Fleischer Thomas, Haugen Mads Haugland, Ankill Jørgen, Silwal-Pandit Laxmi, Børresen-Dale Anne-Lise, Hedenfalk Ingrid, Hatschek Thomas, Tost Jörg, Engebraaten Olav, Kristensen Vessela N
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Mol Oncol. 2024 Aug;18(8):2042-2059. doi: 10.1002/1878-0261.13656. Epub 2024 Apr 26.
Treatment with the anti-angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic data in breast cancer patients to predict response to therapy and pinpoint response-related epigenetic events. Fresh-frozen tumor biopsies taken before, during, and after treatment from human epidermal growth factor receptor 2 negative non-metastatic patients receiving neoadjuvant chemotherapy with or without bevacizumab were subjected to molecular profiling. Here, we report that DNA methylation at enhancer CpGs related to cell cycle regulation can predict response to chemotherapy and bevacizumab for the estrogen receptor positive subset of patients (AUC = 0.874), and we validated this observation in an independent patient cohort with a similar treatment regimen (AUC = 0.762). Combining the DNA methylation scores with the scores from a previously published protein signature resulted in a slight increase in the prediction performance (AUC = 0.784). We also show that tumors receiving the combination treatment underwent more extensive epigenetic alterations. Finally, we performed an integrative expression-methylation quantitative trait loci analysis on alterations in DNA methylation and gene expression levels, showing that the epigenetic alterations that occur during treatment are different between responders and non-responders and that these differences may be explained by the proliferation-epithelial-to-mesenchymal transition axis through the activity of grainyhead like transcription factor 2. Using tumor purity computed from copy number data, we developed a method for estimating cancer cell-specific methylation to confirm that the association to response reflects DNA methylation in cancer cells. Taken together, these results support the potential for clinical benefit of the addition of bevacizumab to chemotherapy when administered to the correct patients.
在一些临床试验中，除化疗外使用抗血管生成药物贝伐单抗治疗乳腺癌已显示出疗效，但需要更好的生物标志物来优化选择治疗患者。在此，我们提出一种组学方法，将DNA甲基化谱与乳腺癌患者的基因表达和蛋白质组学数据结果相结合，以预测治疗反应并确定与反应相关的表观遗传事件。对接受新辅助化疗（有或无贝伐单抗）的人表皮生长因子受体2阴性非转移性患者在治疗前、治疗期间和治疗后采集的新鲜冷冻肿瘤活检组织进行分子分析。在此，我们报告与细胞周期调控相关的增强子CpG处的DNA甲基化可以预测雌激素受体阳性亚组患者对化疗和贝伐单抗的反应（AUC = 0.874），并且我们在具有相似治疗方案的独立患者队列中验证了这一观察结果（AUC = 0.762）。将DNA甲基化评分与先前发表的蛋白质特征评分相结合，预测性能略有提高（AUC = 0.784）。我们还表明，接受联合治疗的肿瘤发生了更广泛的表观遗传改变。最后，我们对DNA甲基化和基因表达水平的改变进行了整合表达-甲基化定量性状位点分析，表明治疗期间发生的表观遗传改变在反应者和无反应者之间有所不同，并且这些差异可能通过颗粒头样转录因子2的活性由增殖-上皮-间质转化轴来解释。使用从拷贝数数据计算出的肿瘤纯度，我们开发了一种估计癌细胞特异性甲基化的方法，以确认与反应的关联反映了癌细胞中的DNA甲基化。综上所述，这些结果支持了在正确的患者中使用贝伐单抗联合化疗可能带来临床益处。
