Multi-platform biomarkers of response to an immune checkpoint inhibitor in the neoadjuvant I-SPY 2 trial for early-stage breast cancer

Michael J Campbell; Denise M Wolf; Christina Yau; Lamorna Brown-Swigart; Julie Wulfkuhle; Isela R Gallagher; Zelos Zhu; Jennifer Bolen; Scott Vandenberg; Clifford Hoyt; Hidetoshi Mori; Alexander Borowsky; Laura Sit; Jane Perlmutter; Smita M Asare; I-SPY2 Investigators; Rita Nanda; Minetta C Liu; Douglas Yee; Angela M DeMichele; Nola M Hylton; Lajos Pusztai; Donald A Berry; Gillian L Hirst; Emanuel F Petricoin; Laura Van't Veer; Laura Esserman

doi:10.1016/j.xcrm.2024.101799

Multi-platform biomarkers of response to an immune checkpoint inhibitor in the neoadjuvant I-SPY 2 trial for early-stage breast cancer

Cell Rep Med. 2024 Nov 19;5(11):101799. doi: 10.1016/j.xcrm.2024.101799. Epub 2024 Nov 6.

Authors

Michael J Campbell¹, Denise M Wolf², Christina Yau³, Lamorna Brown-Swigart², Julie Wulfkuhle⁴, Isela R Gallagher⁴, Zelos Zhu³, Jennifer Bolen⁵, Scott Vandenberg⁶, Clifford Hoyt⁷, Hidetoshi Mori⁸, Alexander Borowsky⁹, Laura Sit³, Jane Perlmutter¹⁰, Smita M Asare¹¹; I-SPY2 Investigators; Rita Nanda¹², Minetta C Liu¹³, Douglas Yee¹⁴, Angela M DeMichele¹⁵, Nola M Hylton¹⁶, Lajos Pusztai¹⁷, Donald A Berry¹⁸, Gillian L Hirst³, Emanuel F Petricoin⁴, Laura Van't Veer², Laura Esserman³

Affiliations

¹ Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
² Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
⁵ Biospecimen Resource Program (BIOS), University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Akoya Biosciences, Marlborough, MA 01752, USA.
⁸ Center for Immunology and Infectious Diseases, University of California, Davis, Davis, CA 95616, USA.
⁹ Center for Immunology and Infectious Diseases, University of California, Davis, Davis, CA 95616, USA; Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA.
¹⁰ Gemini Group, Ann Arbor, MI 48107, USA.
¹¹ Quantum Leap Healthcare Collaborative, San Francisco, CA 94118, USA.
¹² Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
¹³ Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.
¹⁴ Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁵ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁶ Department of Radiology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁷ Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
¹⁸ Berry Consultants, LLC, Austin, TX 78746, USA.

Abstract

Only a subset of patients with breast cancer responds to immune checkpoint blockade (ICB). To better understand the underlying mechanisms, we analyze pretreatment biopsies from patients in the I-SPY 2 trial who receive neoadjuvant ICB using multiple platforms to profile the tumor microenvironment. A variety of immune cell populations and markers of immune/cytokine signaling associate with pathologic complete response (pCR). Interestingly, these differ by breast cancer receptor subtype. Measures of the spatial distributions of immune cells within the tumor microenvironment, in particular colocalization or close spatial proximity of PD-1⁺ T cells with PD-L1⁺ cells (immune and tumor cells), are significantly associated with response in the overall cohort as well as the in the triple negative (TN) and HR⁺HER2^- subtypes. Our findings indicate that biomarkers associated with immune cell signaling, immune cell densities, and spatial metrics are predictive of neoadjuvant ICB efficacy in breast cancer.

Keywords: breast cancer; immune checkpoint blockade; multiplex immunofluorescence; predictive markers; spatial metrics.

MeSH terms

B7-H1 Antigen / antagonists & inhibitors
B7-H1 Antigen / metabolism
Biomarkers, Tumor* / metabolism
Breast Neoplasms* / drug therapy
Breast Neoplasms* / immunology
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Female
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Middle Aged
Neoadjuvant Therapy* / methods
Neoplasm Staging
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / metabolism
Treatment Outcome
Tumor Microenvironment* / drug effects
Tumor Microenvironment* / immunology

Substances

Immune Checkpoint Inhibitors
Biomarkers, Tumor
B7-H1 Antigen
Programmed Cell Death 1 Receptor