Carcinoma of the Breast

Epidemiology

Risk Factors

Modifiable Risk Factors

Non-Modifiable Risk Factors (Relative Risk >4.0)

• Female sex (99% of cases are female)
• Increasing age
• Germline mutations (BRCA1/BRCA2, high penetrance)
• Strong family history (>1 first-degree relative, early onset, multiple cancers)
• Personal history of breast cancer
• High breast density

Protective Factors

• Early first pregnancy (<20 years)
• Prolonged breastfeeding (>12 months)
• Bilateral prophylactic mastectomy (reduces risk ~90%)
• ER antagonists/chemoprevention (reduces ER-positive cancer incidence)
• Bailey and Love's Short Practice of Surgery, 28th Ed

Classification

Histological Classification

• DCIS (Ductal Carcinoma In Situ): Precursor to invasive ductal carcinoma; found as microcalcifications on mammography. If untreated, the subsequent invasive cancer is typically in the same breast.
• LCIS (Lobular Carcinoma In Situ): Marker of increased risk; two-thirds of subsequent cancers occur in the same breast, one-third in the contralateral breast.

• Medullary carcinoma: Soft, hemorrhagic; dense lymphoreticular infiltrate; often BRCA1 phenotype; <10% ER-positive; better prognosis than NST.
• Mucinous carcinoma: Bulky, gelatinous; >90% ER-positive; 5-year survival ~73%.
• Papillary carcinoma: Presents in 7th decade; ~87% ER-positive; rare LN metastases; favorable prognosis.
• Tubular carcinoma: Up to 20% of screen-detected cancers; ~94% ER-positive; excellent prognosis.
• Paget's disease: Eczematous eruption of nipple; Paget cells (large pale vacuolated cells) in epithelial rete pegs; CEA-positive (vs. S-100-positive in melanoma).
• Schwartz's Principles of Surgery, 11th Ed

Molecular/Clinical Subtypes

• ER-positive/HER2-negative tumors = "Luminal" cancers (largest group, ~40-55% of all)
• Triple-negative breast cancer (TNBC) = ER/PR/HER2-negative = worst prognosis, most chemosensitive acutely
• HER2 cancers and TNBC constitute a higher proportion in younger patients and women of African descent
• Bailey and Love's Short Practice of Surgery, 28th Ed; Robbins, Cotran & Kumar Pathologic Basis of Disease

Pathogenesis

Familial/Genetic Causes

• BRCA1 (17q21): 50-85% lifetime risk of breast cancer; up to 40% risk of ovarian cancer; associated mostly with TNBC.
• BRCA2 (13q12.3): 50-60% lifetime risk; 20% ovarian cancer risk; also associated with prostate, pancreatic, and biliary cancer.
• BRCA1/2 account for 80-90% of single-gene familial breast cancers; ~3-6% of all breast cancers.
• Other high-penetrance genes: TP53 (Li-Fraumeni), PTEN (Cowden), STK11 (Peutz-Jeghers), CDH1.

Clinical Presentation

• Most common: Discrete, painless breast lump - most often in the upper outer quadrant (where 50% of terminal duct-lobular units lie)
• Nipple retraction or discharge (blood/serous)
• Skin changes: peau d'orange (obstruction of cutaneous lymphatic drainage), dimpling/tethering (shortening of Cooper's ligaments), ulceration
• Peau d'orange: sign of locally advanced disease
• Cancer en cuirasse: extensive dermal infiltration of chest wall
• Inflammatory carcinoma: diffuse redness/erythema + skin edema involving >1/3 of the breast; no discrete lump; mimics mastitis but does not respond to antibiotics

Spread and Metastasis

• Bone: lumbar vertebrae > neck of femur > thoracic vertebrae > ribs > skull (generally osteolytic; rarely osteosclerotic). Bone marrow replacement → leukoerythroblastic anaemia.
• Liver, lungs, brain; occasionally adrenals and ovaries.
• Limb deposits occur above the elbow and above the knee (haematopoietic marrow distribution).
• Bailey and Love's Short Practice of Surgery, 28th Ed

Investigations (Triple Assessment)

1. Clinical examination
2. Imaging:
   • Mammography (calcifications, mass, architectural distortion)
   • Ultrasound (solid vs. cystic, LN assessment)
   • MRI (extent of disease, multifocal disease, response to NACT)
   • Bone scan, CT chest/abdomen/pelvis for staging
3. Pathology:
   • Core needle biopsy (histology + receptor status: ER, PR, HER2, Ki-67)
   • Fine needle aspiration cytology (FNAC) - less common now
   • Sentinel lymph node biopsy (SLNB) for axillary staging

TNM Staging (AJCC 8th Edition - Summary)

Management

Neoadjuvant Chemotherapy (NACT)

Surgery

• Breast-Conserving Surgery (BCS/lumpectomy/wide local excision): Preferred when feasible; requires negative margins (no tumor on inked margins for invasive cancer; ≥2 mm for DCIS). Followed by radiotherapy.
• Mastectomy: Indicated for large tumors (relative to breast size), multicentric disease, diffuse microcalcification (DCIS), BRCA-positive cancers, local recurrence after BCS, or patient preference. Skin-sparing/nipple-sparing mastectomy possible when tumor is >1 cm from skin.
• Modified Radical Mastectomy (MRM): Mastectomy + level I/II/III axillary node dissection.
• Radical Mastectomy (Halsted): Rarely indicated now - excessive morbidity, no survival benefit.

• SLNB first (if clinically node-negative); full axillary dissection if SLNB positive.

Radiotherapy

• After all BCS
• After mastectomy if: tumor ≥5 cm, skin/chest wall involvement, lymphovascular invasion (grade 3), or axillary LN-positive
• Dose: 45-50.4 Gy in 25 fractions OR 40-42.5 Gy in 15-16 fractions (hypofractionation)

Adjuvant Systemic Therapy

• EBCCTCG Oxford meta-analyses: chemotherapy improves relapse-free survival by ~30% and overall survival by ~10%.
• Bailey and Love's Short Practice of Surgery, 28th Ed

Metastatic (Stage IV) Breast Cancer

• Bone metastases: bisphosphonates (zoledronic acid) or denosumab; radiotherapy for pain
• Visceral metastases: systemic therapy guided by receptor status
• Pleural effusion: drainage + pleurodesis
• Solitary metastasis in good performance status: consider surgical resection

Hereditary Breast Cancer

• Bilateral risk-reducing mastectomy (↓ risk 90%)
• Chemoprophylaxis with tamoxifen/anastrozole (↓ risk ~50%)
• Bilateral salpingo-oophorectomy after family completion (~35-40 years)
• Bailey and Love's Short Practice of Surgery, 28th Ed

Prognosis

1. Axillary lymph node status (most important)
2. Tumor size (T stage)
3. Histological grade (Nottingham grading)
4. ER/PR/HER2 receptor status (biologic subtype)
5. Ki-67 proliferative index
6. Lymphovascular invasion

• Overall risk of death from invasive breast cancer is approximately 20% (declining ~1-2% per year with modern therapy)
• Luminal A has the best prognosis; TNBC has the worst short-term prognosis
• Gene expression signatures (Oncotype DX, MammaPrint) help guide chemotherapy decisions in ER-positive, HER2-negative early breast cancer