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

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.

Human Microbiota and Breast Cancer—Is There Any Relevant Link?—A Literature Review and New Horizons Toward Personalised Medicine

“…HER2 is amplified or overexpressed in 20–30% of all BC patients. It has been demonstrated that HER2 positive BC exhibits sensitivity to HER2 inhibitors, such as trastuzumab, pertuzumab, and trastuzumab emtansine ( Cardoso et al, 2019 ; Cardoso et al, 2020 ; Yi et al, 2020 ). In a recent work, patients treated with neoadjuvant trastuzumab, who achieved pathological complete response (pCR) were characterised by higher abundance of Clostridiales bacteria and lower representation of Bacteroidales as compared to those with residual disease (RD) at surgery.…”

Dissecting the biological heterogeneity of HER2-positive breast cancer

“…Interestingly, in a recent study, the mutational landscape of ERBB2 was also assessed in HER2 amplification-positive patients. The study showed a higher ERBB2 mutation frequency in HER2-amplified tumors than in HER2-negative (19.5 % vs. 4.8 %; p < 0.001) [ 54 ]. One-hundred-ninety-four ERBB2 variants were predicted as driver mutations and 192 variants were predicted as passenger mutations.…”

“…One-hundred-ninety-four ERBB2 variants were predicted as driver mutations and 192 variants were predicted as passenger mutations. The top three frequency mutations were represented by the already known V777L, L755S and D769Y and were all predicted as driver mutations [ 54 ]. These rare mutations, at least in part, seem to be induced by HER2-targeted therapy and ET, and prevails in metastatic tumors, compared to primary ones [ [54] , [55] , [56] ].…”

“…The top three frequency mutations were represented by the already known V777L, L755S and D769Y and were all predicted as driver mutations [ 54 ]. These rare mutations, at least in part, seem to be induced by HER2-targeted therapy and ET, and prevails in metastatic tumors, compared to primary ones [ [54] , [55] , [56] ]. Furthermore, in case of concomitant HER2 mutations and amplification, resistance to trastuzumab has been detected [ 54 ].…”

“…These rare mutations, at least in part, seem to be induced by HER2-targeted therapy and ET, and prevails in metastatic tumors, compared to primary ones [ [54] , [55] , [56] ]. Furthermore, in case of concomitant HER2 mutations and amplification, resistance to trastuzumab has been detected [ 54 ]. Conversely, in this cHER2+ subset, the tyrosin kinase inhibitor (TKI) neratinib showed promising activity [ 57 ], such as the TKI pyrotinib in BC with HER2 mutations without amplification [ 58 ].…”