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

EGAPP REcommEndAtion stAtEmEnt summary of recommendations: 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.Rationale: 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. Analytic validity: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.clinical val...

Changes in Colorectal Carcinoma Genomes under Anti-EGFR Therapy Identified by Whole-Genome Plasma DNA Sequencing

“…However, despite this progress, the EGAPP (Evaluation of Genomic Applications in Practice and Prevention) Working Group (www.egappreviews.org) found only adequate evidence for an association of KRAS genotype at codons 12 and 13 with diminished treatment response to anti-EGFR therapy, but not for BRAF V600E, mutations in NRAS or PIK3CA , or loss of PTEN or AKT expression [6]. One reason for this uncertainty is the lack of genetic follow-up data in clinical studies.…”

“…Other factors than KRAS mutation status likely affect response to anti-EGFR therapy, because the response rates among patients with wild-type KRAS are less than 20% [1], [6], [7]. Recent investigations have identified genes and proteins downstream of KRAS in the mitogen-activated protein kinase signaling pathway, which affect unresponsiveness to anti-EGFR therapy, including the BRAF V600E mutation, mutations in NRAS or PIK3CA (exons 9 and 20), or loss of PTEN or AKT expression [8]–[10].…”

Current Approaches for Predicting a Lack of Response to Anti-EGFR Therapy inKRASWild-Type Patients

“…Notably, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found insufficient evidence to recommend or discourage testing for mutations in BRAF V600E, NRAS, or PIK3CA and/or loss of PTEN or AKT protein. Therefore, the EWG discourages the use of these tests for deciding whether to introduce anti-EGFR therapy with cetuximab or panitumumab until more evidence supports improved clinical outcomes [69]. Moreover, a meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS , BRAF , PIK3CA , and nonfunctional PTEN predict resistance to anti-EGFR therapies [70] and concluded that these biomarkers should be implemented for prediction of clinical benefit from anti-EGFR antibodies in mCRC.…”

Mutación del gen BRAF en pacientes con cánceres de colon y recto con KRAS no mutado

“…Entre los genes candidatos a esta clasificación se encuentran además de los estudiados en este trabajo, el estudio de la inestabilidad microsatelital, p53 y PIP3k entre los más frecuentemente señalados por los estudios publicados 39 . De esta manera, la implementación de estas determinaciones son una necesidad actual y un elemento fundamental en la elección de la terapia dirigida a los portadores de esta frecuente enfermedad tumoral.…”