A novel treatment strategy of HER2-targeted therapy in combination with Everolimus for HR+/HER2- advanced breast cancer patients with HER2 mutations.

The incidence of HER2 somatic mutations in breast cancer is about 2-4%, mainly occurring in the HR+/HER2- subtype. Preclinical studies suggest that HER2 mutations can lead to constitutive HER2 activation, but effective treatment options for the clinical management of patients with HER2 mutations remain obscure. Our study analyzed HER2 mutation status by performing next-generation sequencing using tumor tissues and over 300 plasma samples from 72 metastatic breast cancer patients. We observed that two patients bearing HER2 mutations (Patient #1 bearing S310F and V777L mutations, Patient #2 bearing 778insGSP mutation) achieved a durable partial response to Trastuzumab combined with Everolimus. In vitro experiments showed that T47D and MCF7 cells overexpressing these HER2 mutants (S310F, V777L, 778insGSP and L755S) were sensitive to HER2-targeted therapies combined with the mTOR inhibitor Everolimus. These findings provide a treatment option for patients with HER2 mutations by combining HER2-targeted therapies with Everolimus.