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.