Analysis of PTEN, BRAF, and EGFR Status in Determining Benefit From Cetuximab Therapy in Wild-Type KRAS Metastatic Colon Cancer
Analysis of PTEN, BRAF, and EGFR Status in Determining Benefit From Cetuximab Therapy in Wild-Type KRAS Metastatic Colon Cancer
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DOI：
10.1200/jco.2008.21.6796
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发表时间：
2009-12-10
影响因子：
45.3
通讯作者：
Penault-Llorca, Frederique
中科院分区：
文献类型：
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作者：
Laurent-Puig, Pierre;Cayre, Anne;Penault-Llorca, Frederique
目的KRAS 突变的发生预示着接受抗表皮生长因子受体 (抗 EGFR) 抗体治疗转移性结直肠癌 (mCRC) 的患者无反应且生存期较短，导致欧洲药品管理局限制其在野生型 KRAS 肿瘤患者中的使用。然而，这些患者中只有一半会从治疗中受益，这表明需要确定其他生物标志物来确定基于西妥昔单抗的治疗效果。患者和方法我们回顾性收集了 173 名 mCRC 患者的肿瘤。除一名患者外，所有患者均接受了基于西妥昔单抗的治疗方案作为二线或更好的治疗。通过等位基因区分评估 KRAS 和 BRAF 状态。通过显色原位杂交和荧光原位杂交评估 EGFR 扩增，并通过免疫化学评估 PTEN 表达。结果在 KRAS 野生型肿瘤患者 (n = 116) 中，BRAF 突变 (n = 5) 与缺乏反应微弱相关 (P = .063)，但与较短的无进展生存期 (P < .001) 和较短的总生存期 (OS; P < .001）。在 17.7% 的患者中发现高 EGFR 多体性或 EGFR 扩增，并且与缓解相关 (P = .015)。在 19.9% 的患者中发现 PTEN 缺失表达，并且与较短的 OS 相关 (P = .013)。在多变量分析中，BRAF 突变和 PTEN 表达状态与 OS 相关。结论 在接受基于西妥昔单抗方案治疗的 KRAS 野生型患者中，BRAF 状态、EGFR 扩增和 PTEN 细胞质表达与结果测量相关。需要在临床试验队列中进行后续研究来确认这些标志物的临床效用。
PurposeThe occurrence of KRAS mutation is predictive of nonresponse and shorter survival in patients treated by anti-epidermal growth factor receptor (anti-EGFR) antibody for metastatic colorectal cancer (mCRC), leading the European Medicine Agency to limit its use to patients with wild-type KRAS tumors. However, only half of these patients will benefit from treatment, suggesting the need to identify additional biomarkers for cetuximab-based treatment efficacy.Patients and MethodsWe retrospectively collected tumors from 173 patients with mCRC. All but one patient received a cetuximab-based regimen as second-line or greater therapy. KRAS and BRAF status were assessed by allelic discrimination. EGFR amplification was assessed by chromogenic in situ hybridization and fluorescent in situ hybridization, and the expression of PTEN was assessed by immunochemistry.ResultsIn patients with KRAS wild-type tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but were strongly associated with shorter progression-free survival (P < .001) and shorter overall survival (OS; P < .001). A high EGFR polysomy or an EGFR amplification was found in 17.7% of the patients and was associated with response (P = .015). PTEN null expression was found in 19.9% of the patients and was associated with shorter OS (P = .013). In multivariate analysis, BRAF mutation and PTEN expression status were associated with OS.ConclusionBRAF status, EGFR amplification, and cytoplasmic expression of PTEN were associated with outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.