Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms: Relationships with capecitabine (X) pharmacodynamics in advanced breast cancer (ABC) patients (pts)

Abstract

2062 Background: TS expression and reduced folate levels significantly influence fluoropyrimidine pharmacodynamics. X is a highly effective oral fluoropyrimidine carbamate with proven single agent activity for the treatment of ABC, which improves survival when added to docetaxel. We prospectively analyzed the impact of gene polymorphisms potentially linked to TS expression and 5–10 methylenetetrahydrofolate concentrations (MTHFR gene) on toxicity and response in X-treated ABC pts. Methods: TS gene polymorphisms in the 5' (28 base pair tandem repeats) and 3' (6 base pair deletion) regions were analyzed by PCR. C677T and A1298C MTHFR gene polymorphisms were determined by melting curve analyses (LightCycler). We analyzed DNA from mononuclear cells of 57 pts with ABC, median age 57 (36–79), 60% multiple metastatic sites, prior treatment: 88% anthracycline, 70% taxane and 21% 5-FU, current treatment setting: 21% pts first, 47% second line. Mean initial dose of X was 1048 mg/m2 twice-daily d1–14 every 3 weeks, median number of cycles 7 (1–15). Results: 3'TS genotype (26 pts 110/110, 27 pts 104/110, 4 pts 104/104), C677T MTHFR genotype (22 pts wt/wt, 24 pts wt/mut, 11 pts mut/mut) and A1298C MTHFR genotype (33 pts wt/wt, 19 pts wt/mut, 5 pts mut/mut) were not correlated to any X-related toxicities (WHO criteria grade 0–1 vs 2–4 at 1st cycle). In contrast, 5'TS genotype (11 pts 2R2R, 23 pts 2R3R, 21 pts 3R3R) was significantly linked to hand-foot syndrome and nausea-vomiting (Fisher's Exact test: both p = 0.03). 3R3R pts had less toxicity. Response to treatment was assessed after the 3rd cycle (21% progression, 50% stabilization, 27% partial, 2% complete responses). Clinical benefit (i.e. stabilization or response vs progression) was not linked to any TS or MTHFR gene polymorphisms. Conclusion: Constitutional TS polymorphism in the 5' region may be predictive of X pharmacodynamics, but needs confirmation in a prospective study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Hoffmann-La Roche Hoffmann-La Roche