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Managing mCRC

CE / CME

Opportunities and Challenges in Management of Metastatic Colorectal Cancer

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit

Released: May 02, 2023

Expiration: May 01, 2024

CME/CE Information

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Recommended Molecular Testing 

The number of actionable molecular biomarkers has expanded rapidly during the past few years, and both the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) offer comprehensive recommendations for testing. All patients newly diagnosed with CRC, regardless of stage, should be tested for MSI using panel-based next-generation sequencing (NGS) or dMMR using immunohistochemistry. The testing is recommended to identify patients with Lynch syndrome and to guide therapy in advanced or metastatic disease. Patients with MSI-high/dMMR advanced or metastatic CRC are eligible for treatment with anti–PD-1 immune checkpoint inhibitors (ICIs), whereas patients with resectable clinical T4b disease may be candidates for neoadjuvant ICI.4-6 MSI-high/dMMR tumors may reflect germline mutations, as in Lynch syndrome, or acquired somatic mutations that often are related to a BRAF mutation that silences expression of one of the mismatch repair genes. 

In addition to MSI-high/dMMR, all patients presenting with metastatic disease should be tested for KRAS/NRAS mutations and the BRAF V600E point mutation using panel-based NGS, as well as HER2 amplification, RET fusions, and NTRK fusions.4 

Other than RAS mutations, which are found in up to 40% of CRC tumors, each of these gene alterations is relatively rare but may be concentrated in certain patient populations. For example, HER2 amplification, found in approximately 3% of patients with CRC overall, occurs at higher rates in patients with wild-type RAS or EGFR tumors (5%-14%). BRAF V600E mutations are found in approximately 10% of all patients with mCRC; many of these patients’ tumors are also MSI-high (acquired rather than inherited). NTRK fusions are found in <1% overall but in up to 30% of patients with MSI-high/dMMR disease.4,7,8 

Of note, HER2 testing differs for CRC vs breast cancer. Because CRC specimens are typically first sent for NGS, HER2 amplification typically is identified on that platform. In breast cancer, HER2 amplification routinely is assessed using immunohistochemistry with or without fluorescence in situ hybridization. In CRC, HER2 immunohistochemistry and fluorescence in situ hybridization can be performed if needed 4,5 

When present, RAS mutations predict lack of benefit of EGFR inhibitors (cetuximab and panitumumab). The presence of BRAF V600E confers eligibility for combined BRAF inhibitor and EGFR inhibitor treatment. As important as what to test for is what not to test for: in mCRC there is no need to test for EGFR mutations to determine eligibility for treatment with EGFR inhibitors.4,5

 

Expert Insights From Dr.Lentz: Ensuring Appropriate Comprehensive Testing

 

Hereditary CRC

Lynch syndrome is characterized by germline mutations in the DNA repair genes. All patients who present with MSI-high/dMMR disease should be evaluated for suspected Lynch syndrome using germline sequencing and genetic counseling, as well as patients who present with CRC younger than 50 years of age.4 Anti–PD-1 ICIs are a recommended treatment option for patients with MSI-high/dMMR tumors, either in the setting of Lynch syndrome or not. However, a diagnosis of Lynch syndrome does not currently restrict treatment selection in CRC—patients with Lynch syndrome can still receive chemotherapy and biologic therapies.9,10 

 

Expert Insights From Dr.Lentz: Genetic counseling and Lynch syndrome

 

Which of the following most accurately describes the prognostic relevance of right-sided tumors compared with left-sided tumors, independent of molecular features?

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