Department of General, Visceral & Cancer Surgery, Center for Integrated Oncology (CIO), University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
Pharmacogenomics. 2011 Feb;12(2):205-14. doi: 10.2217/pgs.10.174.
Neoadjuvant treatment strategies have been developed to improve the survival of patients with locally advanced esophageal cancer. Since patients with major histopathological response are the ones who mainly benefit from this therapy, we are looking for causes of nonresponse. The multidrug resistance protein ABCB1 belongs to the ATP-binding cassette superfamily of membrane transporters. By exporting positively charged drugs it plays a role in the acquisition of resistance in anticancer therapy. We examined the ABCB1 gene polymorphism C3435T to predict response and prognosis to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil and 36 Gy) in locally advanced esophageal cancer patients.
MATERIALS & METHODS: A total of 262 patients (216 male; 46 female; median age: 62 years) with locally advanced esophageal cancer (squamous cell cancer: n = 116, adenocarcinoma: n = 146) were included in this study. All patients received a neoadjuvant radiochemotherapy (36.0 Gy, 5-fluorouracil, cisplatin) followed by surgery. Histomorphologic regression was classified according to the Cologne Regression Grade with major response being classifed as having less than 10% vital tumor cells (n = 107) and minor response when 10% or more vital tumor cells (n = 155) were detected in the surgical specimen. Genomic DNA was extracted from paraffin-embedded tissues of all study patients. Allelic genotyping was performed for ABCB1 rs1045642 by real-time PCR using two allele-specific TaqMan(®) probes in competition. Allelic genotyping was correlated with therapy response and prognosis.
Allelic discrimination revealed a TT genotype in 27%, a CC in 19% and a CT genotype in 54% of the study patients. This SNP was not predictive for response of the primary tumor to neoadjuvant radiochemotherapy. The ABCB1 genotype CC was associated with lymph node formation (p = 0.012) and distant metastases (p = 0.019). Patients with a TT genotype exhibited a significantly less positive lymph node status (ypN1 35%) after chemoradiation compared with patients with a CC (ypN1 = 60%) or CT (ypN1 = 46%) genotype. Moreover, patients bearing the TT genotype exhibited no distant metastasis, while five patients with a CC and two patients with CT genotype had distant metastases. In Kaplan-Meier curves, adenocarcinoma patients with a CC genotype showed a worse survival rate than patients with TT or CT (p = 0.048).
Our data supports the impact of ABCB1 on effectiveness of esophageal cancer treatment. SNPs of ABCB1 could be helpful in predicting lymph node regression in the multimodality treatment of locally advanced esophageal cancer.
新辅助治疗策略的发展旨在提高局部晚期食管癌患者的生存率。由于主要组织病理学反应的患者主要受益于这种治疗，因此我们正在寻找无反应的原因。多药耐药蛋白 ABCB1 属于膜转运体的 ATP 结合盒超家族。通过输出正电荷药物，它在癌症治疗的耐药性获得中发挥作用。我们研究了 ABCB1 基因多态性 C3435T，以预测局部晚期食管癌患者新辅助放化疗（顺铂、5-氟尿嘧啶和 36Gy）的反应和预后。
本研究共纳入 262 例局部晚期食管癌患者（216 例男性；46 例女性；中位年龄：62 岁）（鳞状细胞癌：n=116，腺癌：n=146）。所有患者均接受新辅助放化疗（36.0Gy、5-氟尿嘧啶、顺铂），然后手术。组织形态学回归根据科隆回归分级进行分类，主要反应定义为手术标本中少于 10%存活肿瘤细胞（n=107），而次要反应为检测到 10%或更多存活肿瘤细胞（n=155）。从所有研究患者的石蜡包埋组织中提取基因组 DNA。通过实时 PCR 使用两种等位基因特异性 TaqMan®探针在竞争中进行 ABCB1 rs1045642 的等位基因基因分型。等位基因基因分型与治疗反应和预后相关。
等位基因鉴别显示研究患者中 TT 基因型为 27%，CC 为 19%，CT 为 54%。该 SNP 不能预测新辅助放化疗对原发性肿瘤的反应。ABCB1 基因型 CC 与淋巴结形成（p=0.012）和远处转移（p=0.019）相关。与 CC 或 CT 基因型（ypN1=46%）相比，接受放化疗后 TT 基因型患者的阳性淋巴结状态（ypN1=35%）显著降低。此外，携带 TT 基因型的患者没有发生远处转移，而 CC 基因型的 5 例患者和 CT 基因型的 2 例患者发生了远处转移。在 Kaplan-Meier 曲线中，CC 基因型的腺癌患者的生存率明显低于 TT 或 CT 基因型（p=0.048）。
我们的数据支持 ABCB1 对食管癌治疗效果的影响。ABCB1 的 SNP 可能有助于预测局部晚期食管癌多模式治疗中的淋巴结消退。
