Medical Oncology Department, La Paz Universitary Hospital, IDiPAZ, RTICC-RD06/0020/1022, Spain.
Crit Rev Oncol Hematol. 2013 Jan;85(1):45-81. doi: 10.1016/j.critrevonc.2012.05.001. Epub 2012 May 28.
The advent of the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs), cetuximab and panitumumab has expanded the range of treatment options for metastatic colorectal cancer (CRC). Despite these agents have paved the way to individualized therapy, our understanding why some patients respond to treatment whereas others do not remain poor. The realization that detection of positive EGFR expression by IHC does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of benefit to anti-EGFR mAbs. Oncologists are now facing emerging issues in the treatment of metastatic CRC, including the identification of additional genetic determinants of primary resistance to EGFR-targeted therapy for further improving selection of patients, the explanation of rare cases of patients carrying KRAS-mutated tumours who have been reported to respond to cetuximab and panitumumab and the discovery of mechanisms of secondary resistance to EGFR-targeted therapy. Current data suggest that, together with KRAS mutations, the evaluation of EGFR gene copy number (GCN), BRAF, NRAS, PIK3CA mutations or loss of PTEN expression could also be useful for selecting patients with reduced chance to benefit from anti-EGFR mAbs. This review aims to provide an updated of the most recent data on predictive and prognostic biomarkers within the EGFR pathway, the challenges this emerging field presents and the future role of these molecular markers in CRC treatment.
表皮生长因子受体（EGFR）靶向单克隆抗体（mAbs），如西妥昔单抗和帕尼单抗的出现，扩大了转移性结直肠癌（CRC）的治疗选择范围。尽管这些药物为个体化治疗铺平了道路，但我们对为什么有些患者对治疗有反应而有些患者没有反应的理解仍然很差。人们意识到免疫组织化学（IHC）检测到的 EGFR 表达阳性并不能可靠地预测 EGFR 靶向治疗的临床结果，这导致了对替代预测生物标志物的强烈搜索。来自多个 III 期试验的数据表明，KRAS 突变可以被认为是抗 EGFR mAbs 获益的高度特异性负生物标志物。肿瘤学家现在面临转移性 CRC 治疗中的新问题，包括确定对 EGFR 靶向治疗的原发性耐药的其他遗传决定因素，以进一步改善患者的选择，解释携带 KRAS 突变肿瘤的罕见患者报告对西妥昔单抗和帕尼单抗有反应的原因，以及发现 EGFR 靶向治疗的继发性耐药机制。目前的数据表明，除了 KRAS 突变外，评估 EGFR 基因拷贝数（GCN）、BRAF、NRAS、PIK3CA 突变或 PTEN 表达缺失也可能有助于选择从抗 EGFR mAbs 中获益机会较低的患者。这篇综述旨在提供 EGFR 通路中预测和预后生物标志物的最新数据的更新，包括这一新兴领域提出的挑战以及这些分子标志物在 CRC 治疗中的未来作用。
