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Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. 2020

Zongbi Yi, and Guohua Rong, and Yanfang Guan, and Jin Li, and Lianpeng Chang, and Hui Li, and Binliang Liu, and Wenna Wang, and Xiuwen Guan, and Quchang Ouyang, and Lixi Li, and Jingtong Zhai, and Chunxiao Li, and Lifeng Li, and Xuefeng Xia, and Ling Yang, and Haili Qian, and Xin Yi, and Binghe Xu, and Fei Ma

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China.

Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification is an important predictive biomarker for identifying patients with breast cancer, who may benefit from HER2-targeted therapy. However, little is known about the molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. We analysed the HER2 mutation features of 1184 patients with invasive breast cancer. In addition, a single-arm, prospective, phase-II study (NCT03412383) of pyrotinib was conducted in patient with metastatic HER2 amplification-negative, mutation-positive breast cancer. Peripheral blood was collected from each patient and circulating tumour DNA (ctDNA) sequencing was performed using a 1021 gene panel. HER2 mutations were detected in 8.9% (105/1184) of patients. The HER2 amplification-positive patients had a higher mutation frequency than the HER2 amplification-negative patients (19.5% vs. 4.8%, P < 0.001). A multivariate Cox regression analysis indicated that patients with HER2 mutations had a shorter progression-free survival (PFS) than HER2 wild-type patients (median PFS 4.7 months vs. 11.0 months, hazard ratio 2.65, 95% confidence interval 1.25-5.65, P = 0.011). Ten HER2 amplification-negative, mutation-positive patients who received pyrotinib monotherapy were ultimately included in the efficacy analysis. The median PFS was 4.9 months. The objective response rate (complete response + partial response) was 40.0% and the clinical benefit rate (complete response + partial response + stable disease over 24 weeks) was 60%. In conclusion, a HER2 gene mutation analysis is potentially useful to identify biomarkers of trastuzumab resistance in HER2 amplification-positive patients. Patients with HER2-mutated, non-amplified metastatic breast cancers may benefit from pyrotinib.