The reversal of anti-HER2 resistance in advanced HER2-positive breast cancer using apatinib: two cases reports and literature review

Background: Human epidermal growth factor receptor 2 (HER2)-targeted treatment has yielded a notable clinical benefit in patients with HER2-positive breast cancer. However, nearly 50% of patients still suffer disease progression due to resistance to HER2-targeted therapy. After the failure of macromolecular monoclonal antibodies (mAbs) therapy, we can choose small molecule tyrosine kinase inhibitors (TKIs) to reverse HER2 resistance. When small molecule TKIs resistance, we can use mAb combined with small molecule TKI, or antibody-drug conjugates (ADCs) to reverse HER2 resistance. However then due to the availability and price of ADCs, patients may not use them. Consequently, new therapeutic approaches are required to overcome HER2-targeted therapy resistance. Vascular endothelial growth factor and its receptors (VEGF/VEGFRs) promote tumor angiogenesis. They can also activate downstream signaling pathways to promote tumorigenesis. VEGFR is a key regulator of the tyrosine kinase signaling pathway and may be a potential target in HER2-positive breast cancer. Apatinib is a small molecule TKI that specifically binds to VEGFR2 and thus exerts an antitumor effect. Although there is no definite indication for apatinib in breast cancer, it has a good benefit in advanced gastric cancer.Case Description: The two patients we reported were both HER2-positive breast cancer who we followed for more than 10 years. After the failure of multi-line anti-HER2 treatment, apatinib combined with anti-HER2 treatment had PFS of 8.4 months and 10.6 months, respectively. One patient had grade 2 hand-foot syndrome. The other had grade 2 leukopenia and grade 2 thrombocytopenia, both of them improved after control. And the best response of them were PR and SD, respectively.Conclusions: Our cases demonstrate that, in HER2-positive breast cancer patients with HER2-targeted resistance, apatinib may be able to reverse HER2 resistance. These two cases suggest an alternative method for clinical HER2-targeted treatment of drug-resistant breast cancer patients and provide new insights for future research.