Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1

Abstract

Aims: Metaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy than ductal carcinoma. In molecular terms, MBCs usually cluster with triple-negative breast cancers (TNBCs), but have a worse prognosis than TNBCs. Studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches. The aim of the present study was to characterise MBCs on a molecular level and test programmed death-ligand 1 (PD-L1) biomarker expression in MBCs for future therapeutic interventions.

Methods: We profiled 297 samples (MBC (n=75), TNBC (n=106), human epidermal growth factor receptor 2 (HER2)-positive breast cancers (n=32) and hormone-positive breast cancers (n=84)) by next-generation sequencing. Immunohistochemistry for PD-L1 and programmed cell death 1 (PD-1) expression was performed using automated procedures.

Results: The most commonly mutated genes in MBCs included TP53 (56%) and PIK3CA (23%). Pathogenic mutations in other genes, including HRAS, FBXW7, PTEN, AKT1 and SMAD4, were rare. PD-L1 expression was detected in a significantly higher proportion of MBCs (46%) than in other subtypes (6% each in hormone-positive and HER2-positive breast cancers, and 9% in TNBC, not otherwise specified, p<0.001). PD-1-positive tumour infiltrating lymphocytes (TILs) varied greatly in MBCs.

Conclusions: Comprehensive profiling of a large cohort of this rare subtype of breast carcinoma highlighted the predominance of TP53 mutation and increased PD-L1 expression in carcinoma cells. These results can be exploited in clinical trials using immune checkpoint inhibitors.

Keywords: BREAST CANCER; BREAST PATHOLOGY; GENETICS; TUMOUR BIOLOGY.

Figure 1

(A–L) Interface between tumour and tumour infiltrating lymphocytes (TILs) in different metaplastic breast carcinomas (MBCs) categorised into four categories based on programmed death-ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expression, 400× magnification. (A–C) Type 1 (PD-L1 positive, high PD-1): MBC with squamous metaplastic component (A) showing 3+ intensity PD-L1 staining in 50% of the tumour (B) and high PD-1 expression in the peritumoral lymphocytes (210/10 high power fields) (C). (D–F) Type 2 (PD-L1 negative, low PD-1): MBC with spindle cell metaplastic component (D) with tumour cells showing no increase in expression of PD-L1 by tumour cells (E) and no expression of PD-1 by interstitial lymphocytes/plasma cells (F). (G–I) Type 3 (PD-L1 positive, low PD-1): MBC with spindle cell metaplastic component (G) with moderate overexpression of PD-L1 in the tumour cells (H) and no expression of PD-1 in the TILs (I). (J–L) Type 4 (PD-L1 negative, high PD-1): MBC with areas of chondroid metaplastic component (J) with no PD-L1 overexpression in tumour cells (K) and moderate expression of PD-1 positive in TILs (190/10 high power fields) (L).