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

• Published in: Translational oncology Vol. 21; p. 101444
• Main Authors: Ma, Jing, Li, Xuelu, Zhang, Qianran, Li, Ning, Sun, Siwen, Zhao, Shanshan, Zhao, Zuowei, Li, Man
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2022; Neoplasia Press; Elsevier
• Subjects: Breast cancer; Everolimus; HER2 mutation; HER2-targeted therapy; Original Research; Treatment; HER2-targeted therapy; Breast cancer; Treatment; Everolimus; HER2 mutation
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2022.101444

•Trastuzumab combined with Everolimus is an effective treatment for ER+/HER2-HER2-mutant breast cancer patients.•HER2 mutant breast cancer cells are highly sensitive to the combination of HER2-targeted therapies and Everolimus.•Lapatinib combined with Everolimus inhibits HER2 downstream signaling.
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.