Targeted Therapeutic Options and Future Perspectives for HER2-Positive Breast Cancer

Abstract

Despite the improvement achieved by the introduction of HER2-targeted therapy, up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown a significant improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). In ER+ HER2+ patients, target therapies such as phosphoinositide-3-kinase (PI3K) pathway inhibition or cyclin-dependent kinases 4/6 blocking may be effective in controlling downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies. Multiple trials have explored these strategies with some promising results, and probably, in the next years conclusive results will succeed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents such as HER-2 therapy plus checkpoint inhibitors, or new vaccines approaches have been investigated in this setting, with promising but controversial results obtained to date.

Identification of glycogene signature as a tool to predict the clinical outcome and immunotherapy response in breast cancer

“…In the past decades, great advances have been made in the targeted therapy, especially in breast cancer and lung cancer. Trastuzumab, pertuzumab, small molecular tyrosine kinase inhibitor (TKI) and antibody-drug conjugate (ADC) have significantly improved the survival of HER-positive breast cancer patients ( 42 , 43 ). Also, cancer immunotherapy has made rapid development.…”

Microtubule‐associated proteins and enzymes modifying tubulin

“…Conjugating drugs to antibodies is another strategy to deliver drugs that target cells. For example, trastuzumab emtansine consists of the HER2‐targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine (Ferrando‐Diez, Felip, Pous, Bergamino Sirven, & Margeli, 2022; Matikonda, McLaughlin, Shrestha, Lipshultz, & Schnermann, 2022).…”

Dynamic ultrasound molecular‐targeted imaging of senescence in evaluation of lapatinib resistance in HER2‐positive breast cancer

“…Therefore, the anti‐tumor effect induced by cellular senescence has been listed as a cancer treatment strategy 9 . It has been shown that LAP induces reversible senescence in sensitive HER2+ cell lines 7,10 . However, senescent tumor cells are not permanently in a growth‐arrested state.…”