Martinez-Balibrea Eva, Martínez-Cardús Anna, Musulén Eva, Ginés Alba, Manzano José Luis, Aranda Enrique, Plasencia Carmen, Neamati Nouri, Abad Albert
Medical Oncology Service, Hospital Universitari Germans Trias i Pujol, Institut Català d'Oncologia, Badalona, Barcelona, Spain.
Int J Cancer. 2009 Jun 15;124(12):2905-10. doi: 10.1002/ijc.24273.
Recently, the copper efflux transporters ATP7B and ATP7A have been implicated in the transport of and resistance to platinum drugs in breast and ovarian cancers. Because of the extensive use of oxaliplatin in colorectal cancer (CRC), we examined the expression of both transporters in tumors from CRC patients treated with oxaliplatin/5FU and sought to determine whether their expression can predict clinical outcome in these patients. ATP7B and ATP7A levels were determined by quantitative real-time PCR in 50 primary tumors of previously untreated patients with advanced colorectal adenocarcinoma who were subsequently treated with oxaliplatin/5FU. Additionally, ATP7B protein expression was assessed by immunohistochemical staining using a tissue microarray. Patients with the lowest mRNA expression levels of ATP7B had a significantly longer time to progression (TTP) (p = 0.0009) than patients with the highest levels (12.14 months vs. 6.43 months) who also had an increased risk of progression (HR = 3.56; 95% CI, 1.6-7.9; p = 0.002). Furthermore, patients with low levels of both protein and mRNA of ATP7B derived the maximum benefit from oxaliplatin/5FU with the longest TTP as compared with patients with high levels of ATP7B protein and mRNA (14.64 months vs. 4.63 months, respectively, p = 0.01) and showed a nonsignificant trend toward a lower response rate (37.5% and 75%, respectively). In conclusion, ATP7B mRNA and protein expression in colorectal tumors is associated with clinical outcome to oxaliplatin/5FU. Prospective studies are required to evaluate the role of this marker in tailoring chemotherapy.
最近，铜离子外排转运蛋白ATP7B和ATP7A被认为与乳腺癌和卵巢癌中铂类药物的转运及耐药性有关。由于奥沙利铂在结直肠癌（CRC）中广泛应用，我们检测了接受奥沙利铂/5-氟尿嘧啶（5FU）治疗的CRC患者肿瘤中这两种转运蛋白的表达情况，并试图确定它们的表达是否能预测这些患者的临床结局。通过定量实时聚合酶链反应（PCR）测定了50例先前未治疗的晚期结直肠腺癌患者的原发性肿瘤中ATP7B和ATP7A的水平，这些患者随后接受了奥沙利铂/5FU治疗。此外，使用组织微阵列通过免疫组织化学染色评估ATP7B蛋白表达。ATP7B mRNA表达水平最低的患者比表达水平最高的患者有显著更长的疾病进展时间（TTP）（p = 0.0009）（分别为12.14个月和6.43个月），后者的疾病进展风险也增加（风险比[HR]=3.56；95%置信区间[CI]，1.6 - 7.9；p = 0.002）。此外，与ATP7B蛋白和mRNA水平高的患者相比，ATP7B蛋白和mRNA水平低的患者从奥沙利铂/5FU中获益最大，TTP最长（分别为14.64个月和4.63个月，p = 0.01），且缓解率有降低的趋势但无统计学意义（分别为37.5%和75%）。总之，结直肠肿瘤中ATP7B mRNA和蛋白表达与奥沙利铂/5FU的临床结局相关。需要进行前瞻性研究以评估该标志物在化疗个体化中的作用。
