Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer

Ann Oncol. 2009 Feb;20(2):265-71. doi: 10.1093/annonc/mdn592. Epub 2008 Sep 2.


Background and aim: Capecitabine is an orally bioavailable prodrug that is converted to 5-fluorouracil through several enzymatic steps, the last of which is mediated by thymidine phosphorylase (TP). TP has been reported to be expressed at higher levels in cancer tissue compared with normal counterpart. The present study aimed at evaluating the potential relationship between TP expression and benefit from capecitabine in patients with metastatic breast cancer (BC).

Methods: Immunohistochemistry for TP and other biological markers was carried out on paraffin-embedded cancer tissues of 61 patients with BC treated with at least three cycles of capecitabine as single agent for metastatic disease. All patients had received capecitabine 1000 mg/m(2) b.i.d. days 1-14 every 21 days. The following variables were analyzed as potential determinants of benefit from capecitabine: TP expression, estrogen receptor (ER) and progesterone receptor status, human epidermal growth factor receptor-2 (HER-2) status, MIB-1 expression, performance status at the beginning of capecitabine treatment, stage at diagnosis, grade, presence of visceral metastases at the beginning of capecitabine treatment, and previous chemotherapy.

Results: Overall, median time to progression (TTP) was 6.5 months (range 1.4-33). On multivariate analysis, ER status [hazard ratio (HR) for progression = 0.31; 95% confidence interval (CI) = 0.15-0.64; P = 0.002], presence of visceral metastases at the beginning of capecitabine treatment (HR = 2.30; 95% CI = 1.21-4.39; P = 0.01), and capecitabine as first- or second-line treatment (HR = 2.28; 95% CI = 1.21-4.32; P = 0.01) independently predicted TTP. TP was highly expressed in 34 of 61 cases (55.7%). In the subgroup of patients with TP-expressing tumor, TTP was significantly longer in patients who received anthracyclines and taxanes before capecitabine (median TTP 7.5 versus 3.3 months, P = 0.01, log-rank test). Similarly, patients with a TP-positive tumor showed a longer TTP if they received taxanes before capecitabine than patients with TP-positive tumor who did not receive this treatment (7.3 versus 3.4 months, P = 0.03).

Conclusions: These data provide further evidence that TP expression in BC could represent a biomarker of sensitivity to capecitabine treatment. Prospective studies with translational approach are desirable to confirm the predictive and prognostic role of TP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology
  • Capecitabine
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Disease Progression
  • ErbB Receptors / metabolism
  • Female
  • Fluorouracil / analogs & derivatives*
  • Fluorouracil / therapeutic use
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Metastasis
  • Prognosis
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Retrospective Studies
  • Thymidine Phosphorylase / analysis
  • Thymidine Phosphorylase / metabolism*
  • Time Factors
  • Treatment Outcome
  • Ubiquitin-Protein Ligases / metabolism


  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Deoxycytidine
  • Capecitabine
  • MIB1 ligase, human
  • Ubiquitin-Protein Ligases
  • Thymidine Phosphorylase
  • ErbB Receptors
  • Receptor, ErbB-2
  • Fluorouracil