Dihydropyrimidine Dehydrogenase In Patients Research Articles

Abstract OT2-2-07: A phase II study of S-1 (14 days' administration followed by 7 days' rest) for metastatic breast cancer

Abstract Background S-1, an orally administered fluorinated pyrimidine (FP), improves overall survival in the adjuvant setting of gastric and pancreatic cancer. It is also effective for metastatic breast cancer (Yamamoto et al. Anticancer Res 30:3827-32, 2010). Although S-1 is usually administered for 28 days followed by 14 days’ rest, severe adverse events are often observed by Day 15. By altering the schedule into 14 days’ administration followed by 7 days’ rest, discontinuation of treatment can often be avoided in daily practice. This schedule maintains the same dose intensity. Equally, an anti-tumor effect and fewer adverse events are observed in 14 days’ administration followed by 7 days’ rest than in 28 days’ administration followed by 14 days’ rest for the treatment of squamous cell carcinoma of the head and neck (Tsukuda et al. Br J Cancer 93:884-889, 2005). In order to reduce the occurrence and severity of adverse events of S-1, we paid attention to dose reduction according to the renal function of patients. S-1 is comprised of tegafur, 5-chloro-2, 4-dihydroxy-pyridine(CDHP) and potassium oxonate. CDHP enhances the serum concentration of 5-FU by inhibiting dihydropyrimidine dehydrogenase (DPD), and it is excreted by the kidneys. Therefore, an accumulation of DPD in patients with renal dysfunction escalates the serum concentration of 5-FU and induces more severe adverse events. Thus, the dosage of S-1 should be reduced according to renal function. Trial design This is a phase II trial to evaluate the efficacy and toxicity of S-1 (14 days’ administration followed by 7 days’ rest) for metastatic breast cancer. S-1 is administered orally twice daily at a dose of 40-60 mg depending on the BSA and creatinine-clearance from Days 1 to 14, which is followed by 7 days’ rest. This treatment is repeated until disease progression. (Trial registration :UMIN 000014096) Eligibility criteria Patients with histologically confirmed breast cancer, and recurrent and /or metastatic disease are included. Patients with HER2-positive (IHC:3+ or FISH+) tumor are excluded. Patients within 2 lines of previous chemotherapy for metastatic disease are allowed. Eligible patients are aged between 20 years and 80 years with a performance status of 0 to 2 and adequate organ function. Specific aims The primary endpoint is the response rate, and the secondary endpoints are disease control rate, progression-free survival, time to failure, toxicities and feasibility. Statistical methods The sample size was calculated using the Simon method, with a type I error of 5% and a study power of 90%. The unpromising response rate was 15% and the promising rate was 42%. The required number of patients was estimated to be 23. Target accrual Accrual of 25 patients was planned to produce a minimum of 23 evaluable patients. Patient accrual started in June 2014. Citation Format: Akira Hirano, Akinori Hattori, Kaoru Ogura, Hiroaki Inoue, Fumie Okubo, Mari Kamimura, Shiho Sakaguchi, Jun Kinoshita, Reiko Miyamoto, Norie Jibiki, Yoshihiko Naritaka, Tadao Shimizu. A phase II study of S-1 (14 days' administration followed by 7 days' rest) for metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-07.

Polymorphisms in MIR27A Associated with Early-Onset Toxicity in Fluoropyrimidine-Based Chemotherapy.

The microRNA miR-27a was recently shown to directly regulate dihydropyrimidine dehydrogenase (DPD), the key enzyme in fluoropyrimidine catabolism. A common polymorphism (rs895819A>G) in the miR-27a genomic region (MIR27A) was associated with reduced DPD activity in healthy volunteers, but the clinical relevance of this effect is still unknown. Here, we assessed the association of MIR27A germline variants with early-onset fluoropyrimidine toxicity. MIR27A was sequenced in 514 patients with cancer receiving fluoropyrimidine-based chemotherapy. Associations of MIR27A polymorphisms with early-onset (cycles 1-2) fluoropyrimidine toxicity were assessed in the context of known risk variants in the DPD gene (DPYD) and additional covariates associated with toxicity. The association of rs895819A>G with early-onset fluoropyrimidine toxicity was strongly dependent on DPYD risk variant carrier status (Pinteraction = 0.0025). In patients carrying DPYD risk variants, rs895819G was associated with a strongly increased toxicity risk [OR, 7.6; 95% confidence interval (CI), 1.7-34.7; P = 0.0085]. Overall, 71% (12/17) of patients who carried both rs895819G and a DPYD risk variant experienced severe toxicity. In patients without DPYD risk variants, rs895819G was associated with a modest decrease in toxicity risk (OR, 0.62; 95% CI, 0.43-0.9; P = 0.012). These results indicate that miR-27a and rs895819A>G may be clinically relevant for further toxicity risk stratification in carriers of DPYD risk variants. Our data suggest that direct suppression of DPD by miR-27a is primarily relevant in the context of fluoropyrimidine toxicity in patients with reduced DPD activity. However, miR-27a regulation of additional targets may outweigh its effect on DPD in patients without DPYD risk variants.

Results of a comprehensive pharmacogenetic analysis of dihydropyrimidine dehydrogenase in patients treated with fluoropyrimidines and patterns of polymorphisms partially related to treatment tolerability.

e13057 Background: Metabolic clearance of fluoropyrimidines is highly dependent on the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). Deficiency of DPD is associated with drug accumulation and severe toxicities. The DPD gene (DPYD) is highly polymorphic; however, except the G>A mutation in the splicing consensus sequence of intron 14 (IVS14+1G>A), which is responsible of severe enzyme impairment, the association of other variants with adverse reactions is unclear. Therefore, this study was aimed at examining the prevalence of DPYD variants in patients with toxicities and in subjects with good tolerability to fluoropyrimidine-based regimens. Methods: Patients affected by colorectal, breast and head/neck cancers requiring standard treatment with 5-FU or capecitabine in combination with other cytotoxic agents (irinotecan, oxaliplatin, cyclophosphamide or methotrexate) and/or antibodies (cetuximab or bevacizumab) were enrolled: 224 suffered from grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) and 61 control patients developed adverse events to an extent not requiring dose-delay or reduction (i.e., <2 non-hematological and <3 hematological toxicities). DNA was extracted from blood and used to screen patients for known DPD variants (IVS14+1G>A, 496A>G, 1601G>A, 1627A>G, 1896T>C, 2194G>A and 2846T>C) by automatic sequencing. The study was approved by local Ethics Committee. Results: A complex pattern of DPYD variants was identified in both cohorts; the following genotypes were detected in patients with severe toxicities vs controls: 496AG+GG: 24.1 vs 21.3%; 1601GA: 12.5 vs 1.6%; 1627AG+GG: 37.1 vs 32.8%; 1896TC+TT: 6.25 vs 8.2%; IVS14+1GA: 4.9 vs 0%; 2194GA: 25.9 vs 9.8; 2846AT: 1.3 vs 0%. Conclusions: Although there was a higher prevalence of DPYD variants in patients with severe toxicities, their presence also in subjects with good tolerability suggest that their role needs to be re-evaluated, with the exception of IVS14+1GA and 2846AT which were found only in patients with poor tolerability. This study was supported in part by a grant from AIRC to R. Danesi.

The relationship between survival and the expression of dihydropyrimidine dehydrogenase in patients with colorectal cancer

Dihydropyrimidine dehydrogenase (DPD) is considered to be a key enzyme affecting the prognosis for patients with colorectal cancer. We investigated whether a correlation exists between the expression of DPD and survival in patients with colorectal cancer. The present study was designed to quantify the DPD level using an enzyme-linked immunosorbent assay in tumors and normal tissue specimens obtained from 22 colorectal cancer patients. There were no significant differences in the preoperative features, neither in the intra- and post-operative findings of patients between the high DPD and low DPD groups in tumor tissue. In patients showing an expression of DPD in tumor tissue, the overall survival in the low DPD group tended to be longer than that in the high DPD group (P = 0.076). In contrast, in patients showing an expression of DPD in normal tissue, no significant difference was observed in the overall survival between the high DPD and low DPD groups (P = 0.358). In patients showing an expression of DPD in tumor tissue, the disease-free survival in the low DPD group was longer than that in the high DPD group (P = 0.046), whereas in patients showing an expression of DPD in normal tissue, no significant difference was seen in the disease-free survival between the high DPD and low DPD groups (P = 0.473). There tended to be a correlation between the DPD expression in tumor tissue and that in adjacent normal tissue (R = 0.390, P = 0.073). Based on these findings, we demonstrated the importance of DPD expression in tumor tissue as a prognostic factor in patients with colorectal cancer.

Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) has been suggested to be sensitivity-limiting factors of 5-fluorouracil therapy in cancer patients. We conducted a large-scale population study on the activity of TS and DPD in patients with various solid tumors. A total of 2590 clinically removed tumors, consisting of 1112 colon, 724 gastric, 520 breast, and 236 non-small cell lung cancers, were provided to measure TS and DPD activity. TS activity in the gastric, colon, and non-small cell lung cancers was significantly higher than in matched non-cancerous tissue (P<0.0002), but there was no difference in TS expression between tumor and non-cancerous tissue from breast cancer patients. Gastric, breast, and non-small cell lung cancers showed significantly higher DPD activity than their corresponding non-cancerous tissues, but colon cancers did not. There was no correlation between TS activity and DPD activity, and thus each enzyme was considered to be an independent sensitivity-limiting factor for 5-fluorouracil therapy. The median TS activity and median DPD activity in all specimens including gastric, colorectal, breast, and non-small cell lung cancers tested were 0.041 and 110.1 pmol/mg protein, respectively. We classified each of the type of carcinoma into 4 groups by using the median activity of TS and DPD as the cutoff values: a low TS/low DPD group, high TS/low DPD group, low TS/high DPD group, and high TS/high DPD group. About 50% of the gastric, 47% of the colon, 70% of the breast and 30% of the non-small cell lung cancers had high TS activity, and 60% of the gastric, 40% of the colon, 48% of the breast, and 87% of the lung cancers had high DPD activity. Moreover, breast cancer was characterized by high TS activity and lung cancer by high DPD activity as compared with gastric and colon cancers, and their high activity levels may influence to the effectiveness of 5-fluorouracil against cancers of these organs. The results for expression of TS and DPD in clinically dissected tumors would be useful to estimate the efficacy of 5-fluorouracil in the treatment of cancer patients.