Predictive value of orotate phosphoribosyltransferase in colorectal cancer patients receiving 5-FU-based chemotherapy

Abstract

Pretreatment knowledge of chemosensitivity and side-effects of chemotherapy for colorectal cancer (CRC) patients are likely to ensure the best chemotherapeutic outcome. The aim of this study was to identify additional predictive factors of chemosensitivity to the key CRC treatment drug 5-fluorouracil (5-FU). Surgically obtained specimens from 106 patients treated for CRC were immunohistochemically assessed to investigate the correlation between the protein expression of the 5-FU metabolic enzymes orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD), and clinicopathological characteristics as well as the correlation between the protein expression and outcomes of 5-FU-based chemotherapy. A correlation was detected between the high expression of the 5-FU metabolic enzyme OPRT and negative lymph node metastasis (P=0.0496), as well as between DPD and advanced Tumor-Node-Metastasis (TNM) grade cases (IIIA-IVB) and positive lymph node metastases (P=0.0414, respectively). In all 106 patients and in 79 patients undergoing 5-FU-based chemotherapy, survival was improved in those patients with a positive OPRT expression (P=0.0144 and 0.0167, respectively). OPRT expression was higher in the 79 patients with no recurrence (P=0.0179) as well as in patients treated with R0 surgery and 5-FU-based chemotherapy without side-effects (P=0.0126). Disease-free survival (DFS) rate was higher in patients without side-effects, and in patients with a positive OPRT expression without side-effects (P=0.0021 and 0.0031, respectively). Findings of this study demonstrated that OPRT expression positively correlated with fewer side-effects of 5-FU-based chemotherapy and longer patient survival.

Keywords: 5-fluorouracil-based chemotherapy; orotate phosphoribosyltransferase; prognosis; side-effect.

Figure 1

Photomicrographs showing scoring for evaluation of the expression of 5-FU metabolic enzymes. Expression of the 5-FU metabolic enzymes (A–C) OPRT, (D–F) TS and (G and H) DPD was evaluated on a 4-point scale based on the immunohistochemical staining percentage (SP): SP<10%, 0 points; SP≥10 and <30%, 1 point; SP≥30 and <50%, 2 points and SP≥50%, 3 points. 5-FU, 5-fluorouracil; OPRT, orotate phosphoribosyltransferase; TS, thymidylate synthase; DPD, dihydropyrimidine dehydrogenase.

Figure 2

Kaplan-Meier curves showing the correlation between OPRT expression and median survival time (MST). (A) In the 106 patients, survival was improved in patients with a positive OPRT expression (closed circles, n=80) compared with patients with a negative expression (open circles, n=26). (B) In 79 patients treated with 5-FU-based chemotherapy, survival was improved in patients with a positive OPRT expression (closed circles, n=60) compared with patients with a negative expression (open circles, n=19). OPRT, orotate phosphoribosyltransferase; HR, hazard ratio; CI, confidence interval; 5-FU, 5-fluorouracil..

Figure 3

Correlation between OPRT expression and time to recurrence. In 79 patients treated with 5-FU-based chemotherapy, OPRT expression was higher in patients with no recurrence (n=29) compared with those exhibiting early recurrence (recurrence within 1 year with any metastasis at surgery) (n=42). No significant correlation was detected in 8 other patients with recurrence >1 year from surgery. OPRT, orotate phosphoribosyltransferase; 5-FU, 5-fluorouracil.

Figure 4

Kaplan-Meier curves showing patient prognosis with regard to side-effects. (A) Disease-free survival (DFS) after R0 surgery was improved in patients without (closed circles, n=29) compared with patients with side-effects (open circles, n=20). (B) DFS was improved in patients with a positive OPRT expression and no side-effects (triangles, n=25) compared with patients either with a negative (closed circles, n=9) or positive expression of OPRT, and with side-effects (open circle, n=15). OPRT, orotate phosphoribosyltransferase; SE, side-effects; HR, hazard ratio; CI, confidence interval.