Abstract
Simple SummaryIn this review, we summarize the recent outcomes from clinical trials with new agents for metastatic triple-negative breast cancer, specifically focusing on immunotherapies targeting the PD-1/PD-L1 pathway and antibody–drug conjugates. In addition to the clinical data supporting these therapies, we review the impact of the tumor microenvironment on the effectiveness of these therapies. The heterogenous nature of triple-negative breast cancer (TNBC) is an underlying factor in therapy resistance, metastasis, and overall poor patient outcome. The lack of hormone and growth factor receptors lends to the use of chemotherapy as the first-line treatment for TNBC. However, the failure of chemotherapy demonstrates the need to develop novel immunotherapies, antibody–drug conjugates (ADCs), and other tumor- and stromal-targeted therapeutics for TNBC patients. The potential for stromal-targeted therapy is driven by studies indicating that the interactions between tumor cells and the stromal extracellular matrix (ECM) activate mechanisms of therapy resistance. Here, we will review recent outcomes from clinical trials targeting metastatic TNBC with immunotherapies aimed at programed death ligand–receptor interactions, and ADCs specifically linked to trophoblast cell surface antigen 2 (Trop-2). We will discuss how biophysical and biochemical cues from the ECM regulate the pathophysiology of tumor and stromal cells toward a pro-tumor immune environment, therapy resistance, and poor TNBC patient outcome. Moreover, we will highlight how ECM-mediated resistance is motivating the development of new stromal-targeted therapeutics with potential to improve therapy for this disease.
Highlights
Triple-negative breast cancer (TNBC) makes up approximately 15–20% of all breast cancers [1]
In November 2020, the FDA approved pembrolizumab to be used in combination with chemotherapy for patients with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 positive unresectable or metastatic triple-negative breast cancer (TNBC) based off the results of the KEYNOTE-355 trial
This study showed an improvement in 3 year invasive disease-free survival (DFS) (HR 0.48; 95% confidence interval (CI) 0.24–0.97), distant DFS (HR 0.31; 95% CI 0.13–0.74) and overall survival (OS) (HR 0.24; 95% CI 0.08–0.72)
Summary
Triple-negative breast cancer (TNBC) makes up approximately 15–20% of all breast cancers [1]. It is well appreciated that the alterations in collagen fiber architecture that accompany tumor progression (tumor-associated collagen signatures, TACS) are prognostic of poor patient outcome across all subtypes of breast cancer, including TNBC [16,20,22] These alterations in fibrotic ECM direct cell behavior toward tumor progression [9,23,24], result in the exclusion of immune cell infiltration, promote immunosuppression and resistance to immune checkpoint inhibitor (ICI) therapy [25–27], and contribute to the limited distribution of chemotherapeutics that can cause clinical resistance [28]. The fibrotic ECM and immunosuppressive cues that drive breast cancer metastasis and therapy resistance have been identified in primary breast tumors, but they occur at distal sights to regulate metastatic growth [26] Based on this understanding of the ECM, there is mounting interest in developing therapies that target the stromal matrix [46–48]. We will highlight promising novel approaches to target the stroma in combination with immune modulation therapy or as direct molecular targets of ADC therapies
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