Järvinen T A, Holli K, Kuukasjärvi T, Isola J J
Laboratory of Cancer Genetics, Tampere University Hospital and Institute of Medical Technology, University of Tampere, Finland.
Br J Cancer. 1998 Jun;77(12):2267-73. doi: 10.1038/bjc.1998.377.
Although cytotoxic chemotherapy is widely used in advanced breast cancer, there are no powerful predictors for the therapy response. Because topoisomerase IIalpha (Topo IIalpha) is the molecular target for the anthracycline class of anti-cancer drugs, we compared the immunocytochemical assay of Topo IIalpha with other biomarkers in the prediction of clinical response to Topo II inhibitor chemotherapy. Fifty-five patients with advanced breast cancer were treated with a single cytotoxic drug, Topo II-inhibitor, epirubicin (30 mg m(-2) weekly up to 1000 mg m(-2)), as first line cytotoxic chemotherapy. Objective response to treatment was analysed according to UICC criteria. The predictive value of Topo IIalpha expression, c-erbB2 oncoprotein, p53 tumour-suppressor protein, oestrogen (ER) and progesterone receptor (PR), S-phase fraction and DNA ploidy were analysed from representative formalin-fixed paraffin-embedded primary tumour samples. The proportion of Topo IIalpha-positive cells (Topo IIalpha index) failed to predict response to epirubicin therapy. Mean Topo IIalpha scores in 29 responding patients were similar when compared with those with no change in disease progression (n = 13) and those with progressive disease (n = 13) (14.9% +/- 11.4% vs 15.5% +/- 7.6% vs 17.3% +/- 13.2%, not significant). Among the other biomarkers tested, overexpression of c-erbB2 oncoprotein and hormone receptor negativity were significantly associated with poor response. Response rate in patients with c-erbB2-overexpressing tumours was 32% compared with 65% in patients with no c-erbB2 overexpression (P = 0.0058). Accordingly, the response rate for ER-positive patients was 67% compared with 26% in ER-negative patients (P = 0.0021). Although both negative ER status and c-erbB2 overexpression are associated with high Topo IIalpha expression in breast cancer, step-wise logistic regression analysis showed that ER and c-erbB2 were associated with therapy response independent of Topo IIalpha expression. Histological grade, p53, DNA-ploidy, tumour proliferation rate (S-phase fraction), stage of the disease at diagnosis, age of the patient, previous anti-oestrogen therapy or site of metastasis did not predict the response to epirubicin therapy. In conclusion, despite extensive in vitro evidence, expression of Topo IIalpha is unlikely to predict the response to Topo II inhibitor chemotherapy in advanced breast cancer. Among the prognostic biomarkers, overexpression of c-erbB2 oncogene and negative ER may have predictive value in epirubicin therapy in patients with advanced breast cancer.
尽管细胞毒性化疗广泛应用于晚期乳腺癌，但对于治疗反应尚无有力的预测指标。由于拓扑异构酶IIα（Topo IIα）是蒽环类抗癌药物的分子靶点，我们比较了Topo IIα免疫细胞化学检测与其他生物标志物在预测Topo II抑制剂化疗临床反应中的作用。55例晚期乳腺癌患者接受单一细胞毒性药物拓扑异构酶II抑制剂表柔比星（30mg/m²，每周一次，直至1000mg/m²）作为一线细胞毒性化疗。根据国际抗癌联盟（UICC）标准分析治疗的客观反应。从代表性的福尔马林固定石蜡包埋原发性肿瘤样本中分析Topo IIα表达、c-erbB2癌蛋白、p53肿瘤抑制蛋白、雌激素（ER）和孕激素受体（PR）、S期分数和DNA倍体的预测价值。Topo IIα阳性细胞比例（Topo IIα指数）未能预测对表柔比星治疗的反应。29例有反应患者的平均Topo IIα评分与疾病进展无变化者（n = 13）和疾病进展者（n = 13）相似（14.9%±11.4% vs 15.5%±7.6% vs 17.3%±13.2%，无显著性差异）。在检测的其他生物标志物中，c-erbB2癌蛋白过表达和激素受体阴性与反应不良显著相关。c-erbB2过表达肿瘤患者的反应率为32%，而无c-erbB2过表达患者为65%（P = 0.0058）。因此，ER阳性患者的反应率为67%，而ER阴性患者为26%（P = 0.0021）。虽然ER阴性状态和c-erbB2过表达均与乳腺癌中高Topo IIα表达相关，但逐步逻辑回归分析显示，ER和c-erbB2与治疗反应相关，独立于Topo IIα表达。组织学分级、p53、DNA倍体、肿瘤增殖率（S期分数）、诊断时疾病分期、患者年龄、既往抗雌激素治疗或转移部位均不能预测对表柔比星治疗的反应。总之，尽管有大量体外证据，但Topo IIα表达不太可能预测晚期乳腺癌对Topo II抑制剂化疗的反应。在预后生物标志物中，c-erbB2癌基因过表达和ER阴性可能对晚期乳腺癌患者表柔比星治疗具有预测价值。
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