title: Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy?
abstract: CONCLUSIONS
  The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.The EWG found insufficient evidence to recommend for or against BRAF V600E testing for the same clinical scenario. The level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low. The EWG encourages further studies of the potential value of testing in patients with mCRC who were found to have tumors that are wild type (mutation negative) for KRAS to predict responsiveness to therapy.The EWG found insufficient evidence to recommend for or against testing for mutations in NRAS, or PIK3CA, and/or loss of expression of PTEN or AKT proteins. The level of certainty for this evidence was low. In the absence of supporting evidence, and with consideration of other contextual issues, the EWG discourages the use of these tests in guiding decisions on initiating anti-EGFR therapy with cetuximab or panitumumab unless further evidence supports improved clinical outcomes.
  
  
  BACKGROUND
  It has been suggested that patients with mCRC whose tumors harbor certain mutations affecting EGFR pathway signaling are typically unresponsive to therapy with anti-EGFR antibodies (cetuximab and panitumumab). The EWG identified recent evidence reviews that have addressed this topic, and this recommendation statement is based on results of these reviews. In developing these recommendations the EWG considered evidence in the areas described below.
  
  
  RESULTS
  Although no research syntheses that have formally evaluated analytic validity of these tests were found, the EWG was able to draw the following conclusions from assessments included in the evidence reviews under consideration. There is adequate evidence that KRAS mutation analysis reliably and accurately detects common mutations (codons 12 and 13), whereas evidence was inadequate for less frequent KRAS mutations (e.g., codon 61). There is also adequate evidence that testing for BRAF V600E accurately and reliably detects the mutation. For common mutations in NRAS, PIK3CA, and expression of PTEN AKT, there is adequate evidence of accurate and reliable detection. However, much less data exist in support. Furthermore, in the specific context of mCRC, no evidence was found on the analytic validity of immunohistochemistry (IHC) assays for PTEN or AKT expression.
  
  
  RESULTS
  For KRAS mutation analysis, the EWG found convincing evidence for association with treatment response to anti-EGFR therapy, independent of prognostic association. For BRAF V600E mutation testing, the EWG found insufficient evidence for association with treatment response to anti-EGFR therapy independent of prognostic association. The EWG found insufficient evidence for association of results of testing for mutations in NRAS or PIK3CA, and loss of expression of PTEN or ATK proteins, with treatment response to anti-EGFR therapy.
  
  
  RESULTS
  For KRAS mutation analysis, the EWG found adequate evidence that improved health outcomes are achieved by avoiding ineffective chemotherapy and potential side effects and expediting access to the next most effective treatment. Inadequate evidence was found regarding association of BRAF V600E mutation testing or loss of PTEN expression with improved health outcomes among patients with mCRC undergoing anti-EGFR therapy as compared with patients with tumors bearing wild-type BRAF sequence and PTEN expression levels, respectively. No evidence was found to support improved health outcomes associated with testing results for NRAS or PIK3CA variants, or AKT protein expression levels in this clinical scenario.
  
  
  CONCLUSIONS
  CRC is an important and highly prevalent health problem. Improvements in mCRC outcomes associated with pharmacogenetic testing could have important clinical, and potentially public health, impacts. Adverse events related to cancer chemotherapy can be common and severe. Therefore, successfully optimizing treatment to maximize efficacy and minimize side effects is important for reducing mCRC-related morbidity and mortality.
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics; D005820:Genetic Testing / Q000191:economics / Q000379:methods; D017408:Guidelines as Topic; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab