“Trop-2 is a novel therapeutic target, suitable for antibody-drug conjugate development.”

— Francisco J. Esteva, MD, PhD

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IN A SINGLE-ARM multicenter trial reported by Bardia and colleagues¹ and reviewed in this issue of The ASCO Post, the use of sacituzumab govitecan (IMMU-132) showed a response rate of 30% and a clinical benefit rate of 46% in heavily pretreated patients with metastatic triple-negative breast cancer. The median progression-free survival was 6 months, and the median overall survival was 16 months. These data are promising because objective responses and prolonged disease stabilization are infrequent in patients with refractory or relapsed metastatic triple-negative breast cancer. 

Different Molecular Subtypes 

ADVANCED TRIPLE-NEGATIVE breast cancers are highly aggressive tumors that progress through conventional cytotoxic chemotherapies, used either in combination or sequentially as single agents. Triple-negative breast cancer is a heterogeneous disease that includes a diversity of tumors driven by different molecular pathways or genetic alterations. 

Approximately 15% of triple-negative breast cancers carry BRCA mutations, which make them more sensitive to platinum salts and potentially poly (ADP-ribose) polymerase (PARP) inhibitors. The majority of triple-negative breast cancers harbor p53 mutations, which are not “druggable” with available technology. Microarray studies identified six different molecular subtypes within the triple-negative breast cancer group. A subset of patients with triple-negative breast cancer respond to PD-1/PD-L1 checkpoint blockade, which remains an area of active investigation. 

Novel Therapeutic Target 

TROP-2 is a glycoprotein that is overexpressed in triple-negative breast cancer and other epithelial malignancies. Trop-2 overexpression correlates with a poor prognosis in breast cancer and other solid tumors. The study by Bardia and colleagues showed that Trop-2 is a novel therapeutic target, suitable for antibody-drug conjugate development. Sacituzumab govitecan is an antibody directed against Trop-2 bound to SN-38, a potent chemotherapeutic drug. 

Developing targeted chemotherapy using an antibody-drug conjugate approach in triple-negative breast cancer is a step in the right direction. If larger studies confirm the efficacy and safety reported in this early-phase trial, sacituzumab govitecan would represent a major improvement in the treatment of advanced triple-negative breast cancer. Furthermore, this study reflects the importance of target validation and rational drug development, especially in a subtype of breast cancer characterized by a lack of validated therapeutic targets. 

DISCLOSURE: Dr. Esteva reported no conflicts of interest. 

REFERENCE 

1. Bardia A, et al: Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 35:2141-2148, 2017.