Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

J Pathol. 2019 Feb;247(2):214-227. doi: 10.1002/path.5184. Epub 2018 Dec 20.


Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: breast cancer; epithelial-to-mesenchymal transition; genomics; heterogeneity; metaplastic; spindle; squamous.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / analysis
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / classification
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cadherins / analysis
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Cross-Sectional Studies
  • Epithelial-Mesenchymal Transition
  • ErbB Receptors / analysis
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Keratins / analysis
  • Metaplasia
  • Middle Aged
  • Mutation*
  • Neoplasm Grading
  • Neoplasms, Complex and Mixed / chemistry
  • Neoplasms, Complex and Mixed / classification
  • Neoplasms, Complex and Mixed / genetics*
  • Neoplasms, Complex and Mixed / pathology
  • Neurofibromin 1 / genetics
  • PTEN Phosphohydrolase / genetics
  • Phenotype
  • Tumor Burden
  • Tumor Suppressor Protein p53 / genetics


  • Antigens, CD
  • Biomarkers, Tumor
  • CDH1 protein, human
  • Cadherins
  • NF1 protein, human
  • Neurofibromin 1
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Keratins
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • EGFR protein, human
  • ErbB Receptors
  • PTEN Phosphohydrolase
  • PTEN protein, human