Immune checkpoint inhibition in early-stage triple-negative breast cancer

ABSTRACT

Introduction

Breast cancer cells can evade immune recognition by upregulating programmed death-ligand 1 (PD-L1) leading to decreased T cell function. Anti-PD-1 agents, like pembrolizumab, and anti-PD-L1 agents, such as atezolizumab and durvalumab, in combination with chemotherapy were found to have efficacy in metastatic triple-negative breast cancer (TNBC). With sub-optimal long-term outcomes in early-stage TNBC, this combination of immune checkpoint inhibition with chemotherapy was subsequently investigated. A robust immune microenvironment and extensive tumor antigen exposure in early-stage breast cancer is believed to facilitate response to checkpoint inhibitors.

Areas covered

This review focuses on studies that assess the role of neoadjuvant immune checkpoint inhibition along with chemotherapy. The results of key phase I, II and III trials using checkpoint inhibitors in early-stage breast cancer (ESBC) are reviewed along with foundational data from metastatic TNBC, including the role of biomarkers in predicting response to immunotherapy.

Expert opinion

Despite a clear role for neoadjuvant immune checkpoint inhibition in TNBC, many questions remain. The benefit of these agents in the neoadjuvant versus adjuvant setting is unclear and immune-related toxicity is a major concern. Additional studies are needed to elucidate which immune checkpoint inhibitor is most efficacious and best tolerated in early-stage TNBC.

KEYWORDS:

• Immune checkpoint inhibitors
• early-stage breast cancer
• immunotherapy
• pCR
• PD-L1
• pembrolizumab
• triple-negative breast cancer (TNBC)

Article highlights

• Cancer cells in breast tumors cause local immune suppression by upregulation of PD-L1 ligands on the surface.

• PD-L1/PD1 inhibitors overcome this immune blockade, thereby potentiating immune-mediated killing of cancer cells.

• The most studied agents include pembrolizumab, atezolizumab and durvalumab. KEYNOTE-522, I-SPY 2, IMpassion031 and GeparNuevo are key trials that have focused on anti-PD-L1 agents in ESBC.

• Improved pCR rates are achieved with a combination of immunotherapy and chemotherapy in comparison to chemotherapy alone in TNBC and HER2+ breast cancers.

• Pembrolizumab is the only FDA approved checkpoint inhibitor for early-stage TNBC. Research using other agents is still ongoing.

• pCR rates have a positive correlation with higher tumor mutational burden (TMB), stromal tumor-infiltrating lymphocytes (sTIL) levels and PD-L1 positive status.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by Cleveland Clinic.