转移性结直肠癌中对西妥昔单抗治疗疗效和耐药性的基因表达标志物：CALGB 80203（联盟）研究结果
Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).
作者信息
Cushman Stephanie M, Jiang Chen, Hatch Ace J, Shterev Ivo, Sibley Alexander B, Niedzwiecki Donna, Venook Alan P, Owzar Kouros, Hurwitz Herbert I, Nixon Andrew B
机构信息
Duke University Medical Center, Durham, North Carolina.
Alliance Statistical and Data Center, Durham, North Carolina.
出版信息
Clin Cancer Res. 2015 Mar 1;21(5):1078-86. doi: 10.1158/1078-0432.CCR-14-2313. Epub 2014 Dec 17.
PURPOSE
Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis-related genes to identify prognostic or predictive biomarkers for cetuximab treatment.
PATIENTS AND METHODS
Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models.
RESULTS
High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025).
CONCLUSIONS
Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity.
目的
分析来自CALGB 80203研究的福尔马林固定、石蜡包埋肿瘤样本中表皮生长因子受体（EGFR）轴相关基因的表达情况，以确定西妥昔单抗治疗的预后或预测生物标志物。
患者与方法
238例一线转移性结直肠癌（mCRC）患者被随机分配接受FOLFOX或FOLFIRI化疗±西妥昔单抗。对103例患者基线时的组织进行定量逆转录聚合酶链反应（qRT-PCR）分析，以检测HER相关基因的表达水平，包括双调蛋白（AREG）、β细胞素（BTC）、NT5E（CD73）、双特异性磷酸酶4（DUSP4）、表皮生长因子（EGF）、表皮生长因子受体（EGFR）、表位蛋白（EPGN）、表皮调节素（EREG）、肝素结合表皮生长因子（HBEGF）、erb-b2受体酪氨酸激酶2（ERBB2，HER2）、erb-b3受体酪氨酸激酶（ERBB3，HER3）、erb-b4受体酪氨酸激酶（ERBB4，HER4）、PHLDA1和转化生长因子α（TGFA）。使用乘法Cox比例风险模型对表达水平与治疗在无进展生存期（PFS）和总生存期（OS）方面的相互作用进行建模。
结果
HER2（风险比[HR]，0.64；P = 0.002）和EREG（HR，0.89；P = 0.016）的高肿瘤mRNA水平是所有患者中与更长PFS相关的预后标志物。HER3和CD73表达水平被确定为西妥昔单抗获益的潜在预测标志物。在KRAS野生型（WT）肿瘤中，低HER3表达与西妥昔单抗治疗的更长OS相关，而高HER3表达与西妥昔单抗治疗的更短OS相关（化疗+西妥昔单抗：HR，1.15；单纯化疗：HR，0.48；相互作用P = 0.029）。在KRAS-WT（化疗+西妥昔单抗：HR，0.91；单纯化疗：HR，1.57；相互作用P = 0.026）和KRAS突变（Mut）肿瘤患者中，高CD73表达与西妥昔单抗治疗的更长PFS相关（化疗+西妥昔单抗：HR，0.80；单纯化疗：HR，1.29；P = 0.025）。
结论
HER3和CD73的基因表达被确定为西妥昔单抗的潜在预测标志物。这些数据表明HER轴信号传导和免疫调节是西妥昔单抗作用和敏感性的潜在机制。
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