In this study, we investigated the role played by HSP90 in the response to HER2-targeted combination therapy in preclinical breast cancer models in vitro and explored the prognostic/predictive impact of HSP90 expression in a mono-institutional series of HER2+ breast cancer patients who received trastuzumab- or trastuzumab/pertuzumab-based combination therapy as their first-line treatment for metastatic disease. The gene discussed is HSP90AA1; the disease is metastatic neoplasm.