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Methylated NEUROD1 Promoter is a Marker for Chemosensitivity in Breast Cancer

Authors' Affiliations: ¹ Department of Gynecological Oncology, UCL Institute for Women's Health, University College London, London, United Kingdom; ² Tyrolean Cancer Research Institute, Departments of ³ Gynecology, ⁴ Medical Statistics, Informatics, and Health Economics, and ⁵ Pathology, Medical University, Innsbruck, Austria; Departments of ⁶ Pathology and ⁷ Gynecology, General Hospital and Paracelsus University Salzburg, Salzburg, Austria; and ⁸ Department of Medicine, Royal Marsden Hospital, London, United Kingdom

Requests for reprints: Martin Widschwendter, Department of Gynecological Oncology, Institute for Women's Health, University College London, EGA Hospital, 2nd Floor Huntley Street, London WC1E 6DH, United Kingdom. Phone: 44-20-7380-9140; Fax: 44-20-7380-9033; E-mail: M.Widschwendter{at}ucl.ac.uk.

Purpose: Chemotherapy can be an integral component of the adjuvant management strategy for women with early stage breast cancer. To date, no tool is available to predict or monitor the efficacy of these therapies. The aim of this proof-of-principle study was to assess whether NEUROD1 DNA methylation is able to predict the response to neoadjuvant and adjuvant chemotherapy.

Experimental Design: Recently, we showed that NEUROD1 DNA is differentially methylated in neoplastic versus nonneoplastic breast tissue samples. In this study, we used MethyLight and analyzed NEUROD1 methylation in (a) 74 breast cancer tissue samples, (b) two independent sets of pretreatment core biopsies of 23 (training set) and 21 (test set) neoadjuvantly treated breast cancer patients, and (c) pretherapeutic and posttherapeutic serum samples from 107 breast cancer patients treated with adjuvant chemotherapy.

Results: High-grade tumors showed higher NEUROD1 methylation levels. Estrogen receptor–negative breast cancers with high NEUROD1 methylation were 10.8-fold more likely to respond with a complete pathologic response following neoadjuvant chemotherapy. Patients with positive serum pretreatment NEUROD1 methylation, which persisted after chemotherapy, indicated poor relapse-free and overall survival in univariate and multivariate analyses (relative risk for relapse, 6.2; 95% confidence interval, 1.6-24; P = 0.008, and relative risk for death, 14; 95% confidence interval, 1.6-120; P = 0.02).

Conclusions: These data support the view that NEUROD1 methylation is a chemosensitivity marker in estrogen receptor–negative breast cancer.