Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer
Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer
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DOI：
10.1093/annonc/mdn592
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发表时间：
2009-02-01
影响因子：
50.5
通讯作者：
Puglisi, F.
中科院分区：
文献类型：
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作者：
Andreetta, C.;Puppin, C.;Puglisi, F.
背景和目标：卡培他滨是一种口服生物可利用的前药，其通过几个酶促步骤转化为5-氟尿嘧啶，最后一个步骤由胸苷磷酸化酶（TP）介导。TP在癌组织中的表达水平高于正常组织，本研究旨在评估TP表达与卡培他滨治疗转移性乳腺癌（BC）患者获益之间的潜在关系。在石蜡切片上进行TP和其他生物标志物的免疫组织化学，61例BC患者的包埋癌组织，接受至少3个周期的卡培他滨单药治疗转移性疾病。所有患者均接受卡培他滨1000 mg/m2 b.i.d.第1-14天，每21天。以下变量作为卡培他滨获益的潜在决定因素进行了分析：TP表达、雌激素受体（ER）和孕激素受体状态、人表皮生长因子受体-2（HER-2）状态、MIB-1表达、卡培他滨治疗开始时的体能状态、诊断时的分期、分级、卡培他滨治疗开始时是否存在内脏转移以及既往化疗。总体而言，中位至进展时间（TTP）为6.5个月（范围1.4-33）。在多变量分析中，ER状态[进展的风险比（HR）= 0.31; 95%置信区间（CI）= 0.15-0.64; P = 0.002]，卡培他滨治疗开始时存在内脏转移（HR = 2.30; 95% CI = 1.21-4.39; P = 0.01），卡培他滨作为一线或二线治疗（HR = 2.28; 95% CI = 1.21-4.32; P = 0.01）独立预测TTP。TP在61例乳腺癌组织中高表达34例（55.7%）。在TP表达肿瘤患者亚组中，卡培他滨治疗前接受蒽环类和紫杉烷类药物治疗的患者TTP显著延长（中位TTP 7.5 vs 3.3个月，P = 0.01，对数秩检验）。同样，TP阳性肿瘤患者显示较长的TTP，如果他们接受紫杉烷类卡培他滨前比TP阳性肿瘤患者谁没有接受这种治疗（7.3与3.4个月，P = 0.03）。结论：这些数据提供了进一步的证据表明，TP表达在BC可以代表卡培他滨治疗的敏感性的生物标志物。希望通过翻译方法进行前瞻性研究，以确认TP的预测和预后作用。
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.