A New Avenue in Breast Cancer Therapeutics Following DESTINY-04

This Breast Cancer Awareness Month blog was authored by Dr. Elizabeth Lamont, MD, MS, Senior Medical Director at Medidata AI. Dr. Elizabeth Lamont is a medical oncologist and physician scientist with 20+ years of experience caring for patients with cancer and analyzing clinical trials and population-level data to inform cancer care and healthcare policy.

Until recently, a key factor in determining treatment and expected prognosis of patients with breast cancer was the amount of a protein called human epidermal growth factor receptor 2 (HER2) on their tumor cells’ surface. Previously, patients were characterized dichotomously as either “HER2 positive” or “HER2 negative”. Patients who were HER2 positive were potentially candidates for therapies which interrupt the protein’s function, leading to cancer cell death. But recent research suggests the HER2 story may be more nuanced, as some HER2 negative patients may in fact benefit from a HER2-directed therapy. A new classification has resulted to acknowledge the therapeutic nuance: HER2 moderate, HER2 low, and HER2 zero. 

Specifically, results of the recent DESTINY-04 clinical trial has shown that even patients with low amounts of the HER2 protein on their tumor cells appear to benefit from treatment with the HER2-directed antibody drug conjugate (ADC) trastuzumab deruxtecan (TDxd) in the metastatic setting. These results are great news for the approximately one third of breast cancer patients whose tumors are HER2 low. DESTINY-04 showed that T-Dxd extended survival time compared to established treatment for patients with HER2 low metastatic breast cancer. That is, the HER2 low patients randomized to T-Dxd lived substantially longer than patients randomized to standard of care (SOC) therapy: 23.4 months vs. 16.8 months respectively. These exciting results suggest that unlike some prior studies, patients with even low amounts of HER2 protein expression may benefit from some HER2 targeted therapies. 

These promising results are very important for current and future patients. For example, current patients with metastatic breast cancer who are HER2 low may benefit immediately from this new life-prolonging therapy. Anecdotally, oncologists have already started acting on these results and have recounted stories of exciting tumor regression in patients who were extremely ill with what was previously regarded as treatment-resistant breast cancer. 

But, even beyond the thrilling, immediate importance to current patient care, the study results at least raise the possibility of increased rates of breast cancer cure. That is, therapies that work well in advanced incurable settings (i.e., metastatic) are often studied in curative-intent settings (i.e., neoadjuvant and/or adjuvant). We look forward to learning if T-Dxd has similar life-prolonging effects in patients with HER2 low breast cancer who are being treated for cure. If so, more patients may be cured or experience slower disease progression. 

Even more broadly, the important nuance from DESTINY-04 that HER2 low patients may benefit from HER2 directed therapies identifies a possible new therapeutic avenue to pursue to help such patients. Specifically, it seems natural to study many of the multiple established and investigational HER2 targeted therapies including other ADCs, monoclonal antibodies, bispecific antibodies, tyrosine kinase inhibitors, trispecific T-cell engagers, and tumor vaccines in HER2 low patients. Because prior research has shown that some HER2 directed therapies do not arrest disease in HER2 low patients, it is not yet clear if other existing therapies or those in development will be beneficial. But what is clear is that the DESTINY-04 findings represent hope for both current and future breast cancer patients.

¹ Zhang, H., Katerji, H., Turner, B.M. et al. HER2-low breast cancers: incidence, HER2 staining patterns, clinicopathologic features, MammaPrint and BluePrint genomic profiles. Mod Pathol 35, 2022; 1075–1082. https://doi.org/10.1038/s41379-022-01019-5.

² Modi S et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. New England Journal of Medicine, 2022; 387:9-20.