Breast Carcinoma

Epidemiology

• Most cases (75%) are diagnosed after age 50
• Incidence is highest in North America, Northern and Western Europe, and Australia/New Zealand
• Females of African descent have the highest mortality rate and a higher proportion of TNBC
• The current overall risk of death after diagnosis is approximately 20%, declining by 1-2% per year

Risk Factors

• Bilateral prophylactic mastectomy: reduces risk by ~90%
• Chemoprevention with ER antagonists (tamoxifen, raloxifene): reduces incidence of ER-positive cancers

Classification

Breast Cancer Classification Diagram

A. In Situ Carcinomas

• A precursor to invasive ductal carcinoma
• Most often detected on mammographic screening as clustered microcalcifications (see mammogram below)
• When invasion develops from untreated DCIS, it is usually an invasive ductal carcinoma in the same breast
• Classified by nuclear grade (low, intermediate, high) and architecture (comedo, cribriform, micropapillary, solid)

• A marker of increased risk and a precursor lesion
• Non-calcifying; usually not detected by mammography alone
• When invasive carcinoma develops: 2/3 occur in the same breast, 1/3 in the contralateral breast

B. Invasive (Infiltrating) Carcinomas - Histological Types

Clinical Subtypes by Biomarker Expression

Molecular Pathology and Pathogenesis

Hereditary Breast Cancer

• ~12% of all breast cancers result from germline mutations
• BRCA1 and BRCA2 account for half of single-gene mutation cases
• BRCA1 (chromosome 17q21): associated with high-grade, ER-negative, basal-like tumors. Also plays a role in differentiation of ER-negative progenitor cells
• BRCA2 (chromosome 13q12.3): associated with luminal-type tumors
• Other genes: PALB2, ATM, RAD51C, RAD51D, CHEK2 - all involved in homologous recombination repair of double-strand DNA breaks
• Homologous recombination deficiency makes tumor cells susceptible to PARP inhibitors (synthetic lethality)
• In Ashkenazi Jewish populations: ~1 in 40 individuals carries one of three specific mutations (2 in BRCA1, 1 in BRCA2)

Clinical Features

• Painless, firm, irregular breast lump (most common presentation)
• Skin dimpling or tethering (Cooper's ligament involvement)
• Nipple retraction or discharge
• Peau d'orange (skin edema due to lymphatic obstruction - classic for inflammatory breast carcinoma)
• Axillary lymphadenopathy
• Rarely, first presentation is distant metastasis (bone, liver, lung, brain)

• Rapid enlargement, skin erythema, warmth, and peau d'orange
• Due to dermal lymphatic invasion by tumor emboli
• Not necessarily a discrete mass; high-stage at diagnosis; poor prognosis

Diagnosis

Triple Assessment

1. Clinical examination
2. Imaging - Mammography ± ultrasound ± MRI
3. Tissue biopsy - Core-needle biopsy (preferred) or FNA

Imaging

• Suspicious features: spiculated mass, asymmetric thickening, clustered microcalcifications (fine, stippled, linear branching pattern)
• Spot compression and magnification views improve characterization
• Sensitivity limited in dense breasts

• Best for distinguishing solid vs. cystic lesions
• Assesses axillary lymph nodes for malignant morphology

• Detects multifocal/multicentric disease and contralateral tumors not seen on mammography
• Used in BRCA mutation carriers for screening

Biopsy

• Core-needle biopsy is preferred: gives histological diagnosis, grade, receptor status (ER, PR, HER2), and Ki-67
• FNA: cytology only; cannot determine invasive vs. in situ
• All primary invasive breast cancers must be tested for ER, PR, and HER2
• HER2 assessed by immunohistochemistry (IHC) for protein overexpression or FISH for gene amplification

Staging (AJCC 8th Edition)

• T - Tumor size and local extent
• N - Regional lymph node involvement
• M - Distant metastasis

Treatment

Surgery

• Sentinel lymph node biopsy (SLNB) - standard for clinically node-negative disease
• Axillary lymph node dissection (ALND) - if positive nodes confirmed clinically or on SLNB

Systemic Therapy

• Tamoxifen (ER antagonist): premenopausal women; reduces recurrence by ~50%
• Aromatase inhibitors (anastrozole, letrozole, exemestane): postmenopausal women; superior to tamoxifen in postmenopausal setting
• CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib): combined with aromatase inhibitors for ER+ HER2- metastatic disease

• Trastuzumab (Herceptin): monoclonal antibody vs. HER2; dramatically improves outcomes in HER2-amplified disease
• Pertuzumab: dual HER2 blockade combined with trastuzumab
• T-DM1 (ado-trastuzumab emtansine): antibody-drug conjugate for residual disease after neoadjuvant therapy

• Anthracyclines (doxorubicin, epirubicin) and taxanes (paclitaxel, docetaxel) are the backbone agents
• Used in neoadjuvant (before surgery) or adjuvant (after surgery) settings
• TNBC and high-risk HER2+ cancers: neoadjuvant chemo +/- immunotherapy (pembrolizumab for TNBC)

• Olaparib, talazoparib
• Mechanism: synthetic lethality in homologous recombination-deficient tumors

Radiation

• Adjuvant radiation after BCS reduces local recurrence by ~70%
• Post-mastectomy radiation for high-risk features (positive margins, ≥4 nodes, T3/T4)

Prognosis

1. Biologic subtype: Luminal A has the best prognosis; TNBC and HER2+ (pre-targeted therapy) have worse outcomes
2. Anatomic stage: Tumor size and nodal status
3. Grade: Histologic grade (Nottingham grading system - tubule formation, nuclear pleomorphism, mitotic index)
4. Biomarker expression: ER+/HER2- tumors have better prognosis than TNBC
5. Gene expression assays: Oncotype DX (21-gene recurrence score), MammaPrint (70-gene signature) - guide adjuvant chemotherapy decisions in ER+ early breast cancer

• Robbins, Cotran & Kumar Pathologic Basis of Disease (primary reference for pathology, molecular classification)
• Robbins & Kumar Basic Pathology (epidemiology, in situ vs invasive distinctions)
• Schwartz's Principles of Surgery, 11th Ed. (histological types, staging, surgical management, biomarker testing)
• Bailey and Love's Short Practice of Surgery, 28th Ed. (clinical management, metastatic disease)