Breast cancer is the most common cancer and one of the leading causes of cancer-related deaths worldwide. In 2020, more than 2 million cases of breast cancer were diagnosed worldwide, resulting in nearly 685,000 deaths.
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of a variety of tumors, including breast, gastric, lung, and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumors.
HER2 expression is currently defined as positive or negative, as determined by testing the amount of HER2 protein in cancer cells by IHC, and/or by counting the number of copies of the HER2 gene in cancer cells by ISH testing. HER2-positive cancers are defined as IHC3+ or IHC2+/ISH+, and HER2-negative cancers are currently defined as IHC0, IHC1+, or IHC2+/ISH-.
About half of breast cancer patients have tumors with a HER2 IHC score of 1+, or 2+ and a negative ISH test result, a level of HER2 expression currently unsuitable for HER2-targeted therapy. Low HER2 expression occurred in both HR-positive and HR-negative disease.
HER2 testing is often used to determine appropriate treatment options for patients with metastatic breast cancer, and targeting low HER2 expression is expected to provide another approach to slowing disease progression and prolonging survival in patients with metastatic breast cancer. Currently, patients with HR-positive, HER2-low-expressing tumors have limited treatment options after progression on endocrine (hormonal) therapy. Few targeted therapies are available for patients with HR-negative tumors.
The DESTINY-Breast04 study is the first randomized phase III clinical trial in patients with metastatic breast cancer with low HER2 expression. Patients with low HER2 expression, unresectable, and/or metastatic breast cancer were included, who had previously received 1-2 lines of chemotherapy in the metastatic state; HR+ patients were endocrine refractory patients, who were randomized 2:1 and divided into T- The DXd group and the physician’s choice of treatment (TPC) group. The primary endpoint was PFS (HR+) in BICR (Blinded Independent Central Review); secondary endpoints included: PFS in BICR (all patients), OS (HR+ patients, all patients).
The primary endpoint of DESTINY-Breast04 was PFS in HR-positive patients based on a blinded independent central review (BICR). Key secondary endpoints included BICR-based PFS in all randomized patients (regardless of HR status), OS in HR-positive patients, and OS in all randomized patients (regardless of HR status). Other secondary endpoints included investigator-assessed PFS, BICR- and investigator-assessed duration of response, and safety.
DESTINY-Breast04 enrolled approximately 557 patients across multiple centers in Asia, Europe and North America.
Based on the results of the DESTINY-Breast04 trial, T-DXd was granted Breakthrough Therapy Designation in the United States for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH negative) breast cancer who Received one systemic therapy in the metastatic phase or relapsed during or within six months of completion of adjuvant chemotherapy. Patients with hormone receptor (HR)-positive breast cancer should also have received or be ineligible for endocrine therapy.
With the approval of T-DXd (a HER2-targeting ADC) for previously treated patients with HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are jointly exploring the drug’s use in earlier-line patients and its use in Possibility of new breast cancer subtypes.