Layman Rachel M, Thomas Dafydd G, Griffith Kent A, Smerage Jeffrey B, Helvie Mark A, Roubidoux Marilyn A, Diehl Kathleen M, Newman Lisa A, Sabel Michael S, Hayman James A, Pierce Lori J, Hayes Daniel F, Schott Anne F
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0848, USA.
Clin Cancer Res. 2007 Jul 15;13(14):4092-7. doi: 10.1158/1078-0432.CCR-07-0288.
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.
Women with stage II to III breast cancer were given four cycles of neoadjuvant docetaxel 36 mg/m(2) 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).
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.
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.
多西他赛诱导胸苷磷酸化酶（TP）是观察到的多西他赛与卡培他滨（DC）临床前协同作用的一种推测机制。我们评估了多西他赛是否会增加乳腺癌患者的TP蛋白表达，以及其与病理完全缓解（pCR）是否相关。
II至III期乳腺癌女性患者接受四个周期的新辅助治疗，多西他赛36mg/m²静脉注射，30分钟内完成，第1、8和15天给药；卡培他滨2000mg/d，分两次给药，在28天周期的第5至21天给药。在基线和首次给予多西他赛后5天，对乳腺肿瘤进行放射引导下活检以评估TP表达。DC治疗后，患者进行乳腺粗针活检，若存在残留疾病，则接受四个周期的标准剂量密集阿霉素和环磷酰胺（AC）治疗。
pCR率为26.9%（95%置信区间，11.6 - 47.8）。通过定量免疫荧光（QIF）或免疫组织化学均未观察到TP表达上调。新辅助化疗后的放射引导下粗针活检在88%（95%置信区间，69.8 - 97.6）的病例中准确预测了病理反应。TP表达水平和TP上调均与pCR无关。26例患者中有3例因严重毒性导致治疗中断。
与标准紫杉烷方案相比，DC化疗的pCR率相似，但毒性增加。多西他赛后TP表达未上调，且与治疗反应无关。新辅助化疗后的乳腺粗针活检准确预测了病理反应。
