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.
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.
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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $20.79 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lakhani S. R., Ellis I. O., Schnitt S. J., Tan P. H., van de Vijver M. J. WHO Classification of Tumours of the Breast 4th edn (eds Bosman, F. T., Jaffe, E. S., Lakhani, S. R., Oghaki, H.) (IARC, Lyon, 2012).
Hennessy, B. T., Gonzalez-Angulo, A. M., Stemke-Hale, K., Gilcrease, M. Z., Krishnamurthy, S., Lee, J. S. et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116–4124 (2009).
Lai, H. W., Tseng, L. M., Chang, T. W., Kuo, Y. L., Hsieh, C. M., Chen, S. T. et al. The prognostic significance of metaplastic carcinoma of the breast (MCB)-a case controlled comparison study with infiltrating ductal carcinoma. Breast 22, 968–973 (2013).
Nelson, R. A., Guye, M. L., Luu, T. & Lai, L. L. Survival outcomes of metaplastic breast cancer patients: results from a US population-based analysis. Ann. Surg. Oncol. 22, 24–31 (2015).
Al-Hilli, Z., Choong, G., Keeney, M. G., Visscher, D. W., Ingle, J. N., Goetz, M. P. et al. Metaplastic breast cancer has a poor response to neoadjuvant systemic therapy. Breast Cancer Res. Treat. 176, 709–716 (2019).
Lehmann, B. D., Jovanovic, B., Chen, X., Estrada, M. V., Johnson, K. N., Shyr, Y. et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS ONE 11, e0157368 (2016).
Harano, K., Wang, Y., Lim, B., Seitz, R. S., Morris, S. W., Bailey, D. B. et al. Rates of immune cell infiltration in patients with triple-negative breast cancer by molecular subtype. PLoS ONE 13, e0204513 (2018).
Weigelt, B., Kreike, B. & Reis-Filho, J. S. Metaplastic breast carcinomas are basal-like breast cancers: a genomic profiling analysis. Breast Cancer Res. Treat. 117, 273–280 (2009).
Weigelt, B., Ng, C. K., Shen, R., Popova, T., Schizas, M., Natrajan, R. et al. Metaplastic breast carcinomas display genomic and transcriptomic heterogeneity [corrected]. Mod. Pathol. 28, 340–351 (2015).
Adams, S., Gray, R. J., Demaria, S., Goldstein, L., Perez, E. A., Shulman, L. N. et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J. Clin. Oncol. 32, 2959–2966 (2014).
Loi, S., Michiels, S., Salgado, R., Sirtaine, N., Jose, V., Fumagalli, D. et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann. Oncol. 25, 1544–1550 (2014).
Salgado, R., Denkert, C., Demaria, S., Sirtaine, N., Klauschen, F., Pruneri, G. et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 26, 259–271 (2015).
Mittendorf, E. A., Philips, A. V., Meric-Bernstam, F., Qiao, N., Wu, Y., Harrington, S. et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol. Res 2, 361–370 (2014).
Beckers, R. K., Selinger, C. I., Vilain, R., Madore, J., Wilmott, J. S., Harvey, K. et al. Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology 69, 25–34 (2016).
Muenst, S., Schaerli, A. R., Gao, F., Daster, S., Trella, E., Droeser, R. A. et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res. Treat. 146, 15–24 (2014).
Adams, S., Loi, S., Toppmeyer, D., Cescon, D. W., De Laurentiis, M., Nanda, R. et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 405–411 (2019).
Adams, S., Schmid, P., Rugo, H. S., Winer, E. P., Loirat, D., Awada, A. et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 397–404 (2019).
Joneja, U., Vranic, S., Swensen, J., Feldman, R., Chen, W., Kimbrough, J. et al. Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1. J. Clin. Pathol. 70, 255–259 (2017).
Dill, E. A., Gru, A. A., Atkins, K. A., Friedman, L. A., Moore, M. E., Bullock, T. N. et al. PD-L1 expression and intratumoral heterogeneity across breast cancer subtypes and stages: an assessment of 245 primary and 40 metastatic tumors. Am. J. Surg. Pathol. 41, 334–342 (2017).
Tray, N., Taff, J., Singh, B., Suh, J., Ngo, N., Kwa, M. et al. Metaplastic breast cancers: genomic profiling, mutational burden and tumor-infiltrating lymphocytes. Breast 44, 29–32 (2018).
Adams, S. Dramatic response of metaplastic breast cancer to chemo-immunotherapy. NPJ Breast Cancer 3, 8 (2017).
Shitara, K. & Nishikawa, H. Regulatory T cells: a potential target in cancer immunotherapy. Ann. N. Y Acad. Sci. 1417, 104–115 (2018).
Lee, S., Cho, E. Y., Park, Y. H., Ahn, J. S. & Im, Y. H. Prognostic impact of FOXP3 expression in triple-negative breast cancer. Acta Oncol. 52, 73–81 (2013).
Yeong, J., Thike, A. A., Lim, J. C., Lee, B., Li, H., Wong, S. C. et al. Higher densities of Foxp3(+) regulatory T cells are associated with better prognosis in triple-negative breast cancer. Breast Cancer Res. Treat. 163, 21–35 (2017).
Shou, J., Zhang, Z., Lai, Y., Chen, Z. & Huang, J. Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs: a systematic review and meta-analysis. BMC Cancer 16, 687 (2016).
McCart Reed, A. E., Kalaw, E., Nones, K., Bettington, M., Lim, M., Bennett, J. et al. Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications. J. Pathol. 247, 214–227 (2019).
Hendry, S., Salgado, R., Gevaert, T., Russell, P. A., John, T., Thapa, B. et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immunooncology biomarkers working group: part 1: assessing the host immune response, tils in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research. Adv. Anat. Pathol. 24, 235–251 (2017).
Liu, S., Foulkes, W. D., Leung, S., Gao, D., Lau, S., Kos, Z. et al. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Res. 16, 432 (2014).
Lacroix-Triki, M., Geyer, F. C., Lambros, M. B., Savage, K., Ellis, I. O., Lee, A. H. et al. beta-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast. Mod. Pathol. 23, 1438–1448 (2010).
Adwal, A., Croft, P. K.-D., Shakya, R., Lim, M., Kalaw, E., Taege, L. D. et al. Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer. Life Sci. Alliance. 3, e201900562 (2020).
Castagnoli, L., Cancila, V., Cordoba-Romero, S. L., Faraci, S., Talarico, G., Belmonte, B. et al. WNT signaling modulates PD-L1 expression in the stem cell compartment of triple-negative breast cancer. Oncogene 38, 4047–4060 (2019).
Kulangara, K., Zhang, N., Corigliano, E., Guerrero, L., Waldroup, S., Jaiswal, D. et al. Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch. Pathol. Lab Med. 143, 330–337 (2019).
Nanda, R., Chow, L. Q., Dees, E. C., Berger, R., Gupta, S., Geva, R. et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J. Clin. Oncol. 34, 2460–2467 (2016).
Rimm, D. L., Han, G., Taube, J. M., Yi, E. S., Bridge, J. A., Flieder, D. B. et al. Reanalysis of the NCCN PD-L1 companion diagnostic assay study for lung cancer in the context of PD-L1 expression findings in triple-negative breast cancer. Breast Cancer Res. 21, 72 (2019).
Tong, M., Wang, J., He, W., Wang, Y., Pan, H., Li, D. et al. Predictive biomarkers for tumor immune checkpoint blockade. Cancer Manag Res. 10, 4501–4507 (2018).
Liu, C., Workman, C. J. & Vignali, D. A. Targeting regulatory T cells in tumors. FEBS J. 283, 2731–2748 (2016).
Rech, A. J., Mick, R., Martin, S., Recio, A., Aqui, N. A., Powell, D. J. et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl. Med. 4, 134ra62 (2012).
Li, Z., Dong, P., Ren, M., Song, Y., Qian, X., Yang, Y. et al. PD-L1 Expression Is associated with tumor FOXP3+ regulatory T-Cell infiltration of breast cancer and poor prognosis of patient. J Cancer. 7, 784–793 (2016).
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.
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.
All data is included in the publication.
The authors declare no competing interests.
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).
Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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