What are the different molecular types of breast cancer?

Molecular Types of Breast Cancer

Breast cancer should be classified into four main molecular subtypes based on hormone receptor status, HER2 expression, and proliferation markers, as these subtypes have distinct biological behaviors, clinical outcomes, and treatment approaches. 1, 2

Major Molecular Subtypes

Luminal A

• Defined as estrogen receptor (ER) positive, HER2 negative, with low Ki67 (typically ≤20%), high progesterone receptor (PgR) expression, and low-risk molecular signature (if available) 1
• Typically low-grade tumors with strongly ER-positive/PgR-positive status and low proliferative fraction 1
• Best prognosis among all subtypes with highest 5-year survival rates (94-99%) 3
• Represents the most common subtype of breast cancer 2

Luminal B

• Further divided into two categories:
  • Luminal B-like (HER2-negative): ER-positive, HER2-negative with either high Ki67 (>20%) or low PgR expression, or high-risk molecular signature 1
  • Luminal B-like (HER2-positive): ER-positive, HER2-positive with any Ki67 level and any PgR expression 1
• Higher grade tumors with variable degrees of ER/PgR expression and higher proliferative fraction compared to Luminal A 1
• May express lower levels of hormone receptors than Luminal A 1
• Can be further stratified by Ki-67 expression with a cutoff at 25% for prognostic purposes 4

HER2-Positive (non-luminal)

• Characterized by HER2 overexpression/amplification with absence of ER and PgR expression 1
• Shows distinct gene expression patterns from other subtypes 2
• Accounts for approximately 15-20% of all breast cancers 3
• Ki-67 index is important for prognosis with a cutoff at 25% 4
• Typically has higher grade and more aggressive behavior than luminal subtypes 2

Triple-Negative/Basal-like

• Defined as lacking expression of ER, PgR, and HER2 (triple-negative) 1
• Represents approximately 10-20% of invasive breast cancers 1
• There is approximately 80% overlap between triple-negative and intrinsic basal-like subtype 1
• Triple-negative also includes some special histological types such as carcinoma with rich lymphocytic stroma (former medullary), secretory carcinoma, low-grade metaplastic carcinoma, and adenoid cystic carcinoma 1
• Associated with higher prevalence in women of African descent and premenopausal women 1
• Carries poorer prognosis than other subtypes with median overall survival for metastatic disease of approximately 1 year versus 5 years for other subtypes 3
• Can be divided according to proliferation rate (Ki-67) into prognostic categories, with better prognosis for tumors with Ki-67 index ≤25% 4

Clinical and Pathological Characteristics

Genetic Associations

• Triple-negative breast cancer is associated with BRCA1 mutations 1
• Genetic counseling and testing should be offered to patients with triple-negative breast cancer diagnosed before age 60 1
• Triple-negative tumors have more TP53 mutations (44%) compared to Luminal A tumors (15%) 1

Metastatic Patterns

• Different subtypes show distinct metastatic patterns:
  • Luminal cancers predominantly metastasize to bone 2
  • HER2-enriched cancers commonly metastasize to liver and lung 2
  • Triple-negative/basal-like cancers have higher rates of liver and brain metastases 2

Prognostic Factors

• Tumor-infiltrating lymphocytes (TILs) have prognostic value in triple-negative and HER2-positive breast cancer, with a 15-20% relative improvement in survival per 10% increase in TILs 1
• Triple-negative breast cancer has higher risk of recurrence compared to other subtypes 3
• Basal-like subtype shows higher mitotic index, more marked nuclear pleomorphism, and higher combined grade compared to Luminal A 1

Diagnostic Assessment

• For accurate molecular classification, immunohistochemical (IHC) evaluation should include ER, PgR, HER2, and Ki-67 1
• HER2 status should be determined according to ASCO-CAP guidelines:
  • HER2 is positive by IHC (3+) when more than 10% of cells show complete membrane staining 1
  • By in situ hybridization (ISH), HER2 is positive if HER2 gene copies ≥6, or HER2/CEP17 ratio ≥2 and HER2 copies ≥4, or HER2/CEP17 <2 and HER2 copies ≥6 1
• In case of ER/PgR and HER2 negativity in biopsy specimens, retesting in surgical specimens is advisable to account for tumor heterogeneity 1

Clinical Implications

• Molecular subtyping is crucial for treatment decision-making and prognostication 1, 5
• Treatment approaches differ significantly by subtype:
  • Luminal A/B: Endocrine therapy with or without chemotherapy 3
  • HER2-positive: HER2-targeted therapy combined with chemotherapy 3
  • Triple-negative: Chemotherapy as primary systemic treatment 3
• Within clinically HER2-positive disease, patients with HER2-enriched molecular subtype appear to benefit most from neoadjuvant HER2-targeted therapies 5
• Within triple-negative breast cancer, distinction between basal-like and non-basal-like may predict response to specific chemotherapy regimens 5