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Impact of prior systemic therapy on lymphocytic infiltration in surgically resected breast cancer brain metastases

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Abstract

Purpose

Tumor-infiltrating lymphocytes (TILs) have been positively correlated with response to systemic therapy for triple-negative and HER2 + subtypes and improved clinical outcomes in early breast cancer (BC). Less is known about TILs in metastatic sites, particularly brain metastases (BM), where unique immune regulation governs stromal composition. Reactive glial cells actively participate in cytokine-mediated T cell stimulation. The impact of prior medical therapy (chemotherapy, endocrine, and HER2-targeted therapy) on the presence of TILs and gliosis in human breast cancer brain metastases (BCBM) has not been previously reported.

Methods

We examined prior treatment data for 133 patients who underwent craniotomy for resection of BMs from the electronic medical record. The primary endpoint was overall survival (OS) from the time of BM diagnosis. We examined the relationship between prior systemic therapy exposure and the histologic features of gliosis, necrosis, hemorrhage, and lymphocyte infiltration (LI) in BCBMs resected at subsequent craniotomy in univariate analyses.

Results

Complete treatment data were available for 123 patients. BCBM LI was identified in 35 of 116 (30%) patients who had received prior systemic treatment versus 5 of 7 (71.4%) who had not {significant by Fisher’s exact test p = 0.045}. There were no statistically significant relationships between prior systemic therapy and the three other histologic variables examined.

Conclusions

This observation suggests that systemic therapy may interfere with the immune response to BCBMs and cause exhaustion of anti-tumor immunity. This motivates clinical investigation of strategies to enhance LI for therapeutic benefit to improve outcomes for patients with BCBMs.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to patient confidentiality but are available from the corresponding author on reasonable request.

Abbreviations

BBB:

Blood–brain barrier

BM:

Brain metastases

BC:

Breast cancer

BCBM:

Breast cancer brain metastases

GPA:

Graded Prognostic Assessment

H and E:

Hematoxylin and eosin

HR:

Hormone receptor

HER2:

Human epidermal growth factor receptor 2

IL-1β:

Interleukin-1β

IQR:

Interquartile range

LI:

Lymphocyte infiltration

MBC:

Metastatic breast cancer

OS:

Overall survival

PD-L1:

Programmed cell death ligand 1

RT:

Radiotherapy

SERPINS:

Serine protease inhibitors

SRS:

Stereotactic radiosurgery

TNBC:

Triple-negative breast cancer

TILs:

Tumor-infiltrating lymphocytes

USA:

United States of America

WBRT:

Whole brain radiation therapy

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Acknowledgements

We would like to thank Dr Jedd Wolchok from Memorial Sloan Kettering Cancer Center, Immuno-Oncology Service, New York, USA, for his advice and comments.

Funding

This research received no external funding. Dr. Anders is a Translating Duke Health Scholar and is supported by the Translating Duke Health Initiative (TDHI).

Author information

Authors and Affiliations

  1. Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    S. Chew Minmin, A. Bacotti, Y. Chen & A. D. Seidman

  2. Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    E. Brogi

  3. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    M. Sambade, A. M. Deal, D. Trembath & M. J. McKee

  4. Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC, USA

    C. Anders

  5. Weill Cornell Medical College, New York, NY, USA

    A. D. Seidman

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  1. S. Chew Minmin
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by AB, SC, AD, MM, MS, and DT, Supervision was performed by CA, EB, and AS. Statistical analysis was performed by YC. The first draft of the manuscript was written by SC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to A. D. Seidman.

Ethics declarations

Conflict of interests

CKA discloses Research funding: PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, Pfizer, Elucida; Compensated consultant role: Genentech, Eisai, IPSEN, Seattle Genetics, Astra Zeneca, Novartis, Immunomedics, Elucida, Athenex; Royalties: UpToDate, Jones and Bartlett. The other authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical review and approval were waived for this study, as this was a retrospective observational study of data obtained for clinical purposes. This study was registered under Memorial Sloan Kettering IRB waiver #WA0125-06.

Informed consent

Patient consent was waived due to retrospective data being collected anonymously for a quality improvement process that aimed to improve patient care and outcomes through systematic review of care against explicit criteria and standards.

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The abstract of this paper was presented at the 2018 ASCO Annual Meeting as a poster presentation with interim findings. The abstract was published in Journal of Clinical Oncology 2018 36:15_suppl, 2063-2063. DOI: 10.1200/JCO.2018.36.15_suppl.2063 Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018) 2063-2063.

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Chew Minmin, S., Bacotti, A., Chen, Y. et al. Impact of prior systemic therapy on lymphocytic infiltration in surgically resected breast cancer brain metastases. Breast Cancer Res Treat 199, 99–107 (2023). https://doi.org/10.1007/s10549-023-06908-0

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