Circulating tumor DNA shows variable clonal response of breast cancer during neoadjuvant chemotherapy

// Ji-Yeon Kim 1, * , Donghyun Park 2, * , Dae-Soon Son 2, * , Seok Jin Nam 3 , Seok Won Kim 3 , Hae Hyun Jung 4 , Yeon Jeong Kim 2 , Gahee Park 2, 5 , Woong-Yang Park 2, 4 , Jeong Eon Lee 3, 4 and Yeon Hee Park 1, 4, 6 1 Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea 2 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea 3 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea 4 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea 5 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea 6 Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, Korea * These authors have contributed equally to this work Correspondence to: Yeon Hee Park, email: yhparkhmo@skku.edu Jeong Eon Lee, email: jeongeon.lee@samsung.com Keywords: circulating tumor DNA, neoadjuvant chemotherapy, breast cancer Received: June 21, 2017     Accepted: August 23, 2017     Published: September 23, 2017 ABSTRACT Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer (BC). In this study, we aimed to identify genetic alterations during the process of tumor clonal evolution and examine if ctDNA level well indicated clinical response to neoadjuvant chemotherapy (NAC) and BC recurrence. We performed targeted ultra-deep sequencing of plasma DNAs, matched germline DNAs and tumor DNAs from locally advanced BC patients. Serial plasma DNAs were collected at diagnosis, after the 1 st cycle of NAC and after curative surgery. For the target enrichment, we designed RNA baits covering a total of ~202kb regions of the human genome including a total of 82 cancer-related genes. For ctDNA, 15 serial samples were collected and 87% of plasma SNVs were detected in 13 BC samples that had somatic alterations in tumor tissues. The TP53 mutation was most commonly detected in primary tumor tissues and plasma followed by BRCA1 and BRCA2 . At BC diagnosis, the amount of plasma SNVs did not correlate with clinical stage at diagnosis. With respect to the therapeutic effects of NAC, we found two samples in which ctDNA disappeared after the 1 st NAC cycle achieved a pathologic complete response (pCR). In addition, the amount of ctDNA correlated with residual cancer volume detected by breast MRI. This targeted ultra-deep sequencing for ctDNA analysis would be useful for monitoring tumor burden and drug resistance. Most of all, we suggest that ctDNA could be the earliest predictor of NAC response.