Hu Ying Chuan, Komorowski Richard A, Graewin Shannon, Hostetter Galen, Kallioniemi Olli-P, Pitt Henry A, Ahrendt Steven A
Department of Surgery, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Clin Cancer Res. 2003 Sep 15;9(11):4165-71.
Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU), and TS expression may determine clinical response and survival after therapy with 5-FU in colorectal cancer. 5-FU is also widely used in the adjuvant therapy of pancreatic cancer. Therefore, we explored the hypothesis that TS expression was associated with patient prognosis and the response to adjuvant therapy in pancreatic cancer.
Cylindrical tissue cores from a large retrospective, nonrandomized series covering 132 resected patients were used to build a pancreatic cancer tissue microarray. TS expression was determined using immunohistochemistry.
High intratumoral TS expression and low intratumoral TS expression were present in 83 of 132 (63%) and 49 of 132 (37%) tumors, respectively. Median survival among patients with low intratumoral TS expression (18 months) was longer than that among patients with high TS expression (12 months). In multivariate analysis, more advanced pathological stage [risk ratio (RR) = 1.70; P = 0.015], poorly differentiated histology (RR = 1.71; P = 0.015), management with adjuvant therapy (RR = 0.49; P = 0.011), and high TS expression [RR = 1.66; 95% confidence interval (CI) = 1.05-2.63; P = 0.029] were independent predictors of mortality. The risk of death was significantly reduced by any adjuvant therapy (RR = 0.40; 95% CI = 0.18-0.90; P = 0.001) among patients with high TS expression. This difference in survival among patients with low- and high-TS-expressing tumors became more significant when the analysis was restricted to the 73 patients receiving 5-FU-based adjuvant therapy (RR = 0.37; 95% CI = 0.16-0.86; P = 0.0006). In contrast, 5-FU-based adjuvant therapy did not influence survival among patients with low-TS-expressing pancreatic cancer.
High TS expression is a marker of poor prognosis in resected pancreatic cancer. Patients with high intratumoral TS expression benefit from adjuvant therapy.
胸苷酸合成酶（TS）是5-氟尿嘧啶（5-FU）的靶酶，TS表达可能决定结直肠癌患者接受5-FU治疗后的临床反应和生存期。5-FU也广泛用于胰腺癌的辅助治疗。因此，我们探讨了TS表达与胰腺癌患者预后及辅助治疗反应相关的假说。
使用来自一个涵盖132例接受手术切除患者的大型回顾性、非随机系列研究的圆柱形组织芯构建胰腺癌组织微阵列。采用免疫组织化学法测定TS表达。
132例肿瘤中，分别有83例（63%）肿瘤TS瘤内高表达，49例（37%）肿瘤TS瘤内低表达。TS瘤内低表达患者的中位生存期（18个月）长于TS高表达患者（12个月）。多因素分析显示，更晚期的病理分期[风险比（RR）=1.70；P=0.015]、低分化组织学（RR=1.71；P=0.015）、辅助治疗（RR=0.49；P=0.011）以及TS高表达[RR=1.66；95%置信区间（CI）=1.05 - 2.63；P=0.029]是死亡的独立预测因素。在TS高表达患者中，任何辅助治疗均可显著降低死亡风险（RR=0.40；95% CI=0.18 - 0.90；P=0.001）。当分析仅限于73例接受基于5-FU的辅助治疗的患者时，TS低表达和高表达肿瘤患者的生存差异变得更加显著（RR=0.37；95% CI=0.16 - 0.86；P=0.0006）。相比之下，基于5-FU的辅助治疗对TS低表达胰腺癌患者的生存无影响。
TS高表达是手术切除胰腺癌预后不良的标志物。TS瘤内高表达的患者从辅助治疗中获益。
