Cyclophosphamide Dose Intensification May Circumvent Anthracycline Resistance of p53 Mutant Breast Cancers
Cyclophosphamide Dose Intensification May Circumvent Anthracycline Resistance of p53 Mutant Breast Cancers
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DOI：
10.1634/theoncologist.2009-0243
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发表时间：
2010-01-01
期刊：
影响因子：
5.8
通讯作者：
de The, Hugues
中科院分区：
文献类型：
--
作者：
Lehmann-Che, Jacqueline;Andre, Fabrice;de The, Hugues
p53对一线蒽环类化疗方案疗效的预测价值一直存在重大争议。蒽环类药物通常与不同剂量的烷基化剂联合使用，这可能会显著调节肿瘤对这些组合的反应。我们分析了三个系列的新发II-III期乳腺癌患者，这些患者在一线接受了基于蒽环类药物的各种环磷酰胺剂量强度的治疗：65例雌激素受体（ER）（-）肿瘤患者单独接受蒽环类药物治疗（Institut Jules Bordet，布鲁塞尔），51例未选择的乳腺癌患者接受中剂量环磷酰胺治疗（MD Anderson癌症中心，Houston， TX）， 128例其他患者接受剂量密集的环磷酰胺联合治疗（St. Louis, Paris）。化疗和手术后，评估病理完全缓解（pCR）。通过对预处理肿瘤样品进行酵母功能测定来确定P53状态。在汇总结果的多变量分析中，缺乏ER表达和高剂量环磷酰胺给药与更高的pCR可能性相关。在p53状态和环磷酰胺剂量强度之间检测到明显的统计学相互作用。事实上，当将我们的分析限制在ER-肿瘤患者时，我们证实p53突变状态与蒽环类药物耐药有关，但发现p53失活是对高剂量烷基化方案的反应所必需的。后者在三阴性肿瘤中允许非常高水平的pCR。因此，我们的数据强烈表明，在ER- p53突变的乳腺癌患者中，环磷酰胺剂量强化可以显著改善其反应。肿瘤学家2010；15: 246 - 252
The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER- tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER- p53-mutated breast cancer patients could significantly improve their response. The Oncologist 2010; 15: 246-252