No abstract

The development of anti-HER2 agents has been one of the most meaningful advancements in the management of metastatic breast cancer, significantly improving survival outcomes. Despite the efficacy of anti-HER2 monoclonal antibodies, concurrent chemotherapy is still needed to maximize response. Antibody-drug conjugates (ADCs) are a class of therapeutics that combines an antigen-specific antibody backbone with a potent cytotoxic payload, resulting in an improved therapeutic index. Two anti-HER2 ADCs have been approved by the FDA with different indications in HER2-positive breast cancer. Ado-trastuzumab emtansine (T-DM1) was the first-in-class HER2-targeting ADC, initially approved in 2013 for metastatic patients who previously received trastuzumab and a taxane, and the label was expanded in 2019 to include adjuvant treatment of high-risk patients with residual disease after neoadjuvant taxane and trastuzumab-based therapy. In 2020, trastuzumab deruxtecan (T-DXd) was the second approved ADC for patients who had received at least 2 lines of anti-HER2-based therapy in the metastatic setting. The success of these two agents has transformed the treatment of HER2-positive breast cancer and has re-energized the field of ADC development. Given their advanced pharmaceutical properties, next-generation HER2-targeted ADCs have the potential to be active beyond traditional HER2-positive breast cancer and may be effective in cells with low expression of HER2 or ERBB2 mutations, opening a spectrum of new possible clinical applications. Ongoing challenges include improving target-specificity, optimizing the toxicity profile, and identifying biomarkers for patient selection. The aim of this review is to summarize the principal molecular, clinical, and safety characteristics of approved and experimental anti-HER2 ADCs, contextualizing the current and future landscape of drug development.

Purpose: While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1amplified (FGFR1 þ ) metastatic breast cancer (MBC) remains undefined.Experimental Design: We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor-positive (HR þ )/HER2 À MBC and validated the functional role of FGFR1-amplification in mediating response/resistance to hormone therapy in vitro.Results: In the clinical cohort (N ¼ 110), we identified that patients with FGFR1 þ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; P ¼ 0.005), coexisting TP53 mutations (41% vs. 21%; P ¼ 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1 þ HR þ /HER2 À MBC. In preclinical models, estrogen receptor-positive (ER þ )/FGFR1-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER þ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition.Conclusions: Collectively, these findings suggest that while FGFR1 amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER þ /FGFR1 þ MBC.