Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 prospective biomarker study

Kala Visvanathan, Maryjo S. Fackler, Zhe Zhang, Zoila A. Lopez-Bujanda, Stacie C. Jeter, Lori J. Sokoll, Elizabeth Garrett-Mayer, Leslie M. Cope, Christopher B. Umbricht, David M. Euhus, Andres Forero, Anna Maria Storniolo, Rita Nanda, Nancy U. Lin, Lisa A. Carey, James N. Ingle, Saraswati Sukumar, Antonio C. Wolff

Research output: Contribution to journalArticle

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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 crossvalidation 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.

Original languageEnglish (US)
Pages (from-to)751-758
Number of pages8
JournalJournal of Clinical Oncology
Volume35
Issue number7
DOIs
StatePublished - Mar 1 2017

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DNA Methylation
Methylation
Biomarkers
Prospective Studies
Breast Neoplasms
Disease-Free Survival
Survival
Serum
Genes
Genetic Markers
Proportional Hazards Models
Epigenomics
Neoplasms
Logistic Models

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer : TBCRC 005 prospective biomarker study. / Visvanathan, Kala; Fackler, Maryjo S.; Zhang, Zhe; Lopez-Bujanda, Zoila A.; Jeter, Stacie C.; Sokoll, Lori J.; Garrett-Mayer, Elizabeth; Cope, Leslie M.; Umbricht, Christopher B.; Euhus, David M.; Forero, Andres; Storniolo, Anna Maria; Nanda, Rita; Lin, Nancy U.; Carey, Lisa A.; Ingle, James N.; Sukumar, Saraswati; Wolff, Antonio C.

In: Journal of Clinical Oncology, Vol. 35, No. 7, 01.03.2017, p. 751-758.

Research output: Contribution to journalArticle

Visvanathan, K, Fackler, MS, Zhang, Z, Lopez-Bujanda, ZA, Jeter, SC, Sokoll, LJ, Garrett-Mayer, E, Cope, LM, Umbricht, CB, Euhus, DM, Forero, A, Storniolo, AM, Nanda, R, Lin, NU, Carey, LA, Ingle, JN, Sukumar, S & Wolff, AC 2017, 'Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 prospective biomarker study', Journal of Clinical Oncology, vol. 35, no. 7, pp. 751-758. https://doi.org/10.1200/JCO.2015.66.2080
Visvanathan, Kala ; Fackler, Maryjo S. ; Zhang, Zhe ; Lopez-Bujanda, Zoila A. ; Jeter, Stacie C. ; Sokoll, Lori J. ; Garrett-Mayer, Elizabeth ; Cope, Leslie M. ; Umbricht, Christopher B. ; Euhus, David M. ; Forero, Andres ; Storniolo, Anna Maria ; Nanda, Rita ; Lin, Nancy U. ; Carey, Lisa A. ; Ingle, James N. ; Sukumar, Saraswati ; Wolff, Antonio C. / Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer : TBCRC 005 prospective biomarker study. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 7. pp. 751-758.
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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 crossvalidation 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.",
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T2 - TBCRC 005 prospective biomarker study

AU - Visvanathan, Kala

AU - Fackler, Maryjo S.

AU - Zhang, Zhe

AU - Lopez-Bujanda, Zoila A.

AU - Jeter, Stacie C.

AU - Sokoll, Lori J.

AU - Garrett-Mayer, Elizabeth

AU - Cope, Leslie M.

AU - Umbricht, Christopher B.

AU - Euhus, David M.

AU - Forero, Andres

AU - Storniolo, Anna Maria

AU - Nanda, Rita

AU - Lin, Nancy U.

AU - Carey, Lisa A.

AU - Ingle, James N.

AU - Sukumar, Saraswati

AU - Wolff, Antonio C.

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N2 - 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 crossvalidation 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.

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