Breast Cancer

• Breast cancer is the most frequent malignancy in women:
  • Is a heterogeneous disease on the molecular level
• Over the past 10 to 15 years:
  • Treatment concepts have evolved to take this heterogeneity into account:
    • With emphasis being placed on:
      • More biologically-directed therapies and treatment de-escalation to reduce the adverse effects of treatment
    • Despite the inherent molecular heterogeneity, which is a driving principle of modern-day treatments:
      • Some features such as the impact of locoregional tumor burden or metastatic patterns are shared and influence therapy
• Early breast cancer:
  • That is, cancer that is contained in the breast or that has only spread to the axillary lymph nodes:
    • Is considered curable
    • Improvements in multimodal therapy have led to:
      • Increasing chances for cure in approximately 70% to 80% of patients
  • By contrast, advanced (metastatic) disease is not considered curable using currently available therapeutic options:
    • However, advanced breast cancer is a treatable disease:
      • For which the main goals of therapy are to prolong survival and control symptoms with low treatment-associated toxicity:
        • To maintain or improve quality of life (that is, improved quality-adjusted life expectancy).
• 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, and several classifications on the basis of molecular and histological characteristics have been developed
• The histological subtypes described here (top right) are the most frequent subtypes of breast cancer:
  • Invasive:
    • Ductal carcinoma (now referred to as ‘no special type’ (NST)):
      • Develops from:
        • DCIS
      • Fibrous response:
        • To produce a mass
      • Metastasizes via:
        • Lymphatics and blood
    • Lobular carcinoma:
      • Isolated tumor cells:
        • CDH1 mutations
      • Minimal fibrous response
      • Metastasizes preferentially:
        • Via viscera
  • Pre-invasive:
    • Ductal carcinoma in situ:
      • Spreads through ducts and distorts ductal architecture:
        • Can progress to invasive cancer:
          • Unilateral
    • Lobular carcinoma in situ (or lobular neoplasia):
      • Does not distort ductal architecture:
        • Can be bilateral
      • Risk factor rather than precursor

• The intrinsic subtypes of:
  • Perou and Sorlie are based on:
    • A 50-gene expression signature (PAM50)
  • Basal-like:
    • TP53 mutations
    • Genetic instability
    • BRCA mutations
    • Medullary-like histology
    • Poorly differentiatied
  • Claudin- low:
    • Largely triple-negative
    • Metaplastic histology
  • HER2-enriched:
    • HER2 amplification
    • GRB7 amplification
    • PIK3CA mutations
    • TOPO2 and / or MYC amplification
    • NST, pleiomorphic lobular and micropapillary histology
  • Normal-like:
    • Artefact:
      • Expression of normal breast components:
        • Due to low tumor cellularity
• The surrogate intrinsic subtypes:
  • Are typically used clinically:
    • Are based on histology and immunohistochemistry 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
  • Triple-negative:
    • 10% to 15% of the cases
    • ER negative, PR negative, HER2 negative
    • High grade
    • High Ki-67 index
    • NST histology
    • Special type histology:
      • Metaplastic
      • Adenoid cystic
      • Medullary-like
      • Secretory
    • Poor prognosis:
      • Except for some special types
  • HER2-enriched (non-luminal):
    • 13% to 15% of the cases
    • ER negative, PR negative, HER2 positive
    • High grade
    • High Ki-67 index
    • NST histology
    • Aggressive disease:
      • But responds to targeted therapies
    • Intermediate prognosis
  • Luminal B-like HER2 Positive:
    • 13% to 15% of the cases
    • ER positive:
      • But lower ER and PR expression than luminal A-like
    • HER2 positive
    • Higher grade
    • High Ki-67 index
    • NST and pleomorphic
    • Responds to targeted therapies
    • Intermediate prognosis
  • Luminal B-like HER2 Negative:
    • 10% to 20% of the cases
    • ER positive:
      • But ER and PR expression lower than in luminal A-like
    • HER2 negative
    • Higher grade
    • High Ki-67 index
    • High-risk gene expression signature (GES)
    • NST, micro papillary and lobular pleomorphic histology
    • Intermediate prognosis
  • Luminal A-like:
    • 60% to 70% of the cases
    • Strongly ER positive and PR positive
    • HER2 negative
    • Low proliferation rates
    • Typically low grade
    • Low Ki-67 index
    • Low-risk gene expression signature (GES)
    • NST, tubular cribriform histology and classic lobular histology
    • Good prognosis

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