Prognostic Value of Plasma HER2 Gene Copy Number in HER2-Positive Metastatic Breast Cancer Treated with First-Line Trastuzumab

Abstract

Ran Ran,1,* Wenfa Huang,1,* Yaxin Liu,1,* Lin Shao,2 Xiaoran Liu,1 Yunyun Niu,2 Weiyao Kong,1 Shiping Bo,2 Hope S Rugo,3 Sijia Lu,2 Huiping Li1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, People’s Republic of China; 2Department of Clinical Research, Yikon Genomics Co. Ltd., Shanghai, People’s Republic of China; 3University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA*These authors contributed equally to this workCorrespondence: Huiping Li; Hope S Rugo Tel [phone]Email [email protected]; [email protected]: Patients with HER2-positive metastatic breast cancer (MBC) benefit from trastuzumab-based therapy but eventually develop intrinsic or acquired resistance. Whether plasma HER2 gene copy number (GCN) could predict survival after trastuzumab treatment remained controversial. We evaluated the prognostic value of plasma HER2 GCN using low-coverage whole-genome sequencing (LC-WGS).Methods: The plasma was collected from HER2-positive MBC patients whose pre-therapeutic samples were available before first-line trastuzumab-based treatment. Plasma DNA was extracted and assessed by LC-WGS for HER2 GCN. The optimal cut-off point for HER2 GCN to shorter survival was determined by receiver operating characteristic (ROC) curve analysis.Results: A total of 49 patients were retrieved from 2013 to 2017, among whom 21 had multiple organ involvement (≥ 3 sites). Variations of HER2 GCN in pre-therapeutic plasma ranged from 1.89 to 23.86 (median = 2.59). ROC analysis identified the optimal cut-off point for HER2 GCN as 2.82 (P = 0.005), with 23 patients had high-level HER2 GCN and 26 in the low-level group. Both progression-free survival (PFS, P = 0.032) and overall survival (OS, P = 0.006) were adversely associated with high-level HER2 GCN. In multivariate analyses, high HER2 GCN was independently associated with shorter PFS [hazard ratio (HR) = 2.042, P = 0.037], while both high HER2 GCN (HR = 4.909, P = 0.004) and more metastatic organs (HR = 4.019, P = 0.011) were negative prognostic factors for OS.Conclusion: In this population of patients with HER2-positive MBC, individuals with high HER2 GCNs in plasma had worse prognosis after trastuzumab-based therapy. Plasma HER2 GCN may be a prognostic marker in these patients.Keywords: gene copy number, HER2-positive, metastatic breast cancer, whole genome sequencing, plasma

Keywords

• gene copy number
• her2-positive
• metastatic breast cancer
• whole genome sequencing
• plasma