Progress in immune checkpoint inhibition in early-stage triple-negative breast cancer

ABSTRACT

Introduction

Immune checkpoint inhibitors have been particularly effective in treating cancers with robust immune microenvironments and have been successfully incorporated into the management of metastatic ER-negative and HER2-negative breast cancer. This has prompted investigation of immunotherapy in early-stage triple negative breast cancer (TNBC) to address the suboptimal clinical outcomes and limited therapeutic options.

Areas covered

This review highlights the studies examining the use of neoadjuvant immunotherapy with standard chemotherapy in the management of early-stage TNBC and explores ongoing areas of study including the role of adjuvant checkpoint inhibition and novel combination therapies with immunotherapy.

Expert opinion

The current standard of care for early-stage ER-negative, HER2-negative breast cancer measuring ≥2 cm or with lymph node involvement is neoadjuvant chemotherapy with pembrolizumab followed by ongoing pembrolizumab in the adjuvant setting to complete 1 year of total therapy as per the KEYNOTE-522 study. This approach is associated with improved pathologic complete response (pCR) rate and event free survival, irrespective of PD-L1 status. Many questions remain regarding the optimization of chemotherapy partner(s) for immunotherapy, necessity of adjuvant immunotherapy for patients who achieve pCR, inclusion of other therapies in the adjuvant setting (particularly capecitabine or olaparib), and use of adjuvant immunotherapy when it was not received in the neoadjuvant setting.

KEYWORDS:

• Triple negative breast cancer
• early-stage breast cancer
• immunotherapy
• immune checkpoint inhibitors
• PD-L1/PD1 inhibitors
• CTLA-4 inhibitors

Article highlights

• Breast cancer cells can exploit the immune checkpoint pathway by overexpressing PD-L1 which bind to programmed cell death protein 1 (PD-1) on T cells and reduce their activity.

• Immune checkpoint inhibitors counteract tumor cell evasion of the immune system by enhancing T cell-mediated immune response.

• Pembrolizumab remains the only FDA approved checkpoint inhibitor for early-stage TNBC based on findings from KEYNOTE-522. Studies assessing other agents including atezolizumab, durvalumab, and CTLA-4 inhibitors are ongoing.

• The benefit of adjuvant immunotherapy, in the absence of neoadjuvant use, for early stage TNBC has not been established and its use in this situation remains restricted to clinical trials.

• Immune-related adverse events (irAEs) such as thyroid disorders and adrenal insufficiency necessitate mindful patient selection and diligent monitoring when ICI (immune checkpoint inhibitors) are used.

• Biomarkers predictive of treatment response remain elusive and are needed to individualize treatment approach

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

A reviewer on this paper has served as a medical consultant for Synaptical Inc. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.