局部晚期乳腺癌新辅助放疗疗效的分子标志物研究。
Molecular signature of response to preoperative radiotherapy in locally advanced breast cancer.
机构信息
Laboratory for Molecular Genetics, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia.
Medical Genomics, UCL Cancer Institute, University College London, London, UK.
出版信息
Radiat Oncol. 2018 Oct 1;13(1):193. doi: 10.1186/s13014-018-1129-4.
BACKGROUND
Radiation therapy is an indispensable part of various treatment modalities for breast cancer. Specifically, for non-inflammatory locally advanced breast cancer (LABC) patients, preoperative radiotherapy (pRT) is currently indicated as a second line therapy in the event of lack of response to neoadjuvant chemotherapy. Still approximately one third of patients fails to respond favourably to pRT. The aim of this study was to explore molecular mechanisms underlying differential response to radiotherapy (RT) to identify predictive biomarkers and potential targets for increasing radiosensitivity.
METHODS
The study was based on a cohort of 134 LABC patients, treated at the Institute of Oncology and Radiology of Serbia (IORS) with pRT, without previous or concomitant systemic therapy. Baseline transcriptional profiles were established using Agilent 60 K microarray platform in a subset of 23 formalin-fixed paraffin-embedded (FFPE) LABC tumour samples of which 11 radiotherapy naïve and 3 post-radiotherapy samples passed quality control and were used for downstream analysis. Biological networks and signalling pathways underlying differential response to RT were identified using Ingenuity Pathways Analysis software. Predictive value of candidate genes in the preoperative setting was further validated by qRT-PCR in an independent subset of 60 LABC samples of which 42 had sufficient quality for data analysis, and in postoperative setting using microarray data from 344 node-negative breast cancer patients (Erasmus cohort, GSE2034 and GSE5327) treated either with surgery only (20%) or surgery with RT (80%).
RESULTS
We identified 192 significantly differentially expressed genes (FDR < 0.10) between pRT-responsive and non-responsive tumours, related to regulation of cellular development, growth and proliferation, cell cycle control of chromosomal replication, glucose metabolism and NAD biosynthesis II route. APOA1, MAP3K4, and MMP14 genes were differentially expressed (FDR < 0.20) between pRT responders and non-responders in preoperative setting, while MAP3K4 was further validated as RT-specific predictive biomarker of distant metastasis free survival (HR = 2.54, [95%CI:1.42-4.55], p = 0.002) in the postoperative setting.
CONCLUSIONS
This study pinpoints MAP3K4 as a putative biomarker of response to RT in both preoperative and postoperative settings and a potential target for radiosensitising combination therapy, warranting further pre-clinical studies and prospective clinical validation.
背景
放射治疗是乳腺癌各种治疗方式中不可或缺的一部分。具体来说，对于非炎症性局部晚期乳腺癌（LABC）患者，如果新辅助化疗无反应，术前放疗（pRT）目前被作为二线治疗方法。但仍有约三分之一的患者对 pRT 反应不佳。本研究旨在探讨放疗（RT）反应差异的分子机制，以确定预测生物标志物和增加放射敏感性的潜在靶点。
方法
该研究基于塞尔维亚肿瘤学和放射学研究所（IORS）的 134 例 LABC 患者队列，这些患者接受了 pRT 治疗，且未接受过先前或同时的系统治疗。在 23 例福尔马林固定石蜡包埋（FFPE）LABC 肿瘤样本的子集中建立了基线转录谱，其中 11 例为放疗初治，3 例为放疗后样本，通过质量控制，可用于下游分析。使用 Ingenuity Pathways Analysis 软件鉴定了与 RT 反应差异相关的生物学网络和信号通路。通过 qRT-PCR 在 60 例 LABC 样本的独立子集中进一步验证候选基因在术前环境中的预测价值，其中 42 例样本的质量足以进行数据分析，在术后环境中使用来自 344 例淋巴结阴性乳腺癌患者（Erasmus 队列，GSE2034 和 GSE5327）的微阵列数据，这些患者要么接受手术治疗（20%），要么接受手术联合 RT 治疗（80%）。
结果
我们在 pRT 反应性和非反应性肿瘤之间鉴定出 192 个显著差异表达基因（FDR < 0.10），这些基因与细胞发育、生长和增殖的调节、染色体复制的细胞周期控制、葡萄糖代谢和 NAD 生物合成 II 途径有关。APOA1、MAP3K4 和 MMP14 基因在术前 pRT 反应者和无反应者之间差异表达（FDR < 0.20），而 MAP3K4 在术后环境中进一步验证为无远处转移生存的 RT 特异性预测生物标志物（HR = 2.54，[95%CI：1.42-4.55]，p = 0.002）。
结论
本研究将 MAP3K4 确定为术前和术后 RT 反应的潜在生物标志物和放射增敏联合治疗的潜在靶点，值得进一步进行临床前研究和前瞻性临床验证。
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