title: Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study.
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.
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Kala
authors.initials: K
authors.lastname: Visvanathan
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: MaryJo S
authors.initials: MS
authors.lastname: Fackler
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Zoila A
authors.initials: ZA
authors.lastname: Lopez-Bujanda
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Stacie C
authors.initials: SC
authors.lastname: Jeter
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Sokoll
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Cope
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Umbricht
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: David M
authors.initials: DM
authors.lastname: Euhus
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Storniolo
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Rita
authors.initials: R
authors.lastname: Nanda
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: 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. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm