Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study

Author:

Visvanathan Kala1,Fackler MaryJo S.1,Zhang Zhe1,Lopez-Bujanda Zoila A.1,Jeter Stacie C.1,Sokoll Lori J.1,Garrett-Mayer Elizabeth1,Cope Leslie M.1,Umbricht Christopher B.1,Euhus David M.1,Forero Andres1,Storniolo Anna M.1,Nanda Rita1,Lin Nancy U.1,Carey Lisa A.1,Ingle James N.1,Sukumar Saraswati1,Wolff Antonio C.1

Affiliation:

1. Kala Visvanathan, Johns Hopkins University School of Medicine and Bloomberg School of Public Health; MaryJo S. Fackler, Zhe Zhang, Zoila A. Lopez-Bujanda, Stacie C. Jeter, Lori J. Sokoll, Leslie M. Cope, Christopher B. Umbricht, David M. Euhus, Saraswati Sukumar, and Antonio C. Wolff, Johns Hopkins University School of Medicine, Baltimore, MD; Elizabeth Garrett-Mayer, Medical University of South Carolina, Charleston, SC; Andres Forero, University of Alabama at Birmingham, Birmingham, AL; Anna M....

Abstract

Purpose Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA). Patients and Methods Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch). Results Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS ( P < .001) and progressive disease at first restaging ( P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells ( P = .004). Conclusion Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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