Department of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
The authors contributed eually to the article.
Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033819896331. doi: 10.1177/1533033819896331.
More than 30% of estrogen receptor-positive breast cancers are resistant to primary hormone therapy, and about 40% that initially respond to hormone therapy eventually acquire resistance. Although the mechanisms of hormone therapy resistance remain unclear, aberrant DNA methylation has been implicated in oncogenesis and drug resistance.
We investigated the relationship between methylome variations in circulating tumor DNA and exemestane resistance, to track hormone therapy efficacy.
We prospectively recruited 16 patients who were receiving first-line therapy in our center. All patients received exemestane-based hormone therapy after enrollment. We collected blood samples at baseline, first follow-up (after 2 therapeutic cycles) and at detection of disease progression. Disease that progressed within 6 months under exemestane treatment was considered exemestane resistance but was considered relatively exemestane-sensitive otherwise. We obtained circulating tumor DNA-derived methylomes using the whole-genome bisulfide sequencing method. Methylation calling was done by BISMARK software; differentially methylated regions for exemestane resistance were calculated afterward.
Median follow-up for the 16 patients was 19.0 months. We found 7 exemestane resistance-related differentially methylated regions, located in different chromosomes, with both significantly different methylation density and methylation ratio. Baseline methylation density and methylation ratio of chromosome 6 [32400000-32599999] were both high in exemestane resistance. High baseline methylation ratios of chromosome 3 [67800000-67999999] ( = .013), chromosome 3 [140200000-140399999] ( = .037), and chromosome 12 [101200000-101399999] ( = .026) could also predict exemestane resistance. During exemestane treatment, synchronized changes in methylation density and methylation ratio in chromosome 6 [32400000-32599999] could accurately stratify patients in terms of progression-free survival ( = .000033). Cutoff values of methylation density and methylation ratio for chromosome 6 [149600000-149799999] were 0.066 and 0.076, respectively.
Methylation change in chromosome 6 [149600000-149799999] is an ideal predictor of exemestane resistance with great clinical potential.
超过 30%的雌激素受体阳性乳腺癌对初始激素治疗具有抗药性，而大约 40%最初对激素治疗有反应的患者最终会产生抗药性。尽管激素治疗耐药的机制尚不清楚，但异常的 DNA 甲基化与肿瘤发生和耐药有关。
我们研究了循环肿瘤 DNA 甲基组变化与依西美坦耐药之间的关系，以跟踪激素治疗的疗效。
我们前瞻性招募了 16 名正在我们中心接受一线治疗的患者。所有患者入组后均接受依西美坦为基础的激素治疗。我们在基线、第一次随访（治疗 2 个周期后）和疾病进展时采集血样。依西美坦治疗 6 个月内进展的疾病被认为是依西美坦耐药，但否则被认为是相对的依西美坦敏感。我们使用全基因组 bisulfite 测序方法获得循环肿瘤 DNA 衍生的甲基组。通过 BISMARK 软件进行甲基化调用；随后计算依西美坦耐药相关的差异甲基化区域。
16 例患者的中位随访时间为 19.0 个月。我们发现了 7 个与依西美坦耐药相关的差异甲基化区域，位于不同的染色体上，其甲基化密度和甲基化比值均有显著差异。染色体 6 [32400000-32599999]的基线甲基化密度和甲基化比值在依西美坦耐药中均较高。染色体 3 [67800000-67999999]（ =.013）和染色体 12 [101200000-101399999]（ =.026）的高基线甲基化比值（ =.037）也可以预测依西美坦耐药。在依西美坦治疗期间，染色体 6 [32400000-32599999]中的甲基化密度和甲基化比值的同步变化可以准确地对无进展生存期进行分层（ =.000033）。染色体 6 [149600000-149799999]的甲基化密度和甲基化比值的截断值分别为 0.066 和 0.076。
染色体 6 [149600000-149799999]中的甲基化变化是依西美坦耐药的理想预测指标，具有很大的临床潜力。
