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Updated: Dec 27, 2025
Methyl-binding DNA capture Sequencing for Patient Tissues
Published on: October 31, 2016
Methylome Variation Predicts Exemestane Resistance in Advanced ER+ Breast Cancer
Xiao-Ran Liu1,2, Ru-Yan Zhang1,2, Hao Gong3,2
1Department of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
Background:
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.
Purpose:
We investigated the relationship between methylome variations in circulating tumor DNA and exemestane resistance, to track hormone therapy efficacy.
Methods:
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.
Results:
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] (P = .013), chromosome 3 [140200000-140399999] (P = .037), and chromosome 12 [101200000-101399999] (P = .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 (P = .000033). Cutoff values of methylation density and methylation ratio for chromosome 6 [149600000-149799999] were 0.066 and 0.076, respectively.
Conclusion:
Methylation change in chromosome 6 [149600000-149799999] is an ideal predictor of exemestane resistance with great clinical potential.
Insights
Aberrant DNA methylation in circulating tumor DNA can predict exemestane resistance in estrogen receptor-positive breast cancer. Methylation changes in chromosome 6 are particularly promising for tracking hormone therapy efficacy.
Area of Science:
- Oncology
- Genomics
- Epigenetics
Background:
- Estrogen receptor-positive breast cancer frequently develops resistance to hormone therapy, impacting treatment outcomes.
- Mechanisms underlying hormone therapy resistance, including aberrant DNA methylation, are not fully understood.
- Aberrant DNA methylation is implicated in cancer development and acquired drug resistance.
Purpose of the Study:
- To investigate the association between circulating tumor DNA methylome variations and exemestane resistance.
- To explore the potential of methylome analysis for monitoring hormone therapy efficacy.
Main Methods:
- Prospective study of 16 patients receiving first-line exemestane therapy.
- Blood samples collected at baseline, after two cycles, and at disease progression.
- Circulating tumor DNA (ctDNA) methylomes analyzed using whole-genome bisulfite sequencing.
- Differential methylation analysis performed to identify exemestane resistance-related regions.
Main Results:
- Seven differentially methylated regions associated with exemestane resistance were identified.
- High baseline methylation in specific regions of chromosome 6, 3, and 12 predicted resistance.
- Synchronized methylation changes in chromosome 6 [32400000-32599999] correlated with progression-free survival (P = .000033).
Conclusions:
- Methylation changes in chromosome 6 [149600000-149799999] serve as a strong predictor of exemestane resistance.
- This epigenetic marker holds significant clinical potential for managing hormone therapy in breast cancer.
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