Kilari Deepak, Iczkowski Kenneth A, Pandya Chintan, Robin Adam J, Messing Edward M, Guancial Elizabeth, Kim Eric S
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, U.S.A.
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, U.S.A.
Anticancer Res. 2016 Feb;36(2):495-501.
BACKGROUND/AIM: Platinum (Pt)-based neoadjuvant chemotherapy (NAC) is the standard-of-care for muscle-invasive bladder cancer (MIBC). However, the survival benefit with NAC is driven by patients with pathological response at cystectomy. Non-responders are subject to adverse effects of Pt, with delay in definitive treatment. Copper transporter receptor 1 (CTR1) plays an important role in Pt uptake and the level of expression may influence Pt sensitivity. We hypothesized that tumor CTR1 expression correlated with pathological outcome.
We identified matched paraffin-embedded tissues from pre-NAC transurethral bladder tumor resection (TURBT) and post-NAC radical cystectomy (RC) specimens in 47 patients with MIBC who received Pt-based NAC. Tumor and adjacent normal tissues were stained with CTR1 antibody. CTR1 expression was determined through immunohistochemistry by two pathologists blinded to the outcome (0=undetectable; 1+=barely detectable; 2+=moderate; and 3+=intense staining). Pathological response was defined as either down-staging to non-MIBC (≤pT1N0M0) or complete pathological response (pT0). Pathological outcome was compared between the CTR1 expression groups.
Forty-three percent of TURBT and 41% of RC specimens expressed a CTR1 score of 3+. Forty-four percent of patients had a pathological response to NAC, and 17% had pT0 disease at cystectomy. In both pre-NAC TURBT and post-NAC RC specimens, a CTR1 expression score of 3+ correlated with pathological response (p=0.0076 and p=0.023, respectively).
This is the first study to demonstrate a correlation between CTR1 tumor expression and pathological outcome in Pt-treated MIBC. These findings suggest that CTR1 expression may be a biomarker for Pt sensitivity.
背景/目的：铂（Pt）类新辅助化疗（NAC）是肌层浸润性膀胱癌（MIBC）的标准治疗方案。然而，NAC带来的生存获益是由膀胱切除术后出现病理反应的患者驱动的。无反应者会受到铂的不良反应影响，且确定性治疗会延迟。铜转运蛋白受体1（CTR1）在铂摄取中起重要作用，其表达水平可能影响铂敏感性。我们假设肿瘤CTR1表达与病理结果相关。
我们从47例接受铂类NAC的MIBC患者的NAC前经尿道膀胱肿瘤切除术（TURBT）和NAC后根治性膀胱切除术（RC）标本中鉴定出匹配的石蜡包埋组织。肿瘤及相邻正常组织用CTR1抗体染色。由两名对结果不知情的病理学家通过免疫组织化学确定CTR1表达（0 = 不可检测；1+ = 勉强可检测；2+ = 中等；3+ = 强染色）。病理反应定义为降期至非MIBC（≤pT1N0M0）或完全病理反应（pT0）。比较CTR1表达组之间的病理结果。
43%的TURBT标本和41%的RC标本CTR1评分为3+。44%的患者对NAC有病理反应，17%的患者在膀胱切除术后为pT0疾病。在NAC前TURBT和NAC后RC标本中，CTR1表达评分3+均与病理反应相关（分别为p = 0.0076和p = 0.023）。
这是第一项证明在接受铂治疗的MIBC中CTR1肿瘤表达与病理结果之间存在相关性的研究。这些发现表明CTR1表达可能是铂敏感性的生物标志物。
