Targeted Therapies in HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) has transformed from a prognostic biomarker into a pivotal therapeutic target in approximately 20 % of breast cancers. The monoclonal antibody trastuzumab inaugurated this era by binding HER2 and engaging immune-mediated cytotoxicity, and subsequent agents such as pertuzumab and small-molecule inhibitors (lapatinib, neratinib and pyrotinib) have extended progression-free survival through complementary mechanisms. More recently, antibody–drug conjugates (ADCs) have combined precise HER2 recognition with potent cytotoxic payloads, exemplified by trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), yielding significant improvements in response rates across early-stage and metastatic settings. Despite these advances, acquired resistance—driven by receptor downregulation, altered intracellular trafficking, signal bypass through parallel pathways and tumour heterogeneity—remains a major obstacle. Current research therefore focuses on optimising combination regimens, refining ADC design and identifying predictive biomarkers to guide patient selection, with the overarching goal of converting HER2-positive breast cancer into a chronically manageable condition.

Research from Nature Portfolio

Recent studies have illuminated both the successes and limitations of next-generation ADCs. In a phase 2 trial of trastuzumab deruxtecan in metastatic disease, high objective response rates were observed not only in classic HER2-overexpressing tumours but also in those with low or even undetectable HER2 by standard immunohistochemistry. Detailed correlative analyses revealed a strong association between tumour uptake of the conjugate and HER2 staining intensity, yet responses in low-expressing cohorts point to additional mechanisms such as bystander killing and differential payload release. Serial tumour biopsies have begun to characterise emerging resistance phenotypes, including upregulation of drug-efflux transporters and alterations in lysosomal function, thereby providing a roadmap for future combination strategies to forestall treatment failure.

Targeted Therapies in HER2-Positive Breast Cancer publication trend

The graph below shows the total number of articles in targeted therapies in her2-positive breast cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Human epidermal growth factor receptor 2 (HER2): A transmembrane tyrosine kinase receptor overexpressed in approximately 20 % of breast cancers, driving tumour proliferation and survival.

Antibody–drug conjugate (ADC): A targeted therapeutic format that links a monoclonal antibody to a cytotoxic agent via a chemical linker, enabling selective delivery of chemotherapy to antigen-expressing cancer cells.

Trastuzumab deruxtecan (T-DXd): A HER2-directed ADC comprising a humanised anti-HER2 antibody conjugated to a topoisomerase I inhibitor, designed for potent bystander killing of HER2-expressing tumours.

Pyrotinib: An oral, irreversible tyrosine kinase inhibitor that targets HER2 and other ErbB family receptors, used to treat HER2-positive breast cancer.

Autophagy: A lysosome-mediated cellular process of self-digestion that can be harnessed therapeutically to induce cancer cell death under stress conditions.

References

1. Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer. Signal Transduction and Targeted Therapy (2023).
2. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nature Medicine (2023).
3. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduction and Targeted Therapy (2022).
4. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Research (2014).