Research Papers:

Pathological complete response of HER2-positive breast cancer to trastuzumab and chemotherapy can be predicted by HSD17B4 methylation

Satoshi Fujii, Satoshi Yamashita, Takeshi Yamaguchi, Masato Takahashi, Yasuo Hozumi, Toshikazu Ushijima and Hirofumi Mukai _

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Oncotarget. 2017; 8:19039-19048. https://doi.org/10.18632/oncotarget.15118

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Satoshi Fujii1, Satoshi Yamashita2, Takeshi Yamaguchi3, Masato Takahashi4, Yasuo Hozumi5, Toshikazu Ushijima2, Hirofumi Mukai6

1Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan

2Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan

3Department of Medical Oncology, Musashino Red Cross Hospital, Musashino, Tokyo 180-8610, Japan

4Department of Breast Surgery, Hokkaido Cancer Center, National Hospital Organization, Shiroishi-Ku, Sapporo, 003-0806, Japan

5Department of Breast and Endocrine Surgery, Ibaraki Clinical Education and Training Center, Faculty of Medicine, Tsukuba University/Department of Breast Surgery, Ibaraki Prefectural Central Hospital, Kasama, Ibaraki 309-1793, Japan

6Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan

Correspondence to:

Hirofumi Mukai, email: [email protected]

Keywords: DNA methylation, HER2-directed therapy, biomarker, breast cancer

Received: July 27, 2016     Accepted: January 22, 2017     Published: February 06, 2017


Human epidermal growth factor (HER) 2-directed therapy is the standard treatment for HER2-positive breast cancer. Patients who achieved a pathological complete response (pCR) to the therapy are associated with excellent disease-free survival. However, few molecular markers are available to predict pCR. Here, we aimed to establish a DNA methylation marker to predict the response to trastuzumab and chemotherapy. A total of 67 patients were divided into screening (n = 21) and validation (n = 46) sets. Genome-wide DNA methylation analysis of the screening set identified eight genomic regions specifically methylated in patients with pCR. Among these, HSD17B4 encoding type 4 17β-hydroxysteroid dehydrogenase was most significantly differentially methylated. The differential methylation was confirmed by pyrosequencing (P = 0.03), and a cutoff value was determined. This association was successfully validated in the validation set (P < 0.001), and patients with pCR were predicted with a high specificity (79%). Multivariate analysis, including tumor stage and hormone receptor status, showed that HSD17B4 methylation was an independent predictive factor (odds ratio: 10.0, 95% confidence interval 2.54–39.50, P = 0.001). Combination with ER status and HSD17B4 methylation improved the specificity up to 91%. Identification of HER2-positive breast cancer patients who would achieve pCR only by trastuzumab and chemotherapy may lead to surgery-free treatment for this group of breast cancer patients.

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