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?
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?
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DOI：
10.1038/gim.2012.184
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发表时间：
2013-07-01
影响因子：
8.8
通讯作者：
Veenstra, David L.
中科院分区：
文献类型：
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作者：
Calonge, Ned;Fisher, Nancy L.;Veenstra, David L.
建议：基因组学在实践和预防中的应用评估（EGAPP）工作组（EWG）发现，对于正在考虑接受西妥昔单抗或帕尼单抗治疗的转移性结直肠癌（mCRC）患者，有令人信服的证据建议临床使用KRAS突变分析来确定哪些患者是KRAS突变阳性，因此不太可能在开始治疗前从这些药物中获益。证据的确定性水平被认为是高的，避免潜在无效和有害治疗的净健康益处的大小，沿着促进更直接获得可能是下一个最有效的治疗，至少是中等的。EWG发现没有足够的证据推荐或反对BRAF V600 E测试用于相同的临床情况。BRAF V600 E检测指导抗表皮生长因子受体（EGFR）治疗的确定性水平被认为较低。EWG鼓励进一步研究在发现患有KRAS野生型（突变阴性）肿瘤的mCRC患者中进行检测以预测对治疗的反应性的潜在价值。EWG发现没有足够的证据推荐或反对NRAS或PIK 3CA突变和/或PTEN或AKT蛋白表达缺失的检测。该证据的确定性水平较低。在缺乏支持性证据的情况下，考虑到其他背景问题，EWG不鼓励使用这些检测来指导决定是否开始使用西妥昔单抗或帕尼单抗进行抗EGFR治疗，除非有进一步的证据支持改善临床结局。已经表明，肿瘤携带影响EGFR通路信号传导的某些突变的mCRC患者通常对抗EGFR抗体治疗无反应（西妥昔单抗和帕尼单抗）。EWG确定了最近针对该主题的证据审查，本建议声明基于这些审查的结果。在制定这些建议时，EWG考虑了以下领域的证据：分析有效性：虽然没有发现正式评估这些测试分析有效性的研究综合，但EWG能够从正在考虑的证据审查中的评估中得出以下结论。有足够的证据表明，KRAS突变分析可靠和准确地检测常见的突变（密码子12和13），而证据不足，不太频繁的KRAS突变（例如。例如，在一个实施例中，密码子61）。也有足够的证据表明，BRAF V600 E检测准确可靠地检测突变。对于NRAS、PIK 3CA和PTEN AKT表达中的常见突变，有足够的证据可以准确可靠地检测。然而，支持的数据要少得多。此外，在mCRC的特定情况下，没有证据表明免疫组化（IHC）检测PTEN或AKT expression.Clinical效度的分析有效性：对于KRAS突变分析，EWG发现了令人信服的证据，与抗EGFR治疗反应相关，独立于预后相关性。对于BRAF V600 E突变检测，EWG发现与抗EGFR治疗应答相关的证据不足，不依赖于预后相关性。EWG发现NRAS或PIK 3CA突变检测结果与PTEN或ATK蛋白表达缺失与抗EGFR治疗反应之间的关联证据不足。临床应用：对于KRAS突变分析，EWG发现充分证据表明，通过避免无效化疗和潜在副作用以及加快获得下一个最有效的治疗，可以改善健康结果。在接受抗EGFR治疗的mCRC患者中，与携带野生型BRAF序列和PTEN表达水平的肿瘤患者相比，BRAF V600 E突变检测或PTEN表达缺失与健康结局改善相关的证据不足。没有发现证据支持与NRAS或PIK 3CA变体或AKT蛋白表达水平的测试结果相关的健康结果改善。背景问题：CRC是一个重要且高度流行的健康问题。与药物遗传学检测相关的mCRC结局的改善可能具有重要的临床和潜在的公共卫生影响。与癌症化疗相关的不良事件可能是常见和严重的。因此，成功优化治疗以最大限度地提高疗效并最大限度地减少副作用对于降低mCRC相关发病率和死亡率非常重要。
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 validity: 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.Clinical utility: 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.Contextual issues: 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.