title: Pathological complete response of HER2-positive breast cancer to trastuzumab and chemotherapy can be predicted by HSD17B4 methylation.
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.
authors.affiliation: Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Department of Medical Oncology, Musashino Red Cross Hospital, Musashino, Tokyo 180-8610, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Department of Breast Surgery, Hokkaido Cancer Center, National Hospital Organization, Shiroishi-Ku, Sapporo, 003-0806, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department 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.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hozumi
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mukai
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D064029:Peroxisomal Multifunctional Protein-2 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D000068878:Trastuzumab / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D064029:Peroxisomal Multifunctional Protein-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C104587:HSD17B4 protein, human
keywords: DNA methylation; HER2-directed therapy; biomarker; breast cancer