Understanding resistance to immune checkpoint inhibitors in advanced breast cancer

ABSTRACT

Introduction

The addition of immune checkpoint inhibitors (ICIs) to frontline chemotherapy has improved survival for patients with advanced triple-negative breast cancer (TNBC) expressing programmed death-ligand 1 (PD-L1). Nonetheless, most patients develop resistance, with outcomes remaining poor for this population. Moreover, unsatisfactory activity has been observed with ICIs in PD-L1-negative TNBC and in other breast cancer (BC) subtypes, warranting a deeper understanding of resistance to ICIs in BC.

Areas covered

We discuss the immune landscape of distinct BC subtypes, review the clinical activity of immunotherapy in BC, and highlight strategies under development to overcome resistance to ICIs.

Expert opinion

Activity and resistance to ICIs in BC are strongly related to the intrinsic immunophenotype of the tumor tissue. Several promising biomarkers reflecting the immunological state of BC are emerging, with only PD-L1 expression currently adopted into clinical practice. However, limitations make of PD-L1 a sub-optimal biomarker for patient selection, which require efforts to integrate this marker with other immunological features. Concomitantly, a wide variety of drug combinations designed to overcome immune-resistance are being evaluated, with some encouraging signals observed in early-phase trials. Combination strategies tailored to patient and tumor immunophenotype may allow to overcome resistance and fully exploit the potential of ICIs.

KEYWORDS:

• Biomarkers
• breast cancer
• immunogram
• immunotherapy
• resistance

Article highlights

• The addition of immune checkpoint inhibitors (ICIs) to chemotherapy improves clinical outcomes for both early and advanced triple-negative breast cancer (TNBC).

• Pharmacological strategies are being developed to overcome resistance to ICIs and ultimately, maximize their benefit.

• Identifying appropriate tailored ICI combination treatment strategies that overcome resistance in TNBC may enable expansion of the treatment benefits to other breast cancer subtypes that are inherently unresponsive to ICI.

• The emergence of multiple promising biomarkers of immune-response may allow to refine patient selection for immunotherapy in breast cancer.

Acknowledgments

The authors wish to thank Kate Bifolck, BA, and Valerie Hope Goldstein for their editorial and submission assistance (Editors, Dana-Farber Cancer Institute).

Declaration of interest

P Tarantino served as advisor/consultant for AstraZeneca. R Barroso-Sousa reports receiving fees from AstraZeneca, Eli Lilly, Libbs, Merck, Roche, Zodiac, Bard Access, BMS, Novartis, Pfizer and Daichi Sankyo. E Mittendorf served as advisor/consultant for: Bristol Myers Squib, Exact Sciences (formerly Genomic Health), Genentech/Roche, Lily and Merck. G Curigliano received honoraria for speaker, consultancy or advisory role from AstraZeneca, Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipses Pharma, Foundation Medicine, Daiichi Sankyo and Samsung. SM Tolaney has served as an advisor/consultant to Novartis, Eli Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech, Immunomedics, Nektar, Tesaro, Daiichi Sankyo, Athenex, Bristol Meyers Squibb, and Nanostring. JL Guerriero is a consultant for GlaxoSmithKline, Codagenix, Verseau, Kymera and Array BioPharma and receives sponsored research support from GSK, Array BioPharma and Eli Lilly.

Reviewer disclosures

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

Additional information

Funding

This work was supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship.