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Changes in Peripheral and Local Tumor Immunity After Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer Margaret L

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Changes in Peripheral and Local Tumor Immunity After Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer Margaret L Published OnlineFirst August 21, 2020; DOI: 10.1158/1078-0432.CCR-19-3685 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer Margaret L. Axelrod1, Mellissa J. Nixon1, Paula I. Gonzalez-Ericsson2, Riley E. Bergman1, Mark A. Pilkinton3, Wyatt J. McDonnell3, Violeta Sanchez1,2, Susan R. Opalenik1, Sherene Loi4, Jing Zhou5, Sean Mackay5, Brent N. Rexer1, Vandana G. Abramson1, Valerie M. Jansen1, Simon Mallal3, Joshua Donaldson1, Sara M. Tolaney6, Ian E. Krop6, Ana C. Garrido-Castro6, Jonathan D. Marotti7,8, Kevin Shee9, Todd. W. Miller8,9, Melinda E. Sanders2,10, Ingrid A. Mayer1,2, Roberto Salgado4,11, and Justin M. Balko1,2 ABSTRACT ◥ Purpose: The recent approval of anti-programmed death-ligand Results: In non-TNBC, no change in expression of any single 1 immunotherapy in combination with nab-paclitaxel for meta- gene was associated with RFS or OS, while in TNBC upregulation of static triple-negative breast cancer (TNBC) highlights the need to multiple immune-related genes and gene sets were associated with understand the role of chemotherapy in modulating the tumor improved long-term outcome. High cytotoxic T-cell signatures immune microenvironment (TIME). present in the peripheral blood of patients with breast cancer at Experimental Design: We examined immune-related gene surgery were associated with persistent disease and recurrence, expression patterns before and after neoadjuvant chemotherapy suggesting active antitumor immunity that may indicate ongoing (NAC) in a series of 83 breast tumors, including 44 TNBCs, from disease burden. patients with residual disease (RD). Changes in gene expression Conclusions: We have characterized the effects of NAC on the patterns in the TIME were tested for association with recurrence- TIME, finding that TNBC is uniquely sensitive to the immunologic free (RFS) and overall survival (OS). In addition, we sought to effects of NAC, and local increases in immune genes/sets are characterize the systemic effects of NAC through single-cell associated with improved outcomes. However, expression of cyto- analysis (RNAseq and cytokine secretion) of programmed toxic genes in the peripheral blood, as opposed to the TIME, may be þ death-1–high (PD-1HI)CD8 peripheral T cells and examination a minimally invasive biomarker of persistent micrometastatic dis- of a cytolytic gene signature in whole blood. ease ultimately leading to recurrence. Introduction was recently approved for the treatment of patients with metastatic triple-negative breast cancer (TNBC) based on results from a phase III Combination of conventional chemotherapy with an immunother- clinical trial (1). Furthermore, addition of the anti–programmed apeutic targeting programmed death-ligand 1 (PD-L1), atezolizumab, death-1 (PD-1) mAb pembrolizumab to neoadjuvant chemotherapy (NAC) can significantly improve TNBC pathologic complete response (pCR) rates (2). Thus, existing clinical data indicate that chemotherapy 1 Department of Medicine, Vanderbilt University Medical Center, Nashville, Ten- combinations with immunotherapy demonstrate enhanced efficacy 2 nessee. Breast Cancer Research Program, Vanderbilt University Medical Center, compared with chemotherapy alone. However, these results suggest a Nashville, Tennessee. 3Department of Infectious Disease, Vanderbilt University Medical Center, Nashville, Tennessee. 4Department of Oncology, University of growing need to better understand how chemotherapy modulates the Melbourne and Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. tumor immune microenvironment (TIME). 5IsoPlexis Corporation, Branford, Connecticut. 6Department of Medical Oncol- High levels of stromal tumor-infiltrating lymphocytes (sTIL) in the ogy, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Mas- pretreatment biopsy are predictive of pCR in patients with TNBC 7 sachusetts. Department of Pathology & Laboratory Medicine, Dartmouth- treated with NAC (3). In NAC-treated patients with TNBC with 8 Hitchcock Medical Center, Lebanon, New Hampshire. Norris Cotton Cancer residual disease (RD) at surgery or in untreated primary TNBC Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. 9Department of Molecular & Systems Biology, Geisel School of Medicine at tumors, higher sTILs in the resected tumor also confer improved – Dartmouth, Hanover, New Hampshire. 10Department of Pathology, Microbiology prognosis (4 7). However, the immunomodulatory effect of chemo- and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. therapy on sTILs in patients and how chemotherapy influences the 11Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium. TIME are poorly understood. In a study of patients with non–small cell Note: Supplementary data for this article are available at Clinical Cancer lung carcinoma, tumors treated with NAC had higher expression of þ Research Online (http://clincancerres.aacrjournals.org/). PD-L1 and higher density of CD3 T cells, suggesting NAC may be M.L. Axelrod and M.J. Nixon contributed equally to this article. immunomodulatory in some tumor types (8). In addition, in a small breast cancer study, post-NAC natural killer (NK) cells and IL6 Corresponding Author: Justin M. Balko, Vanderbilt University, 2200 Pierce expression were associated with better response. However, this study Avenue, 777 PRB, Nashville, TN 37232. Phone: 615-875-8666; Fax: 615-936- ¼ 1495; E-mail: [email protected] was limited by inclusion of only a small number of TNBCs (n 4; ref. 9). Intriguingly, a larger study of patients with breast cancer Clin Cancer Res 2020;XX:XX–XX (n ¼ 60) showed that pre-NAC sTILs and higher pre-NAC expression doi: 10.1158/1078-0432.CCR-19-3685 of cytotoxic T-cell markers and cytokines were associated with higher Ó2020 American Association for Cancer Research. pCR rate. However, this study did not examine long-term outcomes in AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst August 21, 2020; DOI: 10.1158/1078-0432.CCR-19-3685 Axelrod et al. þ but 2 estrogen receptor–positive (ER ) patients received cytotoxic Translational Relevance þ chemotherapy as part of their regimen. Four patients (ER ) Indications for immunotherapy, alone or in combination, are received courses of hormone therapy as part of their neoadjuvant expanding, including in breast cancer. However, the immunologic regimen, two of which were in conjunction with cytotoxic chemo- þ landscape of breast cancer and how chemotherapy, the current therapy. Five patients (HER2 ) received HER2-directed therapy as standard of care for triple-negative breast cancer (TNBC), influ- part of their neoadjuvant regimen. ences local and systemic immune responses are incompletely For the “Peru” cohort, clinical characteristics and molecular analysis characterized. Herein, we show that increases in expression of of the patients (n ¼ 48 with matched pretreatment tissue) were immune-related genes and gene sets in the tumor over the course of previously described at the Instituto Nacional de Enfermedades chemotherapy are associated with improved prognosis in TNBC, Neoplasicas (12). Clinical and pathologic data were retrieved from but not other subtypes of breast cancer. Conversely, a gene medical records under an institutionally approved protocol (INEN expression signature of immune activation and cytotoxicity in the IRB 10–018). For the “VICC” cohort, which included PBMC and peripheral blood was associated with persistent disease following whole blood analyses, clinical and pathologic data were retrieved from chemotherapy and disease recurrence following surgery. Examin- medical records under an institutionally approved protocol (VICC IRB ing immune-related signatures locally and systemically may serve 030747). For the DARTMOUTH cohort, patient samples were col- as biomarkers of patients likely to benefit from additional immu- lected under a protocol approved by the Dartmouth College Institu- notherapeutic approaches. tional Review Board and the waiver of the subject consent process was IRB approved (IRB 28888). Metadata for the primary cohort of patients is presented in Supplementary Table S1. For the peripheral blood study, two cohorts of patients were used (summarized patients with RD, for whom prognosis is worse than those with pCR in Table 2). For the Vanderbilt cohort, all blood was collected within and only included a limited number of TNBC samples (n ¼ 13; ref. 10). 14 days preceding definitive surgery. Metadata for the Vanderbilt Furthermore, whether immunomodulatory effects of NAC are locor- cohort is presented in Supplementary Table S7. For the DFCI cohort egional or systemic (i.e., able to be detected in the peripheral blood) is (11), all blood was collected in the interlude between completion of unknown. NAC and definitive surgery. To address this gap in knowledge, we examined expression patterns of immune-related genes before and after NAC in a series of 83 breast TILs Quantification tumors, including 44 TNBCs, from patients with RD. As patients with sTILs were analyzed using full face hematoxylin and eosin sections pCR generally experience excellent outcomes, we chose to focus on from pre-NAC diagnostic biopsies or post-NAC RD surgical speci- patients with RD, who may benefit from additional therapies. Changes mens. Samples were scored
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