Di Benedetto Anna, Ercolani Cristiana, Pizzuti Laura, Angelucci Domenico, Sergi Domenico, Marinelli Camilla, Iezzi Laura, Sperati Francesca, Terrenato Irene, Mazzotta Marco, Mariani Luciano, Vizza Enrico, Paoletti Giancarlo, Tomao Silverio, Maugeri-Saccà Marcello, Barba Maddalena, Tinari Nicola, Natoli Clara, Ciliberto Gennaro, Grassadonia Antonino, Vici Patrizia
Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Ther Adv Med Oncol. 2019 Aug 18;11:1758835919853192. doi: 10.1177/1758835919853192. eCollection 2019.
The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT).
Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered.
The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature ( = 0.011). In models of Ki-67 reduction, 'luminal B' subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant ( < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival ( = 0.027) and overall survival ( = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades ( < 0.05 for both).
We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms.
长期以来，人们对乳腺癌内分泌治疗结果背后的逻辑了解甚少。在接受新辅助激素治疗（NAHT）的绝经后、激素受体阳性乳腺癌患者中，探讨了DNA损伤与修复生物标志物（DDR）的预后作用。
纳入55例患者的数据。通过免疫组织化学对基线时和NAHT后收集的配对组织中的磷酸化共济失调毛细血管扩张症和Rad3相关蛋白（pATR）、磷酸化共济失调毛细血管扩张症突变（ATM）激酶以及磷酸化H2A组蛋白家族成员X（γ-H2AX）进行评估。生物标志物既单独考虑，也在特征组合中考虑。Ki-67百分比变化是主要的生物标志物终点。同时也考虑了经典终点。
最有利的Ki-67结果与γ-H2AX/pATM特征相关（P = 0.011）。在Ki-67降低模型中，“管腔B”亚型、更高等级的间变以及γ-H2AX/pATM特征经检验具有显著性（均P < 0.05）。多变量分析证实了结果。未观察到与病理反应的关联。配对乳腺组织中∆γ-H2AX的增加与更长的无事件生存期（P = 0.027）和总生存期（P = 0.042）相关。在Cox模型中，两种生存结果均仅受间变等级影响，最高等级的预后较差（均P < 0.05）。
我们报告了DDR生物标志物对接受NAHT治疗的绝经后激素受体阳性乳腺癌患者重要预后结果的预后作用的新证据。如果在未来规模足够大的试验中得到证实，我们的结果可能有助于指导治疗决策并阐明潜在的生物学机制。
