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Societies Release Clinical Practice Guidelines for Colorectal Cancer Molecular Testing

NEW YORK (GenomeWeb) – A group of professional societies released new guidelines today for molecular testing of patients with colorectal cancer in order to improve patient outcomes.

The guide, co-developed by the American Society for Clinical Pathology, the College of American Pathologists, the Association for Molecular Pathology, and the American Society of Clinical Oncology, appeared online in the Journal of Molecular Diagnostics, as well as journals for each of the other collaborating organizations.

The goal of the recommendations is to help establish standards for molecular testing using a wider range of markers than previous guidelines have addressed, to further advance personalized care for CRC patients.

For example, molecular testing for KRAS alterations affecting exon 2 codons 12 and 13 has become standard of practice, but guidelines have not yet comprehensively caught up to additional clinical trial data demonstrating that other KRAS exons, as well as additional EGFR pathway genes like NRAS, BRAF, PIK3CA, and PTEN, may also affect patients' responses to anti-EGFR drugs.

In addition, while DNA mismatch repair (MMR) status is currently recommended for all patients to identify cases of Lynch syndrome, evidence that it may also have prognostic value, and potentially predictive value in some clinical settings hasn't yet been addressed in professional guidelines.

"While many existing recommendations cover the application of individual molecular biomarkers in colorectal cancer, this guideline fills the need for an overarching set of recommendations spanning the breadth of current knowledge," UCLA's Wayne Grody, project co-chair on behalf of ASCP, said in a statement.

The new guidelines will prove useful for pathologists and oncologists "to support decision making on what molecular tests to order," he added.

To develop the new guide, experts appointed by each of the participating bodies, including pathologists, oncologists, and patient representatives, worked together between July 2013 and late 2015 to perform a comprehensive literature review, which included over 4,000 articles.

The group started with a set of questions to be answered — including which existing biomarkers are most useful to select CRC patients for targeted and conventional therapies, which emerging markers might also be useful in routine testing, and what research is needed to validate them.

The authors said the that resulting recommendations focus on molecular biomarkers identified as being the "most useful" right now in selecting CRC patients that might benefit from treatment with targeted cancer therapies.

The new document includes 21 guideline statements divided between recommendations, expert consensus opinions, and non-recommendations, the latter of which advise against the use of a particular biomarker.

Overall, the guidelines support mutational testing for genes in the EGFR pathway to inform targeted therapy decisions concerning EGFR inhibitors.

Patients with CRC being considered for anti-EGFR drugs must receive RAS mutation testing, the authors wrote. This analysis should include KRAS and NRAS codons 12 and 13 of exon 2, 59 and 61 of exon 3, and 117 and 146 of exon 4 — otherwise known as "expanded" or "extended" RAS testing.

Clinicians should order testing for MMR status to identify patients at a higher risk of having Lynch syndrome and/or for prognostic stratification.

BRAF V600 mutation analysis should also be done to stratify patients in terms of their prognosis. And it should be performed in patients whose tumors do show MMR deficiency with a loss of MLH1 in order to further evaluate for Lynch syndrome.

The guidelines' negative recommendations include a caution regarding insufficient evidence supporting BRAF V600, PIK3CA, and PTEN testing to predict response to targeted therapy.

Additional consensus opinion statements focus on strategies to streamline molecular testing processes in the lab. For example, the authors wrote, labs should consider metastatic or recurrent CRC tissue as the preferred specimen type for predictive biomarker testing.

In the absence of metastatic tissue though, primary tumor tissue is an acceptable alternative, the team said.

The authors also caution that labs should use testing methods that can detect mutations in specimens to at least 5 percent mutant allele frequency, taking into account the analytical sensitivity of the assay in terms of limit of detection and tumor enrichment.

The guide also includes a recommendation that test results and interpretations be "readily understandable by oncologists and pathologists," using the appropriate annotation nomenclature.

Moving forward, the participating organizations said they are launching what they called an ongoing communication and dissemination campaign toward medical professionals and the public, to raise awareness and to assist in the integration of the new guidelines into pathology, laboratory, and clinical practice.

The group also plans to review the guidelines every four years or potentially more frequently if a high-quality publication or finding so merits.

“Realizing that molecular diagnostics is a rapidly evolving field of medicine, the collaborating organizations … are committed to updating this guideline routinely in order to capture and make recommendations for new discoveries in the field," MD Anderson's Stanley Hamilton, project co-chair on behalf of CAP, said in a statement.

Though the actual recommendation and consensus statements do not address newer areas of interest like prediction of immunotherapy response or liquid biopsy technologies, the publication did touch on these emerging approaches.

Authors wrote that there is emerging data indicating that MMR status may predict response to anti PD-1 or PD-L1 immunotherapies.

They also mention the use of circulating tumor cell or cell-free DNA-based liquid biopsy methods either to monitor evolution of disease and response to therapy, or potentially to predict recurrence in order to guide use of adjuvant therapies.

Though these advances are promising they await further validation, the group wrote.