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Differential effects of CD20+ B cells and PD-L1+ immune cells on pathologic complete response and outcome: comparison between inflammatory breast cancer and locally advanced breast cancer patients

Abstract

Purpose

This study evaluated epidemiologic and immune factors associated with pathologic complete response (pCR), breast cancer-specific survival (BCSS) and disease-free survival (DFS) outcomes in inflammatory (IBC) and locally advanced breast cancer (LABC) patients.

Methods

Tumor-infiltrating lymphocytes (TILs) and CD20+ B-cell frequencies (CD20+), and PD-L1 expression on tumor (PD-L1+carcinoma cells) and immune (PD-L1+TILs) cells were analyzed by immunohistochemistry along with clinicopathologic factors as modifiers of pCR and outcomes in 221 IBC and 162 LABC patients. Analysis included Kaplan–Meier curves and Cox proportional hazard models.

Results

IBC and LABC display similar levels of TILs, CD20+, and combined CD20+ and PD-L1+TILs (CD20+PD-L1+TILs), while LABC contained more PD-L1+TILs and PD-L1+ carcinoma cells. Absence of lymphovascular involvement, high TILs, PD-L1+ carcinoma cells, and combined CD20+ and PD-L1+ carcinoma cells correlated with pCR in IBC and LABC patients. High PD-L1+TILs correlated with pCR only in LABC; less lymph node involvement at diagnosis, CD20+ and CD20+PD-L1+TILs correlated with pCR only in IBC (P < 0.04, all comparisons). Achievement of pCR in IBC and LABC patients correlated with BCSS and DFS (P < 0.02). In multivariate analyses, pCR remained an independent prognostic factor of improved DFS in IBC and LABC patients, but of BCSS in only LABC. CD20+PD-L1+TILs remained an independent prognostic factor of improved DFS and BCSS only in IBC.

Conclusion

CD20+PD-L1+TILs are an independent prognostic biomarker of improved outcomes in IBC, but not LABC. Selecting IBC patients by CD20 and PD-L1 status could stratify patients and potentially identify those in whom activating CD20 agents and anti-PD-1/PD-L1 therapy could be explored.

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Abbreviations

BCSS:

Breast cancer-specific survival

BMI:

Body mass index

CI:

Confidential interval

DFS:

Disease-free survival

FFPETs:

Formalin-fixed paraffin embedded tissues

HR:

Hazard ratio

IBC:

Inflammatory breast cancer

LABC:

Locally advanced breast cancer

LVI:

Lymphovascular invasion

NACT:

Neoadjuvant chemotherapy.

pCR:

Pathological complete response

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death ligand 1

TILs:

Tumor infiltrating lymphocytes

TME:

Tumor microenvironment

TN:

Triple-negative

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Acknowledgements

We would like to thank the PMCCC Human Tissue Repository for providing tissue samples and clinical data (Algiers, Algeria); Karen Buehler (TriCore Reference Laboratories, Albuquerque, NM) for technical support with IHC; and the Pathology Shared Resource at the Norris Cotton Cancer Center at Dartmouth with NCI Cancer Center Support Grant 5P30CA023108-37. Donald Fitzpatrick (Computing and Media Services; Dartmouth Biomedical Libraries) for help with the graphs, and Kathleen Bryar for her editorial assistance.

Funding

This study was supported in part by the GlaxoSmithKline Oncology Ethnic Research Initiative Grant (Drs. Arias-Pulido and Chaher; no grant number), and the UICC ICRETT fellowship (Dr. Chaher; ICR/09/043), and the National Institutes of Health (Dr. Prossnitz: CA163890 and CA194496; also supported by the University of New Mexico Comprehensive Cancer Center; P30 CA118100 and the Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence P20 GM121176; and Dr. Fiering R01CA224605). The funding organizations provided financial support and had no influence on the final results or submission of the manuscript.

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Correspondence to Hugo Arias-Pulido.

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Conflict of interest

LAE receives honoraria and research funding to the institution from Aduro Biotech, Astrazeneca, Bristol Meyers Squibb, Corvus, EMD Serono, Genentech, HeritX, Inc., Maxcyte, Merck, Roche, Tempest; and royalties from Aduro Biotech. She has served on Consulting/Advisory boards for AbbVie, Amgen, Astrazeneca, Bayer, Bristol Meyers Squibb, Celgene, Chugai, eTHeRNA, Genentech, Gritstone, Medimmune, Molecuvax, Macrogenics, Novartis, Peregrine, Replimune, Roche, Silverback, Syndax, Vaccinex. ACM receives honoraria from Bristol-Myers Squibb and Roche and research funding to the institution from Bristol-Myers Squibb, Genentech, and HeritX, Inc. Dr. Fiering is a co-founder of and has a financial interest in Mosaic Immunoengineering Inc. The remaining authors declare no conflict of interest.

Ethical approval

This observational retrospective study involving human participants was approved by the Committee for the Protection of Human Subjects at Dartmouth College (STUDY00029655). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Formal patient consent for studies using anonymous human specimens is not required.

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Supplementary file1 (PDF 156 kb) Additional demographic, clinicopathologic and molecular characteristics of IBC and LABC patients.

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Arias-Pulido, H., Cimino-Mathews, A.M., Chaher, N. et al. Differential effects of CD20+ B cells and PD-L1+ immune cells on pathologic complete response and outcome: comparison between inflammatory breast cancer and locally advanced breast cancer patients. Breast Cancer Res Treat (2021). https://doi.org/10.1007/s10549-021-06391-5

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Keywords

  • Inflammatory breast cancer
  • Locally advanced breast cancer
  • Tumor-infiltrating lymphocytes
  • pCR
  • PD-L1
  • CD20
  • Immuno-oncology
  • Patient outcomes