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Carcinoma of the Breast (PA 30.2)

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1. Epidemiology

• Breast cancer is the most common malignancy globally, surpassing lung cancer in 2020 with ~2.3 million new cases, accounting for nearly 12% of all new cancer diagnoses worldwide.
• In the United States, lifetime risk is 1 in 8 females (living to age 90).
• Approximately 75% of breast cancers are diagnosed after age 50.
• The disease is rare under age 25, and incidence rises steeply after age 30.
• Geographic variation: Highest incidence in North America, Northern/Western Europe, and Australia/New Zealand. Incidence is rising in low-resource countries due to lifestyle changes (delayed childbearing, fewer pregnancies, reduced breastfeeding).
• Ethnicity matters: Females of European descent have the highest overall incidence (average diagnosis age 63); females of African descent tend to be diagnosed younger (average 59) and have higher proportions of aggressive subtypes.

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2. Pathogenesis

Familial Breast Cancer

• BRCA1 (chromosome 17q): Tumor suppressor involved in DNA repair by homologous recombination. Loss leads to genomic instability. BRCA1-mutated cancers are frequently high-grade, ER-negative, and "basal-like" (triple negative).
• BRCA2 (chromosome 13q): Also a DNA repair gene. Mutations increase risk of both female and male breast cancer. BRCA2-mutated tumors more often ER-positive.
• Other genes: PTEN (Cowden syndrome), TP53 (Li-Fraumeni syndrome), CDH1 (lobular carcinoma + gastric signet ring carcinoma), PALB2.

Sporadic (Nonfamilial) Breast Cancer

• Driven by somatic mutations accumulating in breast ductal/lobular epithelium.
• Most luminal (ER-positive) cancers have mutations in PIK3CA and CDH1 and amplification of cyclin D1.
• HER2-positive cancers: amplification of the HER2 gene (chromosome 17q), leading to overexpression of HER2 receptor tyrosine kinase, which drives cell proliferation.
• Triple-negative breast cancer (TNBC): Characterized by TP53 mutations, BRCA1 epigenetic silencing, massive genomic instability, high tumor neoantigen burden, and pronounced immune infiltrates - making them more immunogenic and responsive to immunotherapy.

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3. Classification

A. Morphological (Histological) Classification

• DCIS (Ductal carcinoma in situ): Precursor to invasive ductal carcinoma. Most often detected by mammography as calcifications. If untreated, progresses to invasive ductal carcinoma in the same breast.
• LCIS (Lobular carcinoma in situ): Marker of increased risk and precursor lesion. Risk of subsequent invasive carcinoma is bilateral (2/3 ipsilateral, 1/3 contralateral). Cells lack E-cadherin expression (same as invasive lobular carcinoma).

• No special type (NST) - formerly "invasive ductal carcinoma NOS": ~75% of all invasive breast cancers.
• Special histologic types - see Section 4 below.

B. Clinical (Biomarker) Classification

C. Molecular (Intrinsic) Subtypes

• Luminal A: ER+/HER2-, low proliferation - best prognosis
• Luminal B: ER+/HER2-, higher proliferation - intermediate prognosis
• HER2 enriched: HER2 amplified - aggressive
• Basal-like: Mostly TNBC, high grade - poor prognosis
• Normal-like and Claudin-low: Rarer subtypes

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4. Morphologic and Microscopic Features

Gross Morphology

• Most common presentation: hard, irregular mass with spiculated margins (star-like) on mammography.
• Cut surface: gritty, chalky-white due to desmoplastic stroma and foci of calcification.
• Less common: well-circumscribed soft mass (seen in high-grade tumors with lymphocyte infiltrate, "medullary pattern").

Histologic Grading (Nottingham Score)

1. Tubule/gland formation (how much of the tumor forms glandular structures)
2. Nuclear pleomorphism (size and shape variability of nuclei)
3. Mitotic rate

Special Histologic Subtypes

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5. Hormonal Dependency

• Estrogen drives proliferation of luminal cells. ER-positive tumor cells respond to estrogen signaling by upregulating genes involved in cell division.
• Endogenous estrogen excess (from obesity, HRT, early menarche/late menopause) increases risk.
• Anti-estrogen therapies are effective cytostatic treatments for ER-positive cancers:
  • Tamoxifen - competitive ER blocker (used in pre- and post-menopausal women)
  • Aromatase inhibitors (letrozole, anastrozole) - block peripheral estrogen synthesis (used in post-menopausal women)
  • Fulvestrant - ER degrader
  • CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) - used in combination with endocrine therapy for advanced ER+ disease
• Progesterone receptor (PR) status is assessed alongside ER - PR positivity generally indicates a functioning ER signaling pathway and correlates with better response to endocrine therapy.
• HER2 (human epidermal growth factor receptor 2) is technically not a hormone receptor but represents a growth factor signaling axis. HER2 overexpression (due to gene amplification on chromosome 17q) drives proliferation, and is treated with targeted agents (trastuzumab, pertuzumab, lapatinib, trastuzumab-deruxtecan).

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6. Staging and Spread

Staging (AJCC TNM System)

Routes of Spread

• Direct invasion into adjacent breast parenchyma, skin, nipple, and chest wall.
• Cooper ligament involvement leads to skin dimpling.
• Nipple involvement causes nipple retraction.
• Skin lymphatic infiltration causes peau d'orange (orange-peel appearance) - classic of inflammatory carcinoma.

• Axillary lymph nodes (most frequent) - involved in ~50% of cases at diagnosis.
• Internal mammary nodes.
• Supraclavicular and infraclavicular nodes.
• Axillary node status is the single most important prognostic factor for early-stage disease.

1. Bone (most common - especially spine, pelvis, ribs; causes pathological fractures and hypercalcemia)
2. Lung
3. Liver
4. Brain
5. Adrenal glands

• Invasive lobular carcinoma has unique tendency to metastasize to peritoneum, retroperitoneum, leptomeninges (carcinomatous meningitis), GI tract, ovaries, and uterus.
• TNBC and HER2+ cancers metastasize earlier and more aggressively than luminal cancers.

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7. Prognostic Factors

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