In the Translational Breast Cancer Research Consortium (TBCRC) 005 prospective biomarker study, reported in the Journal of Clinical Oncology by Kala Visvanathan, MBBS, MHS, of Johns Hopkins University, and colleagues, a cumulative methylation index was found to be predictive of progression-free survival, overall survival, and disease status at first restaging in women with metastatic breast cancer.
The study included women with measurable disease starting a new systemic therapy and being treated at one of seven U.S. academic medical centers. A new quantitative multiplex assay (cMethDNA) was used to measure a panel of cell-free DNA methylation markers. A total of 10 genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging (timing at the discretion of the treating oncologist). A cumulative methylation index was generated on the basis of six of the genes.
Predictive Ability of Cumulative Methylation Index
Median follow-up was 19.5 months. Median progression-free survival (2.1 vs 5.8 months) and overall survival (12.3 vs 21.7 months) were shorter in women with a high cumulative methylation index. In multivariable analysis adjusting for age, ethnicity, prior therapy, tumor phenotype, and disease burden, a high vs a low cumulative methylation index at week 4 was independently associated with worse progression-free survival (hazard ratio [HR] = 1.79, P = .002) and overall survival (HR = 1.75, P = .003). Women with an objective response to treatment (P < .001) or stable disease (P < .001) were more likely to exhibit a reduction in cumulative methylation index from baseline to week 4. An increase in the cumulative methylation index from baseline to week 4 was associated with worse progression-free survival (P < .001) and an increased risk of progressive disease at first restaging (P < .001).
Adding either week 4 cumulative methylation index or circulating tumor cell levels significantly improved the ability of a model of established risk factors to predict progression-free survival (P < .001 and P = .038) and overall survival (P = .043 and P = .007). Cumulative methylation index at week 4 improved the ability of the model to predict progression-free survival when circulating tumor cell level was included (P = .004).
The investigators concluded: “Methylation of this gene panel is a strong predictor of survival outcomes in [metastatic breast cancer] and may have clinical usefulness in risk stratification and disease monitoring.”
The study was supported by the Avon Foundation for Women, the Breast Cancer Research Foundation, Janssen Diagnostics, the Rubenstein Family Fund, Susan G. Komen Foundation, and National Institutes of Health grants. ■