Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis.
Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis.
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DNA损伤和修复生物标志物在三阴性乳腺癌患者中接受新辅助化学疗法治疗的预测意义：一种探索性分析。
DOI：
10.18632/oncotarget.6001
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发表时间：
2015-12-15
期刊：
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通讯作者：
Maugeri-Saccà M
中科院分区：
文献类型：
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作者：
Vici P;Di Benedetto A;Ercolani C;Pizzuti L;Di Lauro L;Sergi D;Sperati F;Terrenato I;Dattilo R;Botti C;Fabi A;Ramieri MT;Mentuccia L;Marinelli C;Iezzi L;Gamucci T;Natoli C;Vitale I;Barba M;Mottolese M;De Maria R;Maugeri-Saccà M
癌细胞对化疗诱导的DNA损伤的反应是由ATM-Chk2和ATR-Chk1通路调节的。我们研究了在接受新辅助化疗的三阴性乳腺癌（TNBC）患者中，磷酸化的H2AX (γ-H2AX) （DNA双链断裂触发ATM-Chk2级联的标记物）和磷酸化的Chk1 （pChk1）与病理完全缓解（pCR）之间的关系。对66例患者进行一系列前处理活检，采用免疫组织化学方法对其γ-H2AX和pChk1进行回顾性评估。在53例肿瘤中，诊断活检和残留癌的激素受体状态均为阴性，而在13例肿瘤中，化疗后激素受体表达轻微改变。进行了内部验证。在整个队列中，γ-H2AX水平升高与pCR率降低相关，而pChk1水平无关（p = 0.009）。在单因素和多因素logistic回归模型中，该相关性均具有显著性（OR分别为4.51,95% CI: 1.39-14.66, p = 0.012； OR为5.07,95% CI: 1.28-20.09, p = 0.021）。内部验证支持模型的预测值。在排除化疗期间激素受体状态改变的肿瘤后，在多变量模型中进一步证实了γ-H2AX的预测能力（OR 7.07, 95% CI: 1.39-36.02, p = 0.018）。最后，在残余疾病中，观察到γ-H2AX水平显著降低（p < 0.001）。总的来说，γ-H2AX显示出预测TNBC中pCR的能力，值得进行更大规模的前瞻性研究。
Response of cancer cells to chemotherapy-induced DNA damage is regulated by the ATM-Chk2 and ATR-Chk1 pathways. We investigated the association between phosphorylated H2AX (γ-H2AX), a marker of DNA double-strand breaks that trigger the ATM-Chk2 cascade, and phosphorylated Chk1 (pChk1), with pathological complete response (pCR) in triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy. γ-H2AX and pChk1 were retrospectively assessed by immunohistochemistry in a series of pretreatment biopsies related to 66 patients. In fifty-three tumors hormone receptor status was negative in both the diagnostic biopsies and residual cancers, whereas in 13 cases there was a slight hormone receptor expression that changed after chemotherapy. Internal validation was carried out. In the entire cohort elevated levels of γ-H2AX, but not pChk1, were associated with reduced pCR rate (p = 0.009). The association tested significant in both uni- and multivariate logistic regression models (OR 4.51, 95% CI: 1.39–14.66, p = 0.012, and OR 5.07, 95% CI: 1.28–20.09, p = 0.021, respectively). Internal validation supported the predictive value of the model. The predictive ability of γ-H2AX was further confirmed in the multivariate model after exclusion of tumors that underwent changes in hormone receptor status during chemotherapy (OR 7.07, 95% CI: 1.39–36.02, p = 0.018). Finally, in residual diseases a significant decrease of γ-H2AX levels was observed (p < 0.001). Overall, γ-H2AX showed ability to predict pCR in TNBC and deserves larger, prospective studies.