Methylome Variation Predicts Exemestane Resistance in Advanced ER+ Breast Cancer

• Published in: Technology in cancer research & treatment Vol. 19; p. 1533033819896331
• Main Authors: Liu, Xiao-ran, Zhang, Ru-yan, Gong, Hao, Rugo, Hope S., Chen, Ling-bo, Fu, Yuan, Che, Jian-wei, Tie, Jian, Shao, Bin, Wan, Feng-ling, Kong, Wei-yao, Song, Guo-hong, Jiang, Han-fang, Xu, Guo-bing, Li, Hui-ping
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 2020; Sage Publications Ltd; SAGE Publishing
• Subjects: Breast cancer; Chromosome 12; Chromosome 3; Chromosome 6; Chromosomes; Deoxyribonucleic acid; DNA; DNA methylation; DNA sequencing; Drug resistance; Endocrine therapy; Estrogen receptors; Genomes; Original; Patients; Tumorigenesis; exemestane resistance; advanced breast cancer; methylomes; circulating tumor DNA
• ISSN: 1533-0346; 1533-0338
• DOI: 10.1177/1533033819896331

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.