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Breast - Complete Surgical Review

Physiology | Biochemistry | Pathology | Microbiology | Clinical Presentation | Medicine | Pharmacology

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1. ANATOMY & PHYSIOLOGY

Gross Anatomy

• Medial: Perforating branches of the internal thoracic artery (2nd-4th intercostal spaces)
• Lateral: Branches from the axillary artery (lateral thoracic, thoracoacromial)
• Sensory innervation: Lateral and anterior branches of the 4th-6th intercostal nerves

Lymphatic Drainage (surgically critical)

• Lateral breast → axillary nodes (75% of total drainage; Level I > II > III)
• Medial breast → parasternal (internal mammary) nodes
• Axillary levels: Level I (lateral to pectoralis minor), Level II (behind), Level III (medial/infraclavicular)

Microscopic Structure

• Inner luminal epithelial cells - produce milk during lactation
• Basal myoepithelial cells - contractile function, milk ejection, support of basement membrane

Physiological Breast Development

• Puberty: estrogen stimulates ductal growth; progesterone drives lobular development
• Pregnancy: prolactin + human placental lactogen drive alveolar differentiation
• Lactation: prolactin maintains milk production; oxytocin causes myoepithelial contraction, forcing milk from alveolar channels into collecting sinuses (milk ejection reflex - suckling stimulus)
• Menopause: interlobular stroma involutes; glandular tissue regresses

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2. BIOCHEMISTRY

Estrogen Receptor Signaling

• Estrogen binds ERα/ERβ → receptor dimerizes → binds estrogen response elements (ERE) on DNA → transcription of proliferative genes (cyclin D1, c-Myc, VEGF)
• Progesterone receptor (PR) expression is estrogen-dependent (positive PR indicates functional ER pathway)

BRCA1 and BRCA2 Genes

• BRCA1 - chromosome 17q; encodes a DNA damage sensor/repair protein; involved in homologous recombination repair of double-strand breaks
• BRCA2 - chromosome 13q; encodes a DNA repair protein; interacts with RAD51
• 5-10% of all breast cancers are due to inherited BRCA1/2 mutations
• BRCA1 mutation: lifetime breast cancer risk ~65-80%; ovarian cancer risk ~39-46%
• BRCA2 mutation: lifetime breast cancer risk ~45-85%; also increased pancreatic, prostate, and male breast cancer risk
• Male breast cancer is most commonly attributed to BRCA2

HER2/neu (ErbB2)

• Proto-oncogene on chromosome 17q; encodes a receptor tyrosine kinase (transmembrane)
• Amplified/overexpressed in 15-20% of breast cancers
• HER2 has no known ligand - activates by heterodimerization with other HER family members
• Downstream: RAS-MAPK (proliferation) and PI3K-AKT-mTOR (survival) pathways

Key Molecular Pathways

• PI3K/AKT/mTOR: activated by PIK3CA mutations (~40% of ER+ tumors)
• CDK4/6 - Cyclin D1 - Rb axis: drives cell cycle entry (G1→S); targeted therapeutically
• TP53 mutations: common in triple-negative and HER2+ subtypes
• E-cadherin loss: hallmark of lobular carcinoma (loss of cellular cohesion → "single file" invasion)

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3. PATHOLOGY

Benign Conditions

• Non-proliferative: cysts, mild hyperplasia - no increased cancer risk
• Proliferative without atypia (e.g., usual ductal hyperplasia, sclerosing adenosis) - 1.5-2x increased risk
• Proliferative with atypia (atypical ductal hyperplasia [ADH], atypical lobular hyperplasia [ALH]) - 4-5x increased risk; if positive family history, risk up to 10x

• Most common solid benign tumor; young women (20s-30s)
• Intralobular stroma derived - neoplastic stromal cells + reactive epithelial proliferation
• Histology: circumscribed, low cellularity; fibroblasts push/distort epithelium into elongated slitlike structures
• Management: observation if typical on imaging; excision if enlarging or atypical

• Also intralobular stroma derived (spectrum with fibroadenoma)
• Stromal cells outgrow epithelium → "leaf-like" (phyllodes) growth pattern with bulbous nodules of stroma covered by epithelium
• Low/borderline/high grade; high grade may be sarcomatous
• Treatment: wide local excision (WLE) with clear margins - no effective chemotherapy

• Most common cause of unilateral, spontaneous, bloody/serous nipple discharge in premenopausal women
• Grows in large ducts below nipple
• Benign but associated with slightly increased cancer risk

• Peak: first month of breastfeeding
• Organism: Staphylococcus aureus (most common), rarely streptococci
• Treatment: antibiotics (dicloxacillin/flucloxacillin; MRSA → vancomycin or TMP-SMX) + continued milk expression; I&D if fluctuant

• Mixed anaerobic organisms
• Associated with smoking, duct ectasia, periareolar location
• Treatment: antibiotics (co-amoxiclav covers anaerobes); may need I&D and fistula excision

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Premalignant and In Situ Lesions

• Malignant cells confined to ducts/lobules, basement membrane intact
• Most detected by mammography (calcifications - often linear/branching in comedo type)
• Subtypes: comedo (high grade, central necrosis/calcifications), cribriform, micropapillary, solid
• Paget disease of the nipple = DCIS extending up lactiferous ducts into nipple skin → unilateral crusting/oozing exudate over nipple/areola
• Treatment: surgical excision ± radiation → >95% survival at 20 years
• High-grade or extensive DCIS: higher risk of progression to invasive carcinoma

• Bland, monomorphic cells expanding lobules; rarely produces calcifications
• Not truly a precursor lesion but a bilateral risk marker (~1% per year progression to invasive carcinoma in either breast)
• Treatment: surveillance vs. risk reduction with tamoxifen/raloxifene
• E-cadherin negative (unlike DCIS which is E-cadherin positive)

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Invasive Carcinoma - Types

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Molecular Subtypes (Intrinsic Subtypes)

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Grading (Nottingham/Elston-Ellis Grade)

1. Tubule formation
2. Nuclear pleomorphism
3. Mitotic count

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Staging (TNM - AJCC 8th Edition, now includes biomarkers)

• T: T1 ≤2cm; T2 2-5cm; T3 >5cm; T4 chest wall/skin involvement (T4d = inflammatory)
• N: N0 no nodes; N1 1-3 axillary nodes; N2 4-9 nodes; N3 ≥10 nodes or internal mammary
• M: M0 no metastasis; M1 distant metastasis (bone most common, then lung, liver, brain)

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4. MICROBIOLOGY

Breast Infections

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5. CLINICAL PRESENTATION & EXAMINATION

Symptoms and Their Significance

The Triple Assessment

1. Clinical examination
2. Imaging - Mammography (>35y) or Ultrasound (<35y or dense breasts)
3. Tissue biopsy - Core needle biopsy (preferred over FNAC for hormone receptor/HER2 testing)

Screening

• Mammography: standard of care; annual from age 40 (ACS); biennial 50-74 (USPSTF)
• MRI: indicated for BRCA carriers, high-risk women (>20% lifetime risk), implants
• BRCA1/2 carriers: MRI + mammogram annually from age 25-30

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6. SURGICAL MANAGEMENT

Surgical Options for Breast Cancer

Axillary Management

• Developed in 1994; radiotracer (Tc-99m sulfur colloid) ± blue dye injected peritumorally
• First draining node(s) removed and examined (intraoperative frozen section or permanent)
• If sentinel node negative → no further axillary dissection required (NSABP B-32 trial)
• ACOSOG Z0011 trial: even with 1-2 positive sentinel nodes in patients undergoing BCS + whole-breast radiation, completion axillary dissection may be omitted without compromising OS

• Indicated for: clinically positive nodes (confirmed by biopsy), >2 positive sentinel nodes in certain settings, inflammatory breast cancer
• Complications: lymphedema (most feared; 15-25%), shoulder stiffness, nerve injury (long thoracic nerve → winged scapula; thoracodorsal nerve → latissimus weakness)

Breast Reconstruction

• Immediate: at time of mastectomy; psychologically beneficial; better aesthetics; contraindicated if inflammatory breast cancer or when post-mastectomy radiation is planned (risk of implant loss/fibrosis)
• Delayed: after mastectomy on separate date; mandated when radiation or chemotherapy needed first; also for high BMI, poorly controlled diabetes, active smokers

1. Implant-based (most common today):
   • Two-stage: tissue expander placed at mastectomy → gradual expansion → permanent implant exchange (6-12 weeks after expansion complete; delayed further if radiation needed)
   • Direct-to-implant (one-stage): NSM candidates with well-perfused skin flap
   • Implants can be submuscular, subpectoral, or prepectoral (with ADM - acellular dermal matrix)
   • Complication: Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) - rare T-cell lymphoma linked to textured implants
2. Autologous flap reconstruction:
   • TRAM flap (transverse rectus abdominis myocutaneous): pedicled or free; uses lower abdominal skin/fat; associated with abdominal wall weakness
   • DIEP flap (deep inferior epigastric perforator): free flap; spares rectus muscle; gold standard for autologous reconstruction
   • Latissimus dorsi flap: pedicled; often combined with implant; suitable after chest wall radiation
   • SGAP/IGAP flap: gluteal perforator flaps for patients without suitable abdominal tissue

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7. MEDICINE (SYSTEMIC THERAPY & ONCOLOGY)

Adjuvant Chemotherapy

• Used for higher-risk tumors: node-positive, large tumors, triple-negative, HER2+
• Standard regimens: AC-T (doxorubicin/cyclophosphamide → paclitaxel/docetaxel)
• TNBC: AC-T ± carboplatin; consider capecitabine adjuvant after neoadjuvant if residual disease
• Neoadjuvant (pre-operative): to downstage tumors for BCS; pathological complete response (pCR) is a surrogate for improved survival

Prognostic Genomic Tests

• Oncotype DX (21-gene recurrence score): most validated; ER+/HER2-/node-negative (or limited node-positive); score 0-100; guides chemotherapy decisions (TAILORx trial: RS 11-25 → endocrine therapy alone adequate)
• MammaPrint (70-gene signature): FDA-approved for predicting distant recurrence
• Prosigna (PAM50): intrinsic subtype classification + risk of recurrence score

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8. PHARMACOLOGY

A. Endocrine Therapy (for ER+ tumors)

Selective Estrogen Receptor Modulators (SERMs)

• Mechanism: competitive partial antagonist at ER in breast; agonist at uterus and bone
• Reduces breast cancer risk by 38% in high-risk women (chemoprevention - multiple trials including NSABP P-1)
• Adjuvant use: 5-10 years (extended therapy with 10 years shows additional benefit in premenopausal)
• Used in pre- and postmenopausal women
• Side effects: hot flashes, VTE (2-3x risk), endometrial cancer (2-3x risk - agonist effect on uterus), cataracts
• Metabolized by CYP2D6 to endoxifen (active metabolite); CYP2D6 inhibitors (fluoxetine, paroxetine) reduce efficacy

Selective Estrogen Receptor Degraders (SERDs)

Aromatase Inhibitors (AIs) - Postmenopausal women only (or premenopausal + ovarian function suppression)

• Mechanism: inhibit peripheral aromatase (CYP19A1) → block conversion of androgens (androstenedione) to estrogens (estrone) - the main source of estrogen in postmenopausal women
• Side effects: hot flashes, arthralgias/myalgias, vaginal dryness, osteoporosis/fractures (use bisphosphonate co-prescription)
• No increased endometrial cancer or VTE risk (unlike tamoxifen)
• SOFT/TEXT trials: OFS + exemestane superior to tamoxifen in high-risk premenopausal patients

B. CDK4/6 Inhibitors (ER+/HER2- metastatic disease; expanding to adjuvant)

• Palbociclib, Ribociclib, Abemaciclib - inhibit CDK4 and CDK6 → arrest cell cycle at G1
• Combined with letrozole or fulvestrant; significantly improve PFS (PALOMA, MONALEESA, MONARCH trials)
• Abemaciclib: also approved adjuvant for high-risk ER+/HER2- early breast cancer (monarchE trial)
• Key side effects: neutropenia (palbociclib, ribociclib), diarrhea (abemaciclib), QTc prolongation (ribociclib)

C. Anti-HER2 Therapies

• Trastuzumab binds domain IV of HER2 extracellular domain; mediates ADCC via NK cells (Current Surgical Therapy 14e, p.1413; Goldman-Cecil Medicine)

D. PARP Inhibitors (for germline BRCA1/2-mutated tumors)

• Olaparib, Talazoparib - inhibit PARP enzyme → prevent single-strand break repair → replication fork collapse → synthetic lethality in BRCA-deficient cells (defective homologous recombination)
• Olaparib: approved for gBRCA1/2+ early breast cancer (adjuvant, OlympiA trial) and metastatic HER2-
• Used in HER2- (TNBC and ER+) with gBRCA1/2 mutations

E. Immunotherapy (TNBC)

• Pembrolizumab (anti-PD-1): approved with chemotherapy for high-risk early TNBC (KEYNOTE-522) and PD-L1+ metastatic TNBC (KEYNOTE-355)
• Atezolizumab (anti-PD-L1): previously approved for PD-L1+ metastatic TNBC; now primarily replaced by pembrolizumab

F. Antibody-Drug Conjugates (ADC)

• Sacituzumab govitecan (anti-Trop2 ADC): for metastatic TNBC (ASCENT trial) and ER+/HER2-; delivers SN-38 (irinotecan metabolite) intracellularly
• T-DXd: HER2-low (IHC 1+ or 2+/ISH-) tumors - a new actionable category (DESTINY-Breast04)

G. PI3K/mTOR Pathway Inhibitors

• Alpelisib (PI3Kα inhibitor): for PIK3CA-mutated ER+/HER2- metastatic breast cancer (SOLAR-1 trial); combined with fulvestrant; side effects: hyperglycemia, rash, diarrhea
• Everolimus (mTOR inhibitor): combined with exemestane in metastatic ER+/HER2- disease; side effects: stomatitis, pneumonitis, hyperglycemia

H. Chemoprevention Summary

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9. MALE BREAST CANCER

• Rare (~1% of all breast cancers); peak age 60-70 years
• Risk factors: BRCA2 mutation (most important hereditary cause), Klinefelter syndrome (XXY), liver disease, estrogen exposure, obesity
• Almost all are ER+/PR+; treated with tamoxifen (not AIs unless orchiectomy performed, as testes are primary androgen source for aromatization)
• Stage for stage, prognosis similar to female breast cancer

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10. QUICK-REFERENCE KEY FACTS FOR SURGERY EXAMS

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