American Pathologists (CAP), the Association for Molecular Pathology, and the American Society of Clinical Oncology (ASCO).

The guideline is now available online for public comment through April 22, 2015. The final guidance document is targeted for publication later this year.

Four cochairs, representing each of the organizations, along with more than 25 specialists from a wide range of disciplines, including oncologists, pathologists, and patient advocates, participated in drafting the document.

"While other colorectal cancer biomarker guidelines have been published, they tend to focus on one marker or a small panel of markers for one specific clinical use, unlike the collaborative, multidisciplinary approach for this guideline," said cochair Stanley R. Hamilton, MD, FCAP, AGAF, from the University of Texas MD Anderson Cancer Center, in Houston, who was representing CAP.

"This guideline addresses all current molecular markers that can impact treatment decisions for patients with colorectal cancer," Dr Hamilton said in a statement. "To date, there isn't an evidence-based guideline that's quite as all-encompassing and patient-centered as this one."

The draft guidelines address three specific questions regarding molecular testing in colorectal cancer: which are the appropriate tests, what is the appropriate sample, and how should testing be performed?

Highlights of Recommendations and Expert Consensus

Recommendations for colorectal cancer molecular marker tests that should be performed include the following:

• RAS mutational testing of colorectal carcinoma tissue should be performed for patients who are being considered for anti-EGFR therapy. This analysis must 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).
• BRAF V600 mutational analysis should be done in conjunction with deficient mismatch repair (dMMR)/microsatellite instability (MSI) testing for prognostic stratification.
• dMMR/MSI testing must be performed in all colorectal cancers for prognostic stratification and identification of Lynch syndrome patients. (BRAF mutation testing is not needed for Lynch syndrome if there is no MSI-H with loss of MLH1.)

Expert consensus opinion regarding the most appropriate sample for colorectal cancer molecular marker testing includes the following:

• Molecular marker testing (KRAS, extended RAS, BRAF, and dMMR/MSI) of the primary colorectal carcinoma tissue is acceptable. If metastatic tissue is available, that is also acceptable and is preferable in patients with metastatic disease.
• Formalin fixed paraffin embedded tissue is an acceptable specimen. Use of other specimens will require additional adequate validation, as would any changes in tissue processing protocols.

Strong recommendations with regard to colorectal cancer molecular markers are as follows:

• Laboratories must use validated colorectal carcinoma molecular marker testing methods with sufficient performance characteristics for the intended clinical use.
• Performance of molecular marker testing for colorectal carcinoma must be validated in accordance with best laboratory practices.
• Performance of IHC testing for colorectal carcinoma molecular markers must be validated in accordance with best laboratory practices.

Recommendations for Laboratories

The societies also provided guidance for the laboratories performing the testing. They advise that laboratories prioritize colorectal cancer tumor tissue for RAS, BRAF, and dMMR/MSI testing, and that the facilities "anticipate the need for molecular testing in routine diagnostics."

n addition, they recommend that laboratories use testing methods that are able to detect mutations in specimens with at least 5% mutant allele frequency, after factoring in the analytic sensitivity of the assay and tumor enrichment.

The guidelines also offer recommendations relating to analysis and reporting results. For example, when sending out samples, 90% should be mailed within 3 working days. Results should include an interpretation section that is readily understandable by oncologists and pathologists, and prognostic and predictive results should be available as promptly as feasible, within 10 working days from the initial receipt of the specimen in the pathology laboratory.

"Given the rapid evolution of the field, we have 'future proofed' the document with a research section that acknowledges molecular markers and tests on the horizon," said Carmen Allegra, MD, University of Florida Health Cancer Center, Gainesville, who is project cochair on behalf of ASCO, in a statement. "We intend to review these recommendations regularly and will update the guidance document as necessary.