Breast Cancer Pathogenesis

• Mechanisms / Pathophysiology of Breast Cancer:
  • The exact mechanism by which breast cancer is initiated:
    • Is unknown:
      • However, much effort has been made to molecularly characterize breast cancer and delineate its formation and progression
  • At the cell of origin level:
    • The clonal evolution model:
      • In which mutations accumulate
      • Epigenetic changes in tumor cells occur
      • The ‘fittest’ cells survive
    • The cancer stem cell model:
      • In which only the precursor cancer cells:
        • Initiate and sustain progression
          • Cancer stem cells may also evolve in a clonal fashion
  • At the morphological level:
    • There is a continuum of lesions and genetic modifications from normal glands to cancer

• All breast cancers arise in the:
  • Terminal duct lobular units (the functional unit of the breast) of the collecting duct
• The histological and molecular characteristics have:
  • Important implications for:
    • Therapy:
      • Several classifications on the basis of molecular and histological characteristics have been developed:
        • The most frequent histological subtypes of breast cancer include:
          • Invasive lesions:
            • Ductal carcinoma (now referred to as ‘no special type’ (NST))
            • Lobular carcinoma
          • Preinvasive counterparts are:
            • Ductal carcinoma in situ
            • Lobular carcinoma in situ (or lobular neoplasia)
• The intrinsic subtypes of Perou and Sorlie:
  • Are based on:
    • A 50-gene expression signature:
      • PAM50
• The surrogate intrinsic subtypes:
  • Are typically used clinically:
    • Are based on:
      • Histology
      • Immunohistochemistry:
        • Looking for the expression of key proteins:
          • Estrogen receptor (ER)
          • Progesterone receptor (PR)
          • Human epidermal growth factor receptor 2 (HER2)
          • The proliferation marker Ki67
    • Tumors expressing ER and / or PR are termed:
      • Hormone receptor-positive
    • Tumors not expressing ER, PR and HER2 are called:
      • Triple-negative

• At the molecular level:
  • There is evidence showing that breast cancer evolves along two divergent molecular pathways of progression:
    • Mainly related to:
      • ER expression
      • Tumor grade
      • Proliferation:
        • These are described in the intrinsic classification

• Intrinsic classification (Intrinsic Subtypes PAM50):
  • Basal-like:
    • TP-53 mutations
    • Genetic instability
    • BRCA mutations
    • Medullary-like histology
    • Poorly differentiatied tumors
  • Claudin- low:
    • Largely triple-negative
    • Metaplastic
• HER2-enriched:
  • HER2 amplification
  • GRB7 amplification
  • PIK3CA mutations
  • TOPO2 and/or MYC amplification
  • NST, pleiomorphic lobular, and micro-papillary histology
• Normal-like:
  • Artefact:
    • Expression of normal breast components due to low tumour cellularity
• Luminal B:
  • PI3KCA mutations (40%)
  • ESR1 mutations (30% to 40%):
    • Induced by aromatase inhibitor targeted therapy
  • ERBB2 and ERBB3 mutations
  • NST, micropapillary and atypical lobular histology
• Luminal A
  • Activation of ERS1, GATA3, FOXA1, XBP1
  • NST, tubular, cribriform, and classic lobular histology

• Surrogate intrinsic subtypes:
  • Triple-negative:
    • ER negative, PR negative, HER2 negative
    • High grade
    • High Ki67 index
    • NST histology
    • Special type histology:
      • Metaplastic
      • Adenoid cystic
      • Medullary-like
      • Secretory
    • Poor prognosis:
      • Except for some special types
  • HER2-enriched (non-luminal):
    • ER negative, PR negative, HER2 positive
    • High grade
    • High Ki67 index
    • NST histology
    • Aggressive disease:
      • But responds to targeted therapies
    • Intermediate prognosis
  • Luminal B-like HER2 positive:
    • ER positive:
      • But lower ER and PR expression than luminal A-like
    • HER2 positive
    • Higher grade
    • High Ki67 index
    • NST and pleiomorphic
    • Responds to targeted therapies
    • Intermediate prognosis
• Luminal B-like HER2 Negative:
  • ER positive:
    • But ER and PR expression lower than in luminal A-like
    • HER2 negative
    • Higher grade
    • High Ki67 index
    • High-risk GES (gene expression signature)
    • NST, micropapillary and lobular pleiomorphic histology
    • Intermediate prognosis
  • Luminal A-like:
    • Strongly ER positive and PR positive
    • HER2 negative
    • Low proliferation rates
    • Typically low grade
    • Low Ki67 index
    • Low-risk GES (gene expression signature)
    • NST, tubular, cribriform, and classic lobular histology
    • Good prognosis

• Rodrigo Arrangoiz MS, MD, FACS cirujano oncology y cirujano de mamá de Sociedad Quirúrgica S.C en el America British Cowdray Medical Center en la ciudad de Mexico:
  • Es experto en el manejo del cáncer de mama.

👉Es miembro de la American Society of Breast Surgeons:

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

#Arrangoiz

#Surgeon

#Cirujano

#SurgicalOncologist

#CirujanoOncologo

#BreastSurgeon

#CirujanodeMama

#CancerSurgeon

#CirujanodeCancer