Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008
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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.
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.
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.
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).
KeywordsPreoperative chemotherapy Breast cancer Methylation cMethDNA Biomarkers
The authors thank the patients who participated in this study: NIH grant P30 CA006973, SPORE in breast cancer (P50 CA88843), TBCRC and its founding partners (The AVON Foundation, The Breast Cancer Research Foundation and Susan G. Komen for the Cure); Abraxis Bioscience: Merck Oncology: and the Cindy Rosencrans Fund for Triple Negative Breast Cancer Research for generous funding. The authors also thank the TBCRC participating site investigators, research nurses, study coordinators, and the staff of the Breast and Ovarian Cancer Program and Avon Breast Center at Johns Hopkins.
Compliance with ethical standards
Women enrolling in the study signed an informed consent approved by the Institutional Review Boards of participating institutions.
Conflicts of interest
VS has received research Grants from Merck, Celgene Corporation, Abbvie, Pfizer, Novartis, Medimmune, and Puma Biotechnology. RC has received research Grants from Novartis, Puma Biotechnology, Genentech, Merrimack, Clovis, Merck. AMS has received consulting fees from Eli Lilly and Co., and Pfizer. SS has received research Grants from AVON Foundation, Grants, licensing/royalty fees and consulting fees from Cepheid for QM-MSP and cMethDNA assays. MJF has received licensing/royalty fees and consulting fees from Cepheid. The remaining authors have no conflicts of interest to disclose.
- 1.https://seer.cancer.gov/statfacts/html/breast.html. Accessed September 14 2017
- 16.Fackler MJ, Malone K, Zhang Z, Schilling E, Garrett-Mayer E, Swift-Scanlan T, Lange J, Nayar R, Davidson NE, Khan SA et al (2006) Quantitative multiplex methylation-specific PCR analysis doubles detection of tumor cells in breast ductal fluid. Clin Cancer Res 12(11 Pt 1):3306–3310CrossRefPubMedGoogle Scholar
- 19.Dejeux E, Ronneberg JA, Solvang H, Bukholm I, Geisler S, Aas T, Gut IG, Borresen-Dale AL, Lonning PE, Kristensen VN et al (2010) DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response. Mol Cancer 9:68CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Klajic J, Busato F, Edvardsen H, Touleimat N, Fleischer T, Bukholm I, Borresen-Dale AL, Lonning PE, Tost J, Kristensen VN (2014) DNA methylation status of key cell-cycle regulators such as CDKNA2/p16 and CCNA1 correlates with treatment response to doxorubicin and 5-fluorouracil in locally advanced breast tumors. Clin Cancer Res 20(24):6357–6366CrossRefPubMedGoogle Scholar
- 22.Visvanathan K, Fackler MS, Zhang Z, Lopez-Bujanda ZA, Jeter SC, Sokoll LJ, Garrett-Mayer E, Cope LM, Umbricht CB, Euhus DM et al (2017) Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 prospective biomarker study. J Clin Oncol 35(7):751–758CrossRefPubMedGoogle Scholar
- 28.Connolly RM, Leal JP, Goetz MP, Zhang Z, Zhou XC, Jacobs LK, Mhlanga J, Joo HO, Carpenter J, Storniolo AM et al (2015) TBCRC 008: early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer. J Nucl Med 56(1):31–37CrossRefPubMedGoogle Scholar
- 29.Fackler MJ, Umbricht CB, Williams D, Argani P, Cruz LA, Merino VF, Teo WW, Zhang Z, Huang P, Visvananthan K et al (2011) Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence. Cancer Res 71(19):6195–6207CrossRefPubMedPubMedCentralGoogle Scholar
- 33.de Groot JS, Moelans CB, Elias SG, Jo Fackler M, van Domselaar R, Suijkerbuijk KP, Witkamp AJ, Sukumar S, van Diest PJ, van der Wall E (2016) DNA promoter hypermethylation in nipple fluid: a potential tool for early breast cancer detection. Oncotarget 7(17):24778–24791CrossRefPubMedPubMedCentralGoogle Scholar