ORIGINAL ARTICLE Thymidylate synthase and thymidine phosphorylase as predictive markers of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer Su Jin Lee • Yoon La Choi • Yeon Hee Park • Seung Tae Kim • Eun Yoon Cho • Jin Seok Ahn • Young-Hyuck Im Received: 14 August 2010 / Accepted: 1 December 2010 / Published online: 18 December 2010 Ó Springer-Verlag 2010 Abstract Purpose The primary purpose of this study was to eval- uate the role of thymidylate synthase (TS) and thymidine phosphorylase (TP) as biomarkers to predict clinical out- comes of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Methods Of the patients who were previously treated with anthracycline and taxane regimens, 90 patients who had available tissue block for immunohistochemistry with measurable lesions were included. All patients received capecitabine (2,500 mg/m 2 /day) for 14 days every 3 weeks. Results High TS expression was more common among patients with triple-negative (TN) subtype than among patients with other subtypes (33% for hormone receptor?, 8% for HER2?, and 58% for TN, P = 0.023). The median PFS was significantly lower in patients with high TS (6.6 vs. 3.0 months; P = 0.017) and low TP expressions (6.0 vs. 3.3 months; P = 0.013). A high TS and a low TP expressions were identified as unfavorable independent risk factors for PFS to capecitabine monotherapy in multivari- ate analysis (hazard ratio [HR], 1.7, P = 0.037 for high TS score; HR, 1.8, P = 0.014 for low TP score). Conclusions Our data suggest that high TS and low TP scores correlate with a shorter PFS for capecitabine monotherapy in patients with anthracycline- and taxane- pretreated MBC. Keywords Thymidylate synthase Á Thymidine phosphorylase Á Immunohistochemistry Á Capecitabine Á Metastatic breast cancer Introduction Capecitabine, one of the most widely used cytotoxic agents for the treatment of breast cancer, achieves a high tumor control rate with low toxicity, even in heavily pretreated patients with metastatic breast cancer (MBC). Capecitabine with or without ixabepilone is approved by the Food and Drug Administration for the treatment of metastatic breast cancer (MBC) after the use of an anthracycline and taxane regimen, or in patients for whom anthracycline therapy is contraindicated [1–5]. Capecitabine, an oral fluoropyrimi- dine prodrug, is metabolized to 5-fluorouracil (FU) through several steps, the last of which is conversion of 5 0 -deoxy-5- fluorouridine to 5-FU by thymidine phosphorylase (TP). TP expression has been observed in many normal human tis- sues [6]. Because TP is overexpressed in several tumor tissues, capecitabine can be selectively activated in tumor tissues and affect tumor cells [7–10]. TP is the rate-limiting enzyme in the activation of capecitabine, suggesting that TP might contribute to the sensitivity of tumors to this agent [11]. Puglisi et al. suggested that TP may have a role in predicting the response to capecitabine [12]. They also published retrospective data regarding TP expression and the clinical response in patients with MBC treated with capecitabine and provided further evidence of TP Su Jin Lee and Yoon La Choi are equally contributed to this work. S. J. Lee Á Y. H. Park Á S. T. Kim Á J. S. Ahn Á Y.-H. Im (&) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710, Korea e-mail: imyh00@skku.edu Y. L. Choi Á E. Y. Cho Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 123 Cancer Chemother Pharmacol (2011) 68:743–751 DOI 10.1007/s00280-010-1545-0