PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer

Abstract

Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking the programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity and may lead to durable long-term disease control, especially in the triple-negative subtypes of breast cancer (TNBC). Although immune checkpoint blockade is generally well tolerated, specific immune-related adverse events (irAEs) may occur. This review summarizes the clinical efficacy, perspectives, and future challenges of using PD-1/PD-L1-directed antibodies in the treatment of breast cancer.

Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers

“…Authors further analyzed large corporate safety database of Bristol-Meyers Squibb and concluded that patients treated with combination of nivolumab and ipilimumab are more vulnerable to adverse cardiac events compared to nivolumab alone (0.27% vs. 0.06%; P < 0.001), but condition remains rare in both regimen affecting only less than 1% of the patients [28,29]. Currently, many clinical trials are ongoing for the treatment of breast and gynecologic malignancies using immune-checkpoint antibodies alone and in combination with trastuzumab and anthracycline-based regimens [33]. Initial safety data from Phase IB of PANACEA trial evaluating efficacy of trastuzumab and pembrolizumab combination in PD-L1 positive patients were presented at 2017 San Antonio Breast Cancer Symposium, which did not observe any cardiac events in patients; however, 19% of the patients in this study developed immune-related adverse event [34].…”

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

“…Anti-PD-1/PD-L1 therapy is a novel immune-checkpoint inhibition therapy and anti-PD-1/PD-L1 agents, such as nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab have been widely applied to treat various types of cancer (128-130). Anti-PD-1/PD-L1 agents have shown antitumor activity in BC, especially in the triple-negative subtypes of breast cancer (TNBC) (131,132). But PD-L1 expression is associated with HER2 + status and there is an independent poor prognostic impact of PD-L1 in HER2 + BCs (132)(133)(134).…”

“…In a phase 1b trial which 168 patients with MBC received avelumab, avelumab showed an acceptable clinical activity (135). Currently, many clinical trials in HER2 + cohort are ongoing, such as NCT02648477 and NCT02129556 for pembrolizumab, NCT02605915 for atezolizumab and NCT02649686 for durvalumab (131). Anti-PD-1/PD-L1 agents will benefit the patients with HER2…”

Fighting tubulin-targeting anticancer drug toxicity and resistance

“…The lack of known specific molecular targets has led to extensive research to find possible vulnerabilities in TNBC. The biologic drugs already evaluated or under active research and that have shown antitumor activity in TNBC include angiogenesis inhibitors, PARP1 inhibitors, immune checkpoint inhibitors and AR antagonists, the latter used for the specific treatment of the luminal androgen receptor TNBC subtype that expresses high levels of AR (Lehmann et al 2015, Cerrato et al 2016, Hartkopf et al 2016. As a different approach, chemically modified taxanes have been, and are still, extensively being tested in clinical trials, alone or in combination with other chemotherapeutics.…”