Oncotarget

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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Abstract

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

ABSTRACT

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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