Trastuzumab Deruxtecan in HER2-Ultralow, Hormone Receptor-Positive Breast Cancer

An important study presented at the 2024 San Antonio Breast Cancer Symposium (SABCS) and published simultaneously on 14 December in The New England Journal of Medicine is opening the door to a new era in advanced breast cancer treatment.

Conducted by Dr. Aditya Bardia and his team, the study compared chemotherapy with the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) to assess its potential to improve progression-free survival. These findings could reshape current clinical practice in advanced breast cancer treatment.

The DESTINY-Breast06 Study

SABCS provides a global platform for sharing and discussing the latest advances in breast cancer. The study's lead investigator, Dr. Aditya Bardia, highlighted its importance, saying, “This year's presentations reflect our academic commitment to innovative research aimed at improving survival rates and quality of life in breast cancer treatment,” emphasizing the significance of the study.

Breast cancer is the most common cancer among women worldwide, underscoring the need to continually improve treatment options. Until now, trastuzumab deruxtecan has been used as a treatment with demonstrated efficacy only in HER2-positive or HER2-low tumors. It is now being investigated in hormone receptor (HR)-positive tumors and in patients with HER2-low or HER2-ultralow expression, but studies demonstrating efficacy in these settings are limited. The need for effective, tolerable later-line treatments in these groups makes this study particularly important.

Study Design and Methods

The phase III DESTINY-Breast06 study enrolled patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer whose disease had progressed after at least one endocrine therapy. A total of 866 patients were randomly assigned to two groups:

1. Trastuzumab Deruxtecan Group (T-DXd): This group received the antibody-drug conjugate T-DXd.
2. Chemotherapy Group: This group received standard chemotherapy selected by the physician.

Patients had not previously received chemotherapy and were enrolled because they did not respond to endocrine therapy. The study assessed T-DXd's effect on progression-free survival (PFS) and other treatment outcomes.

Results: A Marked Improvement in Progression-Free Survival

Of the patients, 713 had HER2-low and 153 had HER2-ultralow breast cancer.

The results showed that T-DXd markedly prolonged progression-free survival (PFS):

• T-DXd Group: Median progression-free survival was 13.2 months in this treatment group.
• Chemotherapy Group: Median progression-free survival was only 8.1 months in this treatment group.

This finding indicates that T-DXd reduced cancer progression by 38% compared with chemotherapy (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75; P<0.001).

T-DXd was also effective across all patient subgroups, particularly those with rapid progression after endocrine therapy (<6 months). This demonstrates the medicine's promise for a broad patient population.

Side Effects

In 52.8% of patients in the trastuzumab deruxtecan group and 44.4% in the chemotherapy group, grade 3 or higher adverse events were observed. Interstitial lung disease (ILD) or pneumonitis occurred in the trastuzumab deruxtecan group in 49 patients (11.3%). Of these events, 3 were grade 5 in severity. In contrast, in the chemotherapy group, only 1 patient (0.2%) had grade 2 pneumonitis reported.

A New Era in Treating HER2-Low Tumors

Previously, T-DXd had been approved only for later-line use in patients with HER2-low tumors. By showing that T-DXd could replace chemotherapy after resistance to hormonal therapy in hormone receptor-positive patients, this study presents findings that could fundamentally change treatment approaches.

Patients who were completely HER2-negative (IHC 0) were not included. Further studies are therefore needed to assess efficacy in completely HER2-negative patient groups.

Potential Impact on Clinical Practice

These findings could lead to important changes in advanced breast cancer treatment:

1. Potential to Replace Chemotherapy: Using T-DXd instead of chemotherapy in earlier treatment lines could improve patient responses and quality of life.
2. Efficacy in a Broad Patient Population: Effective across all subgroups, including patients with rapid progression, T-DXd offers hope to more patients.

Conclusion: A New Era in Advanced Breast Cancer Treatment

Trastuzumab deruxtecan could fundamentally change current approaches by offering a more effective, tolerable, patient-centered option for advanced breast cancer. The results represent a promising innovation that could improve not only survival but also quality of life.

Although more extensive studies and long-term follow-up are needed for full integration into clinical practice, these T-DXd results can be considered an important step toward establishing a new standard in advanced breast cancer treatment.