Breast Cancer Guide: Epidemiology, Risk Factors & Classif...

Carcinoma of the Breast --- Epidemiology Most common malignancy in women globally; 1.7 million new cases/year, 1/3 die of disease Incidence and mortality rising, driven by social changes Rare before age 25; incidence rises sharply after age 30 Kenya (2022): 7,243 cases = 25.5% of all female cancers; 3,398 deaths (18.9% of female cancer deaths) --- Risk Factors Relative Risk Factors --- --- 4.0 Female gender, increasing age, germline mutations (high penetrance), strong family history ( 1 first-degree relative, young age, multiple cancers), personal history of breast cancer, high breast density 2.1–4.0 Germline mutations (moderate penetrance), high-dose chest radiation at young age, family history (1 first-degree relative) 1.1–2.0 Early menarche (<12 yrs), late menopause ( 55 yrs), late first pregnancy ( 35 yrs), nulliparity, no breastfeeding, exogenous hormone therapy, postmenopausal obesity, physical inactivity, high alcohol intake Protective factors: Early first pregnancy (<20 years) Prolonged breastfeeding Bilateral prophylactic mastectomy (↓ risk ~90%) Chemoprevention with ER antagonists (tamoxifen/raloxifene) — reduces ER+ cancers --- Molecular Classification Three major groups defined by ER and HER2 expression: Feature Luminal HER2 TNBC --- --- --- --- ER/HER2 status ER+, HER2− HER2+ (ER± ) ER−, HER2−, PR− % of cancers ~40–55% (low/mod prolif) + ~10% (high prolif) ~20% ~15% mRNA subtype Luminal A / Luminal B HER2-enriched / Luminal B Basal-like Common mutations PIK3CA, TP53 PIK3CA, TP53 (70–80%) PIK3CA (9%), TP53 (70–80%) Typical patient Older women; mammography-detected Young women; BRCA2 or TP53 carriers Young women; African heritage; BRCA1 carriers Chemo response <10% (low) ER−: 30–60%; ER+: ~15% ~30% Metastatic pattern Bone (70%) viscera, brain Bone, viscera, brain (all common) Bone (40%), viscera (35%), brain (25%) Relapse Low rate; late recurrence possible Bimodal (early + 10 yr peaks) Early peak <8 yrs; late recurrence rare Key point: TNBC and HER2 cancers = almost 50% of cancers in young women but <20% in older women. --- Hereditary Breast Cancer — Key Genes Gene Syndrome Risk to Age 70 Notes --- --- --- --- BRCA1 Familial breast/ovarian 40–90% (F); 1% (M) Majority TNBC; also ovarian, fallopian tube, pancreas BRCA2 Familial breast/ovarian 30–60% (F); 6% (M) Majority ER+; also ovarian, pancreas, prostate TP53 Li-Fraumeni 50–60% (F) Majority ER+/HER2+; also sarcoma, leukemia, brain PTEN Cowden 20–80% (F) Also thyroid, endometrium CDH1 Hereditary diffuse gastric ~50% (F) Lobular type; also gastric signet ring ATM Ataxia-telangiectasia 15–30% (F) Moderate penetrance CHEK2 Hereditary breast 10–30% (F) Majority ER+; also prostate, thyroid, colon --- Pathogenesis — Three Pathways 1. Luminal pathway (ER+ / HER2−) — most common BRCA2 mutations → 1q gain, 16q loss → Flat epithelial atypia → Atypical ductal hyperplasia → DCIS → Invasive luminal carcinoma Key driver mutation: PIK3CA 2. TNBC pathway (ER− / HER2−) BRCA1 mutations → TP53 mutations → p53 signature lesion (?) → DCIS → TNBC 3. HER2 pathway Germline TP53 mutations → HER2 amplification → DCIS → HER2+ cancer No definite precursor lesion identified --- Carcinoma In Situ Ductal Carcinoma In Situ (DCIS) Clonal proliferation confined within ducts/lobules by intact basement membrane Myoepithelial cells preserved (though may be reduced) Can spread extensively through the ductal system Detection: Almost always by mammography (calcifications from necrosis/secretions); rare nipple discharge Without screening, <5% of cancers are in situ; rises to 15–30% with mammography Architectural patterns: Comedo — central necrosis with calcification; higher grade Cribriform — "cookie-cutter" rounded spaces with calcified secretions Micropapillary — bulbous protrusions without fibrovascular cores Papillary — true papillae with fibrovascular cores; lacks myoepithelial layer Clinical: Low-grade DCIS progresses to invasive cancer at ~1%/year if untreated Death from metastasis occurs in 1–3% Mastectomy is curative in 95% Breast conservation → slightly higher recurrence (half DCIS, half invasive) --- Lobular Carcinoma In Situ (LCIS) Dyscohesive clonal proliferation (loss of E-cadherin due to CDH1 mutation/dysfunction) Almost always incidental — no calcifications, no mammographic density Incidence unchanged by mammographic screening Bilateral in 20–40% of cases Morphology: uniform round/oval cells, signet ring cells (mucin+), no necrosis, no calcifications Almost always ER+, PR+, HER2− True precursor in some cases (shares mutations with associated invasive lobular carcinoma) --- Paget Disease of the Nipple 1–4% of breast cancers Presents as unilateral erythematous, crusted nipple lesion → easily mistaken for eczema Paget cells: malignant cells extending from underlying DCIS through lactiferous sinuses into nipple skin 50–60% have a palpable mass → almost always invasive carcinoma Without palpable mass → usually only DCIS Usually ER−, HER2+ Prognosis determined by the underlyin