缺氧反应表达作为未经治疗的晚期乳腺癌生存生物标志物
The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer.
作者信息
Gunawan Irwan, Hatta Mochammad, Benyamin Andi Fachruddin, Islam Andi Asadul
机构信息
Department of General Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia.
Biology Molecular and Immunology Laboratory, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia.
出版信息
Asian Pac J Cancer Prev. 2020 Mar 1;21(3):629-637. doi: 10.31557/APJCP.2020.21.3.629.
OBJECTIVE
Hypoxia-associated biomarkers profiling may provide information for prognosis, staging, and subsequent therapy. We aim to evaluate whether the quantitative gene and protein expression of hypoxic response tumor markers - carbonic anhydrase IX (CAIX) and hypoxia- inducible factor 1 alpha (HIF1A) - may have a role in predicting survival in advanced breast cancer of Indonesian population.
METHODS
Tumor tissues and peripheral blood samples were collected from treatment - naïve locally advanced (LABC) or metastatic breast cancer patients (MBC) at Wahidin Sudirohusodo General Hospital (Makassar, South Sulawesi) and its referral network hospitals from July 2017 to March 2019. The level of mRNA (of blood and tumor tissue samples) and soluble protein (of blood samples) of CAIX and HIF1A were measured by RT-qPCR and ELISA methods, respectively, besides the standard histopathological grading and molecular subtype assessment. The CAIX and HIF1A expression, patients' age, tumor characteristics, surgery status, and neoadjuvant chemotherapy drug classes were further involved in survival analyses for overall survival (OS) and progression-free survival (PFS).
RESULTS
Forty (30 LABC, 10 MBC) eligible patients examined were 21 hormone-receptors positives (15 Luminal A, 6 Luminal B) and 19 hormone-receptors negatives (10 HER2-enriched, 9 triple-negative). The CAIX blood mRNA and CAIX soluble protein levels in hormone-receptors negative patients were higher than in hormone-receptor-positive patients (p < 0.05). In univariate analysis, both CAIX and HIF1A levels predict OS (except HIF1A protein) with CAIX tissue mRNA has the highest hazard ratio (HR 8.04, 95%CI:2.45-26.39), but not PFS. Cox proportional hazard model confirmed that CAIX tissue mRNA is the independent predictor of OS (HR 6.10, 95%CI: 1.16-32.13) along with surgical status and tumor advancement type (LABC or MBC).
CONCLUSIONS
CAIX mRNA expression of tumor tissue in treatment-naïve advanced breast cancer has a predictive value for OS.
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目的
缺氧相关生物标志物分析可为预后、分期及后续治疗提供信息。我们旨在评估缺氧反应肿瘤标志物——碳酸酐酶IX（CAIX）和缺氧诱导因子1α（HIF1A）的基因和蛋白定量表达是否在预测印度尼西亚人群晚期乳腺癌患者的生存情况中发挥作用。
方法
2017年7月至2019年3月期间，从瓦希丁·苏迪罗胡索多综合医院（南苏拉威西省望加锡）及其转诊网络医院中，收集未经治疗的局部晚期（LABC）或转移性乳腺癌患者（MBC）的肿瘤组织和外周血样本。除了进行标准的组织病理学分级和分子亚型评估外，分别采用RT-qPCR和ELISA方法检测CAIX和HIF1A的mRNA水平（血液和肿瘤组织样本）及可溶性蛋白水平（血液样本）。CAIX和HIF1A表达、患者年龄、肿瘤特征、手术状态及新辅助化疗药物类别进一步纳入总生存期（OS）和无进展生存期（PFS）的生存分析。
结果
40例符合条件的患者（30例LABC，10例MBC）中，21例激素受体阳性（15例Luminal A，6例Luminal B），19例激素受体阴性（10例HER2富集型，9例三阴性）。激素受体阴性患者的CAIX血液mRNA和CAIX可溶性蛋白水平高于激素受体阳性患者（p < 0.05）。单因素分析中，CAIX和HIF1A水平均可预测OS（HIF1A蛋白除外），其中CAIX组织mRNA的风险比最高（HR 8.04，95%CI：2.45 - 26.39），但不能预测PFS。Cox比例风险模型证实，CAIX组织mRNA与手术状态和肿瘤进展类型（LABC或MBC）一起，是OS的独立预测因子（HR 6.10，95%CI：1.16 - 32.13）。
结论
未经治疗的晚期乳腺癌患者肿瘤组织中CAIX mRNA表达对OS具有预测价值。
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