title: Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1.
abstract: OBJECTIVE
  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 includedTP53(56%) andPIK3CA(23%). Pathogenic mutations in other genes, includingHRAS,FBXW7,PTEN,AKT1andSMAD4, 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 ofTP53mutation and increased PD-L1 expression in carcinoma cells. These results can be exploited in clinical trials using immune checkpoint inhibitors.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.
authors.forename: Upasana
authors.initials: U
authors.lastname: Joneja
authors.affiliation: Department of Pathology, University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina.|School of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: Semir
authors.initials: S
authors.lastname: Vranic
authors.affiliation: Caris Life Sciences, Phoenix, Arizona, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Swensen
authors.affiliation: Caris Life Sciences, Phoenix, Arizona, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Feldman
authors.affiliation: Caris Life Sciences, Phoenix, Arizona, USA.
authors.forename: Wangjuh
authors.initials: W
authors.lastname: Chen
authors.affiliation: Caris Life Sciences, Phoenix, Arizona, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kimbrough
authors.affiliation: Caris Life Sciences, Phoenix, Arizona, USA.
authors.forename: Nianqing
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Caris Life Sciences, Phoenix, Arizona, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Palazzo
authors.affiliation: Caris Life Sciences, Phoenix, Arizona, USA.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
mesh_terms: D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D016159:Tumor Suppressor Protein p53
keywords: BREAST CANCER; BREAST PATHOLOGY; GENETICS; TUMOUR BIOLOGY