Guidelines Establish the Role of Molecular Testing in Treatment of Patients With CRC

Molecular testing of patients with colorectal cancer (CRC) should be incorporated into standard practice to establish the mutations each patient has that would affect their response to treatment with EGFR-targeted therapies, according to new guidelines from the American Society for Clin- ical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO).¹

Together the ASCP, CAP, AMP, and ASCO convened a panel of experts to determine a set of guidelines that establish molecular biomarker testing to guide personalized care for patients with CRC who are being considered for treatment with anti-EGFR therapies and/or conventional chemotherapy.

“The evidence-based recommendations for these guidelines focused on molecular biomarkers identified as the most useful in patients with CRC, in order to select patients who can benefit from enhanced treatment with targeted therapies,” said Antonia R. Sepulveda, MD, PhD, of Columbia University in New York City, the project co-chair on behalf of AMP, in a statement.

While EGFR-targeted therapies continue to be a mainstay in treating patients with CRC, certain mutations affect responses to them. KRAS mutations, for example, have been associated with resistance to these therapies. The identification of this negative predictive biomarker several years ago led to an uptake in testing for other potential biomarkers in this patient population.

A retrospective analysis of the effects ofKRAS, BRAF, NRAS, andPIK3CAmutations on response to treatment with cetuximab (Erbitux), an anti-EGFR monoclonal antibody, and chemotherapy demonstrated thatBRAF,NRAS, andPIK3CAexon 20 mutations were also associated with lower responses in patients with chemotherapy-refractory metastatic CRC.²

“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,” said Wayne W. Grody, MD, PhD, of the University of California Los Angeles School of Medicine, the project co-chair on behalf of ASCP, in a statement.

To identify patients with mutations who may not benefit from treatment with anti-EGFR agents, the panel highly recommended that all patients with CRC undergo testing for RAS mutations, especially 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. These specific RAS mutations were singled out in a meta-analysis of the effect of extended RAS mutations on survival with anti-EGFR therapies.³Patients harboring any of these RAS mutations were unlikely to achieve a significant benefit from an anti-EGFR monoclonal antibody, whereas patients with RAS wild-type tumors showed a significant progression-free survival and overall survival (OS) benefit. The results were consistent whether patients received cetuximab or panitumumab (Vectibix), another anti-EGFR therapy, with or without chemotherapy.

Testing was also recommended forBRAFV600 mutations, including in tumors with mismatch repair (MMR)-deficiency with loss of 1MLH1in patients who potentially may have Lynch syndrome.

Patients with aBRAFmutation demonstrated decreased outcomes when treated with anti-EGFR therapy compared with those with unmutated tumors. However, the guidelines also noted that the poorer outcome could be a result of a decreased OS after relapse rather than a suggestion of an increased likelihood of relapse. The authors noted that patients withBRAFmutations could instead benefit from treatment with a BRAF inhibitor in addition to EGFR-targeted therapy, which has shown promise in early trials. Specifically, though,BRAFV600 mutations alone could not be considered a biomarker for response to EGFR inhibitors due to conflicting evidence.

The guidelines noted that MMR status may have a predictive role in evaluating for Lynch syndrome. The incidence of Lynch syndrome can often be attributed to a germline mutation of 1 of the 4 MMR genes: MLH1, MSH2, MSH6, and PMS2.4 Identification of the syndrome has important implications for the patient’s family members because their risk of developing cancer would be significantly increased.

Also, testing for microsatellite instability (MSI) would help identify patients for treatment with immunotherapy, such as pembrolizumab (Keytruda), which is currently undergoing a review from the FDA for the treatment of patients with MSI-high cancer.

A post hoc analysis of the PETACC-8 trial demonstrated that patients withBRAFV600 orKRASmutations and microsatellite-stable disease were more likely to have a shorter disease-free survival and OS when treated with FOLFOX-based chemotherapy, with or without cetuximab, than patients with MSI disease,⁵which further supported the need forBRAFandKRASmutation testing.

Insufficient evidence was found supportingPIK3CAmutations as a biomarker for therapy selection outside of a clinical trial.¹Although several analyses have shown worse responses and PFS rates among patients with a PIK3CA mutation, primarily in exon 20, the impact of the mutation has been inconsistent across disease stages and various studies. However, the authors did note that a benefit has been seen from treatment with aspirin in patients with aPIK3CAmutation; more prospective studies are underway to investigate this result.