Faculty Collaboration Database

Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer. Clin Cancer Res 2020 Nov 01;26(21):5668-5681

Date

08/23/2020

Pubmed ID

32826327

Pubmed Central ID

PMC7642197

DOI

10.1158/1078-0432.CCR-19-3685

Scopus ID

2-s2.0-85098286523 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

PURPOSE: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME).

EXPERIMENTAL DESIGN: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1-high (PD-1^HI) CD8⁺ peripheral T cells and examination of a cytolytic gene signature in whole blood.

RESULTS: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden.

CONCLUSIONS: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.

Author List

Axelrod ML, Nixon MJ, Gonzalez-Ericsson PI, Bergman RE, Pilkinton MA, McDonnell WJ, Sanchez V, Opalenik SR, Loi S, Zhou J, Mackay S, Rexer BN, Abramson VG, Jansen VM, Mallal S, Donaldson J, Tolaney SM, Krop IE, Garrido-Castro AC, Marotti JD, Shee K, Miller TW, Sanders ME, Mayer IA, Salgado R, Balko JM

Author

Todd W. Miller PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Albumins
Antineoplastic Combined Chemotherapy Protocols
B7-H1 Antigen
CD8-Positive T-Lymphocytes
Female
Gene Expression Regulation, Neoplastic
Humans
Lymphocytes, Tumor-Infiltrating
Middle Aged
Neoadjuvant Therapy
Neoplasm Proteins
Neoplasm Recurrence, Local
Paclitaxel
Prognosis
Programmed Cell Death 1 Receptor
Treatment Outcome
Triple Negative Breast Neoplasms
Tumor Microenvironment