What is the biological classification of breast cancer (Breast CA)?

Biological Classification of Breast Cancer

Breast cancer is classified into distinct molecular subtypes based on hormone receptor status (ER/PR), HER2 expression, and proliferation markers, with the primary subtypes being Luminal A, Luminal B (HER2-negative and HER2-positive), HER2-positive (non-luminal), and triple-negative/basal-like. 1

Core Molecular Subtypes

The biological classification system divides breast cancer into clinically actionable categories that directly determine treatment strategies and predict outcomes 1:

Luminal A-like

• ER-positive, HER2-negative, Ki67 low (<20%), PgR high 2
• Strongly ER/PgR-positive with low proliferative fraction and typically low histologic grade 2
• Best prognosis among all subtypes with excellent response to endocrine therapy 1

Luminal B-like

Two distinct variants exist 2:

HER2-negative variant:

• ER-positive, HER2-negative with either high Ki67 (≥20%) or low PgR 2
• Higher grade and proliferative fraction than Luminal A 2

HER2-positive variant:

• ER-positive, HER2-positive, any Ki67 or PgR level 2
• Requires both endocrine and anti-HER2 targeted therapy 2

HER2-positive (non-luminal)

• HER2-positive with ER and PgR absent 2
• Characterized by HER2 gene amplification (≥6 copies or HER2/CEP17 ratio ≥2) 2
• Distinct gene expression patterns and metastatic behavior, preferentially spreading to liver and lung 1

Triple-Negative/Basal-like

• ER-negative, PgR-negative, HER2-negative 2, 1
• Accounts for 10-20% of invasive breast cancers 2, 1
• Approximately 75% express basal markers and harbor TP53 mutations 1
• Preferentially metastasizes to liver and brain rather than bone 1
• Threefold increased risk in African-American and African women 2

Essential Biomarker Assessment

All breast cancers require assessment of ER, PgR, and HER2 status before treatment planning 2:

• ER/PgR: Determined by immunohistochemistry with quantification (Allred score or H-score) 2
• HER2: Assessed by IHC (3+ is positive when >10% complete membrane staining) or ISH (positive if HER2 copies ≥6 or ratio ≥2 with copies ≥4) 2
• Ki67 proliferation index: Provides additional prognostic information, particularly for distinguishing Luminal A from Luminal B subtypes 2, 3

Critical Clinical Implications

Metastatic Pattern Differences

Subtype determines organ-specific metastatic patterns 1:

• Luminal (ER/PR-positive): Predominantly bone metastases (51% overall) 1
• HER2-enriched: Liver and lung metastases 1
• Triple-negative: Liver and brain metastases 1

Re-biopsy Requirements

At metastatic recurrence, biopsy is mandatory to reassess tumor biology (ER, PgR, HER2), as receptor status can change in 20-40% of cases 2. Treatment decisions should consider biomarker heterogeneity and prior therapy exposure 2.

ER-low Tumors (1-9% positivity)

These represent a distinct entity with reduced endocrine therapy sensitivity, though CDK4/6 inhibitor combinations may provide benefit 2.

Additional Prognostic Biomarkers

Beyond the core classification, several biomarkers guide treatment in specific contexts 2:

• Germline BRCA1/2 mutations: Required testing in HER2-negative metastatic disease 2
• PD-L1 status: Essential for triple-negative breast cancer to determine immunotherapy eligibility 2
• PIK3CA mutations: Tested in ER/PgR-positive, HER2-negative metastatic disease 2
• Tumor-infiltrating lymphocytes (TILs): Prognostic in triple-negative and HER2-positive disease, predicting chemotherapy response 2

Common Pitfalls to Avoid

Never rely solely on primary tumor biomarkers for metastatic disease treatment decisions—receptor conversion occurs frequently and directly impacts therapy selection 2. Avoid bone biopsies when possible due to decalcification artifacts that compromise biomarker assessment 2. HER2 testing must only be performed in accredited laboratories with quality assurance programs, as false results are common 2, 3.