Molecular Diagnostics

Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1

Abstract

Background

Metaplastic breast carcinoma encompasses a heterogeneous group of tumours with differentiation into squamous and/or spindle, chondroid, osseous or rhabdoid mesenchymal-looking elements. Emerging immunotherapies targeting Programmed Death Ligand 1 (PD-L1) and immune-suppressing T cells (Tregs) may benefit metaplastic breast cancer patients, which are typically chemo-resistant and do not express hormone therapy targets.

Methods

We evaluated the immunohistochemical expression of PD-L1 and FOXP3, and the extent of tumour infiltrating lymphocytes (TILs) in a large cohort of metaplastic breast cancers, with survival data.

Results

Metaplastic breast cancers were significantly enriched for PD-L1 positive tumour cells, compared to triple-negative ductal breast cancers (P < 0.0001), while there was no significant difference in PD-L1 positive TILs. Metaplastic breast cancers were also significantly enriched for TILs expressing FOXP3, with FOXP3 positive intra-tumoural TILs (iTILs) associated with an adverse prognostic outcome (P = 0.0226). Multivariate analysis identified FOXP3 iTILs expression status as an important independent prognostic factor for patient survival.

Conclusions

Our findings indicate the clinical significance and prognostic value of FOXP3, PD-1/PD-L1 checkpoint and TILs in metaplastic breast cancer and confirm that a subset of metaplastics may benefit from immune-based therapies.

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Fig. 1: Tumour Infiltrating Lymphocytes in MBC.
Fig. 2: PD-L1 expression and prognostic implications in MBC.
Fig. 3: FOXP3 expression and prognostic implications in MBC.
Fig. 4: WNT activity and expression of immune checkpoint markers in MBC.

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Acknowledgements

We thank the patients and their families and acknowledge the support of Metro North Hospital and Health Services in the collection of the clinical subject data and clinical subject materials.

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Authors

Contributions

A.E.M.R., P.T.S. and S.R.L. conceived experiments, analysed data, and drafted the paper. A.E.M.R., E.K., M.L., I.G., J.K., A.S., L.T., K.J., J.B. carried out experiments. K.F., C.N. collated samples and clinical data. J.K. and J.S. analysed data. S.R.L., S.A.O’.T., R.Y., G.H., S.F., P.H.T., D.P., R.P., G.T., N.P., K.J., M.B., A.S., L.T. and J.B. performed pathology review. All authors were involved in writing the paper and had final approval of the submitted and published versions.

Corresponding authors

Correspondence to Sunil R. Lakhani or Amy E. McCart Reed.

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Ethics approval and consent to participate

Human research ethics committees approved the use of all clinical samples and data (The University of Queensland (2005000785) and the Royal Brisbane and Women’s Hospital (2005/022)). Signed consent for study participants was waived due to the archival nature of the material. The study was performed in accordance with Declaration of Helsinki.

Data availability

All data is included in the publication.

Competing interests

The authors declare no competing interests.

Funding information

S.A.O’.T. is funded by the National Breast Cancer Foundation (PRAC‐16‐006 and IIRS-19-084) and the Sydney Breast Cancer Foundation. Pathology Queensland—Study Education and Research Committee supported the study. The study was funded by a Cancer Australia/National Breast Cancer Foundation PdCCRS grant (APP1082435) and an NHMRC Program Grant (APP1113867).

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Kalaw, E., Lim, M., Kutasovic, J.R. et al. Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-01065-3

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