Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008

Roisin Connolly, Mary Jo Fackler, Zhe Zhang, Xian C. Zhou, Matthew P. Goetz, Judy C. Boughey, Bridget Walsh, John T. Carpenter, Anna Maria Storniolo, Stanley P. Watkins, Edward Gabrielson, Vered Stearns, Saraswati Sukumar

Research output: Contribution to journalArticle

Abstract

Background: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. Methods: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. Results: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37–0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients. Conclusion: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Sep 16 2017

Fingerprint

DNA Methylation
Methylation
Drug Therapy
Serum
Neoplasms
Breast Neoplasms
Logistic Models
Placebos
Genes
vorinostat
Carboplatin
Odds Ratio
Hormones
Polymerase Chain Reaction

Keywords

  • Biomarkers
  • Breast cancer
  • cMethDNA
  • Methylation
  • Preoperative chemotherapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008. / Connolly, Roisin; Fackler, Mary Jo; Zhang, Zhe; Zhou, Xian C.; Goetz, Matthew P.; Boughey, Judy C.; Walsh, Bridget; Carpenter, John T.; Storniolo, Anna Maria; Watkins, Stanley P.; Gabrielson, Edward; Stearns, Vered; Sukumar, Saraswati.

In: Breast Cancer Research and Treatment, 16.09.2017, p. 1-10.

Research output: Contribution to journalArticle

Connolly, Roisin ; Fackler, Mary Jo ; Zhang, Zhe ; Zhou, Xian C. ; Goetz, Matthew P. ; Boughey, Judy C. ; Walsh, Bridget ; Carpenter, John T. ; Storniolo, Anna Maria ; Watkins, Stanley P. ; Gabrielson, Edward ; Stearns, Vered ; Sukumar, Saraswati. / Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008. In: Breast Cancer Research and Treatment. 2017 ; pp. 1-10.
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abstract = "Background: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. Methods: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. Results: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40{\%} lower chance of obtaining pCR (odds ratio, OR 0.60, 95{\%} CI 0.37–0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients. Conclusion: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).",
keywords = "Biomarkers, Breast cancer, cMethDNA, Methylation, Preoperative chemotherapy",
author = "Roisin Connolly and Fackler, {Mary Jo} and Zhe Zhang and Zhou, {Xian C.} and Goetz, {Matthew P.} and Boughey, {Judy C.} and Bridget Walsh and Carpenter, {John T.} and Storniolo, {Anna Maria} and Watkins, {Stanley P.} and Edward Gabrielson and Vered Stearns and Saraswati Sukumar",
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T1 - Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008

AU - Connolly, Roisin

AU - Fackler, Mary Jo

AU - Zhang, Zhe

AU - Zhou, Xian C.

AU - Goetz, Matthew P.

AU - Boughey, Judy C.

AU - Walsh, Bridget

AU - Carpenter, John T.

AU - Storniolo, Anna Maria

AU - Watkins, Stanley P.

AU - Gabrielson, Edward

AU - Stearns, Vered

AU - Sukumar, Saraswati

PY - 2017/9/16

Y1 - 2017/9/16

N2 - Background: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. Methods: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. Results: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37–0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients. Conclusion: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).

AB - Background: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. Methods: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. Results: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37–0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients. Conclusion: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).

KW - Biomarkers

KW - Breast cancer

KW - cMethDNA

KW - Methylation

KW - Preoperative chemotherapy

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