By Paolo Tarantino, MD
Dana-Farber Cancer Institute/Harvard Medical School
“Overall, a major shift in the way we treat breast cancer has occurred in 2022, with the demonstration that patients with tumors that do not overexpress HER2 can still derive meaningful survival advantages from HER2-targeted ADCs.” – Dr. Paolo Tarantino, Dana Farber Cancer Institute.
Breast tumors that exhibit overexpression and/or amplification of HER2 (HER2-positive tumors) were identified about 30 years ago as particularly aggressive entities, with a higher risk of recurrence and progression compared to HER2-negative tumors. To better treat these tumors, which account for about 20% of all breast cancers, a large array of anti-HER2 treatments have been developed, with eight anti-HER2 agents currently approved by the Food and Drug Administration, which have significantly improved the way we treat this subtype. Today, most patients with early-stage HER2-positive breast cancer can be cured by chemotherapy and anti-HER2 agents, and great strides have also been achieved in the metastatic setting thanks to HER2-targeted agents. However, no benefit with HER2-targeted agents has ever been demonstrated for the large majority of patients (about 80%) whose breast cancer is considered HER2-negative.
Nonetheless, despite being defined as HER2-negative, some of these tumors still express a significant amount of HER2 protein on the tumor cells, in the absence of HER2 gene amplification. These tumors, recognized by an immunohistochemical (protein) expression of 1+ or 2+/non-amplified, have been recently denominated HER2-low and were demonstrated to account for approximately half of all breast cancer diagnoses. The presence of HER2-low expression in these tumors provided the rationale to test in this population a novel type of HER-targeted drugs, namely antibody-drug conjugates (ADCs), molecules able to selectively deliver highly potent chemotherapy toward HER2-expressing cells. One of these ADCs, trastuzumab deruxtecan (T-DXd), had already shown unprecedented activity in patients with HER2-positive breast cancer, and when it was tested in a small trial including 54 patients with HER2-low metastatic breast cancer, it demonstrated encouraging activity. However, before being implemented in clinical practice, these results needed to be confirmed in a randomized trial.
Confirmation arrived in 2022 when the randomized phase 3 DESTINY-Breast04 trial was presented at the Presidential Session of the ASCO Annual Meeting. In this study, which enrolled patients with HER2-low metastatic breast cancer who had experienced progression to endocrine treatment and chemotherapy, T-DXd demonstrated a tripling of response rate (50% vs. 16%) doubling of progression-free survival (ten vs. five months) and a significant improvement in overall survival (23.4 vs 16.8 months) compared to conventional chemotherapy. These impressive results were observed irrespective of age, hormone-receptor expression, or any other key patient or tumor-related variable. Moreover, T-DXd was demonstrated to improve quality of life compared to chemotherapy in this patient population, and no unexpected safety signals were observed with the drug. Based on this data, T-DXd was approved for the treatment of HER2-low breast cancer on August 5, 2022, and is now an available treatment option not only for the 20% of patients with HER2-positive tumors but also for the additional 50% of patients with HER2-low tumors, which includes patients with hormone-receptor positive tumors and patients with triple-negative tumors.
Many questions remain in the field, particularly regarding expanding the benefit of T-DXd to a larger population of patients. Indeed, about 30% of patients have HER2-0 tumors and do not currently qualify for treatment with T-DXd. Could these patients still benefit from T-DXd? The answer to this question may partially derive from the DESTINY-Breast06 phase 3 trial, an ongoing trial that is relatively similar to DESTINY-Breast04, but also includes certain HER2-0 patients. Results from this study are expected soon and may lead to further expansion in the access to T-DXd for patients with metastatic breast cancer. However, the most meaningful expansion of the benefit of T-DXd may potentially occur in the early, curable setting. Many patients with early-stage breast cancer are treated with chemotherapies such as anthracyclines and taxanes to reduce the risk of recurrence. Studies are currently ongoing to evaluate whether targeted delivery of chemotherapy may result in higher efficacy compared to traditional chemotherapies even in this early-stage setting, and hopefully prevent recurrences in a larger population of patients.
Overall, a major shift in the way we treat breast cancer has occurred in 2022, with the demonstration that patients with tumors that do not overexpress HER2 can still derive meaningful survival advantages from HER2-targeted ADCs. Several ongoing trials are expected to refine the way we use these drugs, hopefully expanding their benefit to a larger population of patients affected by breast cancer.
Modi S, Jacot W, Yamashita T, et al: Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. New England Journal of Medicine, 2022. DOI: 10.1056/NEJMoa2203690