Pereira Marina Alessandra, Ramos Marcus Fernando Kodama Pertille, Dias Andre Roncon, Faraj Sheila Friedrich, Cirqueira Cinthya Dos Santos, de Mello Evandro Sobroza, Zilberstein Bruno, Alves Venancio Avancini Ferreira, Ribeiro Ulysses
Department of Gastroenterology, Cancer Institute, University of São Paulo Medical School, São Paulo 01246-000, Brazil.
Department of Pathology, Cancer Institute, University of São Paulo Medical School, São Paulo 01246-000, Brazil.
Chin J Cancer Res. 2018 Oct;30(5):526-536. doi: 10.21147/j.issn.1000-9604.2018.05.06.
Adjuvant chemotherapy with 5-fluorouracil (5-FU) has been widely used in gastric cancer (GC) patients to prevent relapse after curative resection. 5-FU acts by inhibiting thymidylate synthase (TS), and high levels of TS correlate with resistance to treatment with fluoropyrimidines. The aim of this study was to evaluate the expression of TS in GC patients, and its relation with clinicopathological characteristics and prognosis in adjuvant chemotherapy with 5-FU.
We retrospectively evaluated 285 patients who underwent D2-gastrectomy with curative intent. TS expression was determined by immunohistochemistry (IHC) in tumor cells by tissue microarray (TMA). TS level was evaluated according to the intensity and percentage of cells marked by a score system. Patients were divided in three groups according to their TS-score: negative, low and high.
TS expression was positive in 92.3% of GC. TS-high, TS-low and TS-negative were observed in 46.3%, 46.0% and 7.7% of patients, respectively. High-TS GC were associated with older age (P=0.007), high neutrophil/lymphocyte ratio (P=0.048), well/moderately differentiated histology (P=0.001), intestinal Lauren type (P<0.001) and absence of perineural invasion (P=0.003). Among 285 patients, 133 stage II/III patients (46.7%) received chemotherapy with 5-FU. In survival analysis, TS-high was associated with worse disease-free survival (DFS) in stage III GC patients who received 5-FU-based chemotherapy (P=0.007). Multivariate analysis revealed that total gastrectomy, poorly differentiated tumors and high TS-score were associated with worse DFS in stage III GC patients.
High TS-score in stage III GC was associated with poor DFS in patients treated with fluoropyrimidine-based chemotherapy.
5-氟尿嘧啶（5-FU）辅助化疗已广泛应用于胃癌（GC）患者，以预防根治性切除术后复发。5-FU通过抑制胸苷酸合成酶（TS）发挥作用，TS水平高与对氟嘧啶治疗的耐药性相关。本研究旨在评估GC患者中TS的表达及其与5-FU辅助化疗的临床病理特征和预后的关系。
我们回顾性评估了285例接受D2根治性胃切除术的患者。通过组织微阵列（TMA）免疫组织化学（IHC）测定肿瘤细胞中的TS表达。根据评分系统标记的细胞强度和百分比评估TS水平。根据TS评分将患者分为三组：阴性、低和高。
92.3%的GC患者TS表达呈阳性。TS高、TS低和TS阴性患者分别占46.3%、46.0%和7.7%。高TS的GC与年龄较大（P=0.007）、中性粒细胞/淋巴细胞比值高（P=0.048）、组织学高/中分化（P=0.001）、肠型Lauren分型（P<0.001）和无神经周围侵犯（P=0.003）相关。在285例患者中，133例II/III期患者（46.7%）接受了5-FU化疗。在生存分析中，TS高与接受基于5-FU化疗的III期GC患者较差的无病生存期（DFS）相关（P=0.007）。多变量分析显示，全胃切除术、低分化肿瘤和高TS评分与III期GC患者较差的DFS相关。
III期GC患者中高TS评分与基于氟嘧啶化疗的患者较差的DFS相关。
