Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

Abstract

The sensitivity to 5-fluorouracil (5-FU) has been reported to be associated with target molecule thymidylate synthase (TS), fluoropyrimidine-metabolising enzymes such as orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD). We performed an immunohistochemical study on the clinical significance of TS, OPRT, and DPD expression using 151 resected non-small-cell lung cancer (NSCLC) patients postoperatively treated with a combination of tegafur and uracil (UFT). Eightytwo carcinomas were TS-positive, 105 carcinomas were OPRT-positive, 68 carcinomas were DPD-positive. No correlation was observed in the HSCORE between the TS and OPRT expression (r ¼ 0.203), between the TS and DPD expression (r ¼ 0.098), or between the OPRT and DPD expression (r ¼ 0.074). Regarding the survival of NSCLC patients treated with UFT, the 5-year survival rate of patients with TS-negative tumours was significantly higher than that with TS-positive tumours (P ¼ 0.0133). The 5-year survival rate of patients with OPRT-positive stage II to III tumours was significantly higher than that with OPRT-negative stage II to III tumours (P ¼ 0.0145). In addition, the 5-year survival rate of patients with DPD-negative tumours was also significantly higher than that with DPD-positive tumours (P ¼ 0.0004). A Cox multivariate regression analysis revealed the TS status (hazard ratio 2.663; P ¼ 0.0003), OPRT status (hazard ratio 2.543; P ¼ 0.0005), and DPD status (hazard ratio 2.840; Po0.0001) to all be significant prognostic factors for the survival of resected NSCLC patients postoperatively treated with UFT.

Randomized Phase II Study of Adjuvant Chemotherapy with Long-term S-1 versus Cisplatin+S-1 in Completely Resected Stage II–IIIA Non–Small Cell Lung Cancer

“…Nakano and colleagues reported that the 5-year survival rate of patients with OPRT-positive stage II to III tumors was significantly higher than that of patients with OPRT-negative tumors (24). Conversely, Takeda and colleagues reported that there is no significant association between tumor response and expression levels of OPRT (25).…”

“…Indeed, SNPs and expression levels of UMPS/ OPRT have been reported to predict the efficacy and toxicity of 5FU in other human cancers and cell lines (21)(22)(23). Several reports on NSCLC treated with 5FU have shown associations between expression levels of UMPS/OPRT and clinical outcomes (24,25).…”

Biomarkers for efficacy of adjuvant chemotherapy following complete resection in NSCLC stages I–IIIA

“…There are two contradicting studies reporting on thymidylate synthase expression. NAKANO et al [26] observed that patients (stage I-III) with low thymidylate synthase expression (low was defined as <30; H-score range: 0-300) had a worse OS with a hazard ratio of 2.663 ( p=0.0003). By contrast, MIYOSHI et al [27] reported that thymidylate synthase negative patients (stage I-II) had an 89% 5-year survival rate, unlike thymidylate synthase positive patients who had 50% 5-year survival ( p=0.001).…”

“…NAKAGAWA et al [59] found male sex to be associated with poorer OS (HR It is frequently observed that expression of biomarkers may vary between histological subtypes [14,15,18,22,23,25,26,51], which is another reason that the prognostic and predictive potential may vary depending on the frequencies of various histological subtypes in the study populations. Some articles in this review included several histological subtypes, while other articles focused solely on one histological subtype (tables 1-4), which needs to be kept in mind when comparing different studies on the same biomarker.…”

<b>Orotate phosphoribosyltransferase localizes to the Golgi complex and its expression levels affect the sensitivity to anti-cancer drug 5-fluor</b><b>ouracil </b>

“…DISCUSSION 5-FU is a widely used anti-cancer agent for the therapy of various malignancies, including gastric cancers, colorectal cancers, mammary cancers, non-small cell lung cancers, and head and neck cancers. The anticancer activity of 5-FU is closely associated with the intratumoral expression of 5-FU-metabolizing enzymes, including thymidylate synthase, OPRT, and dihydropyrimidine dehydrogenase (11). Clinical reports have described a relation between the expression or activities of these enzymes in the tumors and the clinical response or survival of cancer patients upon 5-FU-based chemotherapy (4,9).…”