Is K-RAS (Kirsten rat sarcoma viral oncogene homolog) and immunohistochemistry to determine HER2 (human epidermal growth factor receptor 2) overexpression indicated in invasive colonic adenocarcinoma?

From the Guidelines

K-RAS and HER2 (C-ERB B2) immunohistochemistry are indicated in invasive colonic adenocarcinoma, with K-RAS testing being mandatory before initiating anti-epidermal growth factor receptor (EGFR) therapy and HER2 testing being recommended in RAS wild-type patients to detect those who may benefit from HER2 blockade. The purpose of K-RAS mutation testing is to predict response to anti-EGFR therapies like cetuximab and panitumumab, which are only effective in patients with wild-type (non-mutated) K-RAS 1. Approximately 40-45% of colorectal cancers harbor K-RAS mutations, and these patients will not benefit from anti-EGFR therapy. Some key points to consider when testing for K-RAS and HER2 include:

• K-RAS testing should be performed on either the primary tumor or any metastatic site, with a suggested turnaround of 10 days 1
• HER2 testing is recommended in RAS wild-type patients to detect those who may benefit from HER2 blockade, and can be done using immunohistochemistry (IHC) or FISH 1
• HER2 overexpression occurs in about 2-5% of colorectal cancers, and these patients may benefit from HER2-targeted therapies such as trastuzumab plus pertuzumab or trastuzumab plus lapatinib 1
• The molecular profile of colorectal cancer helps guide personalized treatment decisions, improving outcomes by ensuring patients receive therapies most likely to be effective for their specific tumor characteristics. It is also important to note that other biomarkers, such as BRAF V600E mutation, deficient mismatch repair (dMMR)/microsatellite instability (MSI), and NTRK fusions, may also be relevant in the diagnosis and treatment of invasive colonic adenocarcinoma, and should be tested for as part of the initial molecular work-up 1.

From the FDA Drug Label

1. 2 K-Ras Wild-type, EGFR-expressing Colorectal Cancer (CRC) ERBITUX is indicated for the treatment of K-Ras wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test Limitations of Use: ERBITUX is not indicated for treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown

• K-RAS mutation status is indicated for the treatment of metastatic colorectal cancer with ERBITUX.
• IMMUNOHISTOCHEMISTRY for EGFR expression is also required.
• However, C-ERB B2 (HER2) OVEREXPRESSION is not mentioned in the label as an indication for ERBITUX in invasive colonic adenocarcinoma.
• The label does mention that ERBITUX is indicated for K-Ras wild-type, EGFR-expressing metastatic colorectal cancer, but it does not specify invasive colonic adenocarcinoma.
• Therefore, based on the label, K-RAS and EGFR expression by immunohistochemistry are relevant for ERBITUX treatment, but HER2 overexpression is not directly mentioned as an indication for invasive colonic adenocarcinoma 2

From the Research

K-RAS and IMMUNOHISTOCHEMISTRY TO 3 and C-ERB B2(HER2) OVEREXPRESSION in Invasive Colonic Adenocarcinoma

• K-RAS mutations are commonly found in colorectal cancer, with studies suggesting that they appear early in tumorigenesis, at the intermediate adenoma stage, and can be used as a biomarker for early detection in about 40% of colonic tumors 3.
• The overexpression of HER2 is an important target for treatment with monoclonal antibody (mAb) trastuzumab, and is an emerging therapeutic biomarker in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) mAbs cetuximab and panitumumab 4, 5.
• Immunohistochemistry is a relevant method for detecting HER2 amplification, and routine testing for extended RAS, BRAF, dmmr or high msi, and NTRK fusions is necessary to determine the best sequencing of chemotherapy and biologic agents for patients with mCRC 6.
• The expression of EGFR and HER2 has been examined in paired primary tumours and their metastatic sites, with results showing discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours 4.
• HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR therapies, and HER2 testing is important to inform treatment decisions and could optimize outcomes for patients 5.

Biomarkers and Treatment Outcomes

• The prognostic and predictive significance of expanded RAS mutation testing, BRAF mutations, ERBB2 (her2) amplification, microsatellite instability (msi) and deficient mismatch repair (dmmr) protein, NTRK fusions, PIK3CA mutations, and met amplifications is important for personalizing therapies for each patient with mCRC 6.
• Meta-analyses of proportions (ORR) and hazard ratios (PFS, OS) have been performed to assess the prognostic or predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes, with results showing a 2.84-fold higher risk of death or progression in patients with HER2-positive (vs. HER2-negative) RAS WT mCRC treated with anti-EGFR regimens 5.
• The incorporation of novel biomarkers into therapy selection for patients with metastatic colorectal cancer has significantly improved outcomes, and optimal treatment planning now takes into account diverse characteristics of patients and their tumours to create personalized therapeutic plans 6.