New Molecular Testing Guidelines Pending for Colorectal Cancer

Carmen J. Allegra, MD

All patients with colorectal cancer being considered for treatment with the epidermal growth receptor (EGFR) inhibitors cetuximab and panitumumab should undergo extended RAS mutational testing to predict their response to the drugs, according to a new molecular marker testing guideline being developed by the American Society of Clinical Oncology (ASCO) and three leading pathology organizations.

The draft guideline calls for extended mutational analysis that includes KRAS and NRAS codons 12 and 13 of exon 2, codons 59 and 61 of exon 3, and codons 117 and 146 of exon 4.

The guideline, which is scheduled to be finalized later this year or early next year, also recommends BRAF V600 mutational analysis in conjunction with deficient mismatch repair/microsatellite instability (dMMR/MSI) testing for patients with metastatic colorectal carcinoma (mCRC), and dMMR/MSI testing in all patients for prognostic stratification and identification of Lynch syndrome.

The project is the first attempt to draw up a comprehensive guideline in the fast-moving area of CRC molecular testing, the authors said.

“This guideline addresses all current molecular markers that can impact treatment decisions for patients with colorectal cancer. To date, there isn’t an evidence- based guideline that’s quite as all-encompassing and patient-centered as this one,” said Stanley R. Hamilton, MD, The University of Texas MD Anderson Cancer Center, who serves as project co-chair on behalf of College of American Pathologists (CAP).

Existing CRC biomarker guidelines have tended to focus on one marker or a small panel of markers for one specific clinical use, he said.

At the same time, the guideline advises that there is currently insufficient evidence to recommend BRAF V600 status as predictive marker for response to anti-EGFR inhibitors; PIK3CA mutual analysis for therapy selection outside of a clinical trial; and PTEN analysis for therapy selection outside of a clinical trial.

If the guideline provokes any controversy, it would likely stem from that dearth of evidence, said Carmen J. Allegra, MD, a medical oncologist at the University of Florida Health Cancer Center and the project co-chair on behalf of ASCO.

“There are some areas where the mutations don’t occur very commonly, so there isn’t a lot of information out there in the literature to help guide us,” he said. “The default is to say there just isn’t enough to have a definitive position. There are others who would say, well, wait a minute, there seems to be enough information. That’s a little bit in the eye of the beholder.”

By acknowledging molecular markers and tests on the horizon, the authors have “future-proofed” the documents, and they will continue meeting and updating the guideline as necessary, he said.

The draft was released jointly on March 30 by ASCO, CAP, the American Society for Clinical Pathology (ASCP), and the Association for Molecular Pathology (AMP). The public comment period ended April 22 and some recommendations are being modified to address issues that were identified. New evidence found during an updated literature search is also being reviewed for possible inclusion.

The guideline is being offered as developments in research on molecular markers continue to make their way into clinical practice. They include findings that patients who have mutations in KRAS exon 3 and 4 and NRAS exon 2 and 3 do not benefit from anti-EGFR therapy and could suffer harm from those agents. “Really, the most powerful piece of information we have about these mutations is focused around RAS,” Allegra said. “And that is not a positive predictor; it’s a negative predictor.”

National Comprehensive Cancer Network guidelines recommend that all patients with mCRC have tumor tissue genotyped for KRAS and NRAS mutations. In March, the FDA approved updated labeling for panitumumab to indicate that RAS mutation status should be assessed before treatment is initiated and that patients whose tumors harbor the mutation or whose RAS status is unknown should not receive the drug.

Bridging Evidence Gap

With research into newly available genomic data constantly reshaping the frontier of oncology, Allegra said the guideline drafted by the four organizations aims to bridge the gap between research and individual physicians.

“When you are in practice, it is not always easy to keep up with all the nuances in the field, so these guidelines really provide a convenient mechanism for oncologists to keep up with the latest,” he said.

“Given that an oncologist isn’t going to have the time to read through or think about the literally thousands of papers that went into this guideline, it’s essential that somebody interrogates the literature very deeply and comes up with a set of opinions and guidelines based on that literature.”

The dissemination of the draft, and eventually of the finalized guideline, may also help improve physician awareness of molecular marker testing as a diagnostic tool, Allegra said.

While the document recommends molecular marker testing to guide selection of targeted therapies, it does not address how or when in the course of treatment the therapies should be used. The field is moving in the direction of identifying additional targeted therapies and the best ways to use them, but Allegra said those determinations are outside the project’s scope.

The draft also provides an expert consensus opinion on sampling, saying that testing of primary colorectal carcinoma tissue is acceptable but metastatic CRC tissue is preferable in patients with mCRC. Formalin-fixed paraffin-embedded tissue is acceptable, while use of cytology or other specimens will require additional adequate validation, as would any changes in tissue-processing protocols.

References

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