Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany.
Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany.
Int J Oncol. 2018 Mar;52(3):755-767. doi: 10.3892/ijo.2018.4241. Epub 2018 Jan 8.
Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identification of molecular biomarkers may help to select patients for individualized adjuvant therapy. Evidence has accumulated that determination of the methylation status of the PITX2 gene provides a predictive value in various breast cancer subgroups, either treated with endocrine-based therapy or anthracycline-containing chemotherapy. To further explore the validity of this novel predictive candidate biomarker, in the present exploratory retrospective study, determination of the PITX2 DNA-methylation status was assessed for non-metastatic TNBC patients treated with adjuvant anthracycline-based chemotherapy by molecular analysis of breast cancer tissues. The PITX2 DNA-methylation status was determined in fresh-frozen tumor tissue specimens (n=56) by methylation-specific qRT-PCR (qMSP) and the data related to disease-free and overall survival, applying an optimized DNA-methylation score of 6.35%. For non-metastatic TNBC patients treated with adjuvant systemic anthracycline-based chemotherapy, a low PITX2 DNA-methylation status (<6.35) defines TNBC patients with poor disease-free and overall survival. Univariate and multivariate analyses demonstrate the statistically independent predictive value of PITX2 DNA-methylation. For non-metastatic TNBC patients, selective determination of the PITX2 DNA-methylation status may serve as a cancer biomarker for predicting response to anthracycline-based adjuvant chemotherapy. The assay based on methylation of the PIXT2 gene can be applied to frozen and routinely available formalin-fixed, paraffin-embedded (FFPE) breast cancer tumor tissues that will not only define those TNBC patients who may benefit from anthracycline-based chemotherapy but also those who should be spared the necessity of such potentially toxic treatment. Such patients should be allocated to alternative treatment options.
三阴性乳腺癌（TNBC）构成了一种预后较差的异质性乳腺癌亚组；与其他乳腺癌亚组相比，TNBC 的生存率可能较低。对于这种疾病，系统辅助化疗方案往往产生不理想的临床结果。为了改善 TNBC 的治疗方案，识别分子生物标志物可能有助于选择患者进行个体化辅助治疗。有证据表明，PITX2 基因的甲基化状态的测定在接受内分泌治疗或含蒽环类化疗的各种乳腺癌亚组中具有预测价值。为了进一步探索这种新型预测候选生物标志物的有效性，在本探索性回顾性研究中，通过对乳腺癌组织的分子分析，评估了接受辅助蒽环类化疗的非转移性 TNBC 患者的 PITX2 DNA 甲基化状态。通过甲基化特异性 qRT-PCR（qMSP）测定新鲜冷冻肿瘤组织标本（n=56）中的 PITX2 DNA 甲基化状态，并应用优化的 DNA 甲基化评分 6.35%，相关数据与无病生存和总生存相关。对于接受辅助系统蒽环类化疗的非转移性 TNBC 患者，低 PITX2 DNA 甲基化状态（<6.35）定义为无病生存和总生存不良的 TNBC 患者。单因素和多因素分析表明 PITX2 DNA 甲基化具有统计学上的独立预测价值。对于非转移性 TNBC 患者，选择性测定 PITX2 DNA 甲基化状态可能是预测蒽环类辅助化疗反应的癌症生物标志物。基于 PIXT2 基因甲基化的检测可应用于冷冻和常规可用的福尔马林固定、石蜡包埋（FFPE）乳腺癌肿瘤组织，不仅可以定义那些可能受益于蒽环类化疗的 TNBC 患者，还可以定义那些应避免接受这种潜在毒性治疗的患者。这些患者应分配到替代治疗方案中。
