YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development.

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

Real-World Comparative Analysis of Trastuzumab Originator and Biosimilars: Safety, Efficacy, and Cost Effectiveness.

BACKGROUND: Despite the global use of trastuzumab biosimilars, concerns remain regarding their efficacy and safety. In particular, when used concurrently with pertuzumab, trastuzumab biosimilars lack extensive real-world data and safety information. Additionally, as cancer drug expenditures continue to rise worldwide, cost savings from biosimilars have become increasingly important. OBJECTIVE: This study aims to assess the safety, efficacy, and cost effectiveness of trastuzumab originators and their biosimilars in real-world clinical settings, focusing on a large patient population. METHODS: The analysis included 31,661 patients with HER2-positive breast cancer from the Medical Data Vision Co., Ltd. database in Japan. Additionally, adverse event reports for the trastuzumab originator and its biosimilars were obtained for 58,799 patients from the World Health Organization's VigiBase, the global adverse event reporting database. RESULTS: No significant differences were observed in heart failure hospitalizations, liver dysfunction, or infusion reaction rates in both the Medical Data Vision Co., Ltd. database and the World Health Organization's VigiBase. In the Medical Data Vision Co., Ltd. database, the addition of pertuzumab did not significantly influence the incidence of adverse events, and the use of biosimilars significantly reduced medical costs, with no significant difference in breast cancer recurrence rates. CONCLUSIONS: By analyzing two large and diverse datasets from multiple perspectives, we obtained reliable results that the trastuzumab originator and its biosimilars have similar safety profiles. The concurrent use of pertuzumab was also found to be safe. The use of biosimilars can lead to cost savings. These findings provide crucial insights for the evaluation and adoption of biosimilars in clinical practice.