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Neoadjuvant Docetaxel and Capecitabine and the Use of Thymidine Phosphorylase as a Predictive Biomarker in Breast Cancer

Authors' Affiliations: Departments of ¹ Internal Medicine, ² Pathology, ³ Biostatistics, ⁴ Radiology, ⁵ Surgery, and ⁶ Radiation Oncology, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Rachel M. Layman, Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C354 Med Inn Building, Box 0848, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0848. Phone: 734-615-4762; Fax: 734-647-8792; E-mail: rlayman{at}umich.edu.

Purpose: Thymidine phosphorylase (TP) induction by docetaxel is a proposed mechanism for the observed preclinical synergy of docetaxel and capecitabine (DC). We evaluated whether TP protein expression is increased by docetaxel and correlates with pathologic complete response (pCR) in breast cancer patients.

Experimental Design: Women with stage II to III breast cancer were given four cycles of neoadjuvant docetaxel 36 mg/m² i.v. over 30 min on days 1, 8, and 15 and capecitabine 2,000 mg/d, in two divided doses, on days 5 to 21 of a 28-day cycle. Radiology-directed biopsies of the breast tumors were done at baseline and 5 days after the first dose of docetaxel to evaluate TP expression. Following DC therapy, patients had core breast biopsies, and if residual disease was present, received four cycles of standard dose-dense doxorubin and cyclophosphamide (AC).

Results: The pCR rate was 26.9% (95% confidence interval, 11.6-47.8). Up-regulation of TP expression was not observed by either quantitative immunofluorescence (QIF) or immunohistochemistry. Radiology-directed core biopsy after neoadjuvant chemotherapy accurately predicted pathologic response in 88% (95% confidence interval, 69.8-97.6) of the cases. Neither level of TP expression nor TP up-regulation correlated with pCR. Significant toxicity resulted in therapy discontinuation in 3 of 26 patients.

Conclusions: DC chemotherapy exhibited a similar pCR rate compared with standard taxane regimens, with increased toxicity. TP expression was not up-regulated after docetaxel and did not correlate with therapeutic response. Core breast biopsy after neoadjuvant chemotherapy accurately predicted pathologic response.