Abstract
BackgroundMetaplastic 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.MethodsWe 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.ResultsMetaplastic 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.ConclusionsOur 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.
Highlights
Metaplastic breast carcinoma encompasses a heterogeneous group of tumours with differentiation into squamous and/or spindle, chondroid, osseous or rhabdoid mesenchymal-looking elements
We present data demonstrating that Metaplastic breast carcinoma (MBC) has a unique profile of expression of immune-regulatory markers Programmed Death Ligand 1 (PD-L1) and FOXP3, and that they differ significantly in their expression from the broader group of non-metaplastic triple-negative BC (TNBC)
We show that 73% of MBCs have tumoural expression of PD-L1, marking them as a suitable cohort for immunotherapy targeting the PD-1/PD-L1 checkpoint, especially in light of the impressive response to pembrolizumab as documented by Adams et al.[21]
Summary
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. 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. Metaplastic breast carcinoma (MBC) is a rare morphological subtype of breast cancer that accounts for 0.2–5% of invasive breast cancers.[1] Inherently heterogeneous, MBC are characterised by neoplastic cells differentiating into heterologous elements including squamous, spindle, osseous, chondroid and others. In TNBC, PD-L1 expression is variably reported, with 2013–80%14 of samples positively stained, with no prognostic association;[14] in an additional cohort, 30% of tumours were positive, and in this context, there was an association between PD-L1 expression with poor overall survival.[15]
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