Abstract
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.
Highlights
Human epidermal growth factor receptor 2 (HER2, known as ERBB2) amplification or overexpression is detected in 20–30% of patients with breast cancer and is associated with a poor prognosis[1,2]
We identified 529 HER2 somatic mutations, including 386 different mutant sites, in 105 patients (Fig. 1a and Supplementary Data 1)
Next-generation sequencing-based assays indicate that HER2 somatic mutations are present in approximately 2–5% of primary breast cancers[10,15]
Summary
Human epidermal growth factor receptor 2 (HER2, known as ERBB2) amplification or overexpression is detected in 20–30% of patients with breast cancer and is associated with a poor prognosis[1,2]. Overexpression of the HER2 protein or amplification of the HER2 gene is an important predictive biomarker for identifying patients with breast cancer, who may benefit from HER2-targeted therapy. Next-generation sequencing has indicated that somatic mutations in HER2 are present in ~2–5% of primary breast cancers[3,5,6,7,8,9]. Most HER2 somatic mutations have been reported in HER2 amplification-negative breast cancers[10]. Previous studies of HER2 mutations have mainly focused on early-stage breast cancer based on primary tissues. Little is known about the molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer
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