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

Abstract

AimsMetaplastic 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.MethodsWe 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.ResultsThe 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.ConclusionsComprehensive 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.

Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010–2014

“…A phase 1b trial has recently shown evidence of activity of pembrolizumab in heavily treated TN breast cancer [25]. A study that recently profiled 75 MBC tumors demonstrated significantly higher programmed death-ligand 1 expression (46%) in MBC compared with other breast cancer subtypes: HR positive (6%), HER2 positive (6%), triple negative breast cancer (TNBC) not otherwise specified (9%) [22]. This same review reported that tumor infiltrating lymphocytes varied greatly in MBC tumors.…”

In-vitro effect of pembrolizumab on different T regulatory cell subsets

“…Additionally, Adams et al . reported a remarkable response to combination therapy consisting of pembrolizumab and Nab‐paclitaxel in a patient with metaplastic breast cancer, associated commonly with over‐expression of PD‐L1 , as part of an ongoing clinical trial (http://clinicaltrials.gov identifier: NCT02752685).…”

“…PD-L1 expression was associated with poor prognosis in a study conducted by Qin et al [28], who assessed correlations between PD-L1 expression and patient clinical characteristics in 870 breast cancer patients, and recently a clinical trial has assessed the safety profile and anti-tumour efficacy of pembrolizumab in triple-negative breast cancer patients that have shown acceptable safety and promising antitumour effects [29], with Phase II trials currently under way (clinicaltrials.gov identifier: NCT02447003). Additionally, Adams et al [30] reported a remarkable response to combination therapy consisting of pembrolizumab and Nab-paclitaxel in a patient with metaplastic breast cancer, associated commonly with over-expression of PD-L1 [31], as part of an ongoing clinical trial (clinicaltrials.gov identifier: NCT02752685).…”

Theranostic molecular profiling of pleomorphic ductal carcinoma of the breast

“…Gene amplification of cyclin‐dependent kinase inhibitor 1B ( CDKN1B ) and fibroblast growth factor receptor 1 ( FGFR1 ) genes was detected in one case, each. These results indicate that PDCs exhibit significantly less targetable genetic alterations in contrast to related TNBC and metaplastic breast carcinomas . A single case with a mutation in BRCA1 gene indicates a potential benefit to platinum compounds and PARP inhibitors .…”