SURGERY — BREAST

●​ Polymastia and Associated Syndromes:

EMBRYOLOGY OF THE BREAST
○​ Turner's syndrome (ovarian agenesis and dysgenesis) may have
●​ Mammary Ridges (Milk Lines): polymastia.
○​ Appear in the fifth or sixth week of fetal development. ○​ Fleischer's syndrome (displacement of nipples and bilateral renal
○​ Two ventral bands of thickened ectoderm. hypoplasia) may have polymastia.
○​ Extend from the base of the forelimb (axilla) to the inguinal area. ●​ Accessory Axillary Breast Tissue:
○​ Paired breasts develop along these ridges in most mammals. ○​ Uncommon.
○​ Not prominent in the human embryo and disappear quickly, ○​ Usually bilateral.
except for small portions in the pectoral region.
FUNCTIONAL ANATOMY OF THE BREAST
●​ Breast Structure:
○​ Composed of 15 to 20 lobes, each containing several lobules.
○​ Fibrous connective tissue bands (Cooper's suspensory ligaments)
provide structural support, inserting perpendicularly into the
dermis.

●​ Accessory Breasts (Polymastia) and Nipples (Polythelia):

○​ May occur along the milk line due to failure of normal regression.
●​ Breast Development:
○​ Ingrowth of ectoderm forms a primary tissue bud in the
mesenchyme.
○​ Primary bud initiates 15 to 20 secondary buds. ●​ Breast Location and Extent:
○​ Epithelial cords extend from secondary buds into the ○​ Extends from the second or third rib to the inframammary fold at
mesenchyme. the sixth or seventh rib.
○​ Major (lactiferous) ducts develop, opening into a shallow ○​ Extends transversely from the lateral border of the sternum to the
mammary pit. anterior axillary line.
○​ Mesenchyme proliferation transforms the mammary pit into a ○​ Deep surface rests on the fascia of the pectoralis major, serratus
nipple during infancy. anterior, external oblique abdominal muscles, and the upper
●​ Inverted Nipple: extent of the rectus sheath.
○​ Results from failure of a pit to elevate above skin level. ○​ Retromammary bursa is located between the investing fascia of
○​ Congenital malformation occurring in 4% of infants. the breast and the fascia of the pectoralis major muscles.
●​ Breasts at Birth: ○​ Axillary tail of Spence extends laterally across the anterior axillary
○​ Identical in males and females. fold.
○​ Only major ducts are present. ○​ Upper outer quadrant contains the greatest volume of tissue.
○​ Enlargement may be evident.
○​ "Witch's milk" secretion may be produced due to maternal
hormones crossing the placenta.
●​ Breast Development at Puberty:
○​ Estrogen and progesterone initiate proliferation of epithelial and
connective tissue in females.
○​ Breasts remain incompletely developed until pregnancy.
●​ Breast Form and Variations:
●​ Amastia:
○​ Protuberant conical form.
○​ Rare.
○​ Base is roughly circular, 10 to 12 cm in diameter.
○​ Results from an arrest in mammary ridge development during the
○​ Considerable variations in size, contour, and density among
sixth fetal week.
individuals.
●​ Poland's Syndrome:
●​ Breast Changes with Age and Pregnancy:
○​ Hypoplasia or absence of the breast.
○​ Nulliparous breast: hemispheric with flattening above the nipple.
○​ Costal cartilage and rib defects.
○​ Pregnancy and lactation: larger, increased volume and density.
○​ Hypoplasia of subcutaneous tissues of the chest wall.
○​ Senescence: flattened, flaccid, pendulous, decreased volume.
○​ Brachysyndactyly.
●​ The upper outer quadrant of the breast contains a greater volume of
●​ Breast Hypoplasia:
tissue than do the other quadrants.
○​ May be iatrogenically induced before puberty by trauma, infection,
NIPPLE-AREOLA COMPLEX
or radiation therapy.
●​ Symmastia: ●​ Pigmented and variably corrugated epidermis.
○​ Rare anomaly. ●​ Pigmentation darkens and nipple elevates during puberty.
○​ Webbing between the breasts across the midline. ●​ Areola enlarges and pigmentation further enhances during pregnancy.
●​ Accessory Nipples (Polythelia): ●​ Areola contains sebaceous glands, sweat glands, and accessory glands
○​ Occur in <1% of infants. (Montgomery's tubercles).
○​ May be associated with urinary and cardiovascular system ●​ Smooth muscle fibers (circumferential and longitudinal) in the nipple
abnormalities. cause erection with sensory stimuli.
●​ Supernumerary Breasts: ●​ Dermal papilla contains numerous sensory nerve endings and
○​ May occur anywhere along the milk line. Meissner's corpuscles.
○​ Most frequent between the normal nipple location and the ●​ Rich sensory innervation is crucial for milk letdown during infant sucking.
symphysis pubis.

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 SURGERY — BREAST

INACTIVE AND ACTIVE BREAST BLOOD SUPPLY, INNERVATION AND LYMPHATICS

●​ Inactive and Active Breast Ducts: BLOOD SUPPLY
○​ Each lobe terminates in a major (lactiferous) duct (2-4 mm
●​ Principal supply from:
diameter) opening into the ampulla of the nipple (0.4-0.7 mm
○​ Perforating branches of the
orifice).
internal mammary artery.
○​ Lactiferous sinus: dilated portion of the major duct below the
○​ Lateral branches of the
nipple-areola complex, lined with stratified squamous epithelium.
posterior intercostal arteries.
○​ Major ducts: two layers of cuboidal cells.
○​ Branches of the axillary artery
○​ Minor ducts: single layer of columnar or cuboidal cells.
(highest thoracic, lateral
○​ Myoepithelial cells (ectodermal origin) reside between epithelial
thoracic, pectoral branches of
cells in the basal lamina and contain myofibrils.
the thoracoacromial artery).
●​ Internal mammary artery perforators
(second, third, and fourth) arborize as medial mammary arteries.
●​ Lateral thoracic artery branches supply serratus anterior, pectoralis major
and minor, and subscapularis muscles, and give rise to lateral mammary
branches.
●​ Veins follow arteries, draining toward the axilla (perforating branches of
internal thoracic vein, perforating branches of posterior intercostal veins,
tributaries of axillary vein).
●​ Batson's vertebral venous plexus
○​ Invests the vertebrae and extends from the base of the skull to the
sacrum
○​ May provide a route for breast cancer metastases.
■​ Vertebrae
■​ Skull
■​ Pelvic bones
●​ Inactive Breast:
■​ CNS
○​ Sparse epithelium, primarily ductal.
○​ Early menstrual cycle: minor ducts are cordlike with small lumina.
○​ Ovulation: estrogen stimulation increases alveolar epithelium INNERVATION
height, duct lumina become prominent, some secretions ●​ Sensory innervation: lateral cutaneous branches of third through sixth
accumulate. intercostal nerves (lateral mammary branches) and anterior branches of
○​ Decreased hormonal stimulation: alveolar epithelium regresses. the supraclavicular nerve (cervical plexus).
●​ Active (Pregnant and Lactating) Breast: ●​ Intercostobrachial nerve (lateral cutaneous branch of second intercostal
○​ Proliferative and developmental maturation. nerve) may be visualized during axillary dissection; resection causes loss
○​ Lymphocytes, plasma cells, and eosinophils accumulate in of sensation in medial upper arm.
connective tissues. LYMPHATIC DRAINAGE
○​ Minor ducts branch and alveoli develop (asymmetric
●​ Lymph vessels parallel blood vessels.
development).
●​ Six axillary lymph node groups:
○​ Parturition: breast enlargement due to hypertrophy of alveolar
○​ Axillary vein (lateral): receives most lymph from upper extremity.
epithelium and accumulation of secretory products.
○​ External mammary (anterior/pectoral): receives most lymph
○​ Alveolar epithelium: abundant endoplasmic reticulum,
from lateral breast.
mitochondria, Golgi complexes, and lysosomes.
○​ Scapular (posterior/subscapular): receives lymph from lower
posterior neck, posterior trunk, and posterior shoulder.
○​ Central: receives lymph from axillary vein, external mammary,
scapular groups, and directly from the breast.
○​ Subclavicular (apical): receives lymph from all other axillary
groups.
○​ Interpectoral (Rotter's): between pectoralis major and minor,
receives lymph directly from the breast, drains to central and
subclavicular groups.
●​ Lymph Node Levels:
Levels Enlargement

Level I Lateral/below pectoralis minor (axillary vein, external

mammary, scapula)

Level II Superficial/deep to pectoralis minor (central,

interpectoral)

●​ Milk Production: Level III Medial/above pectoralis minor (subclavicular)

○​ Protein component: synthesized in the endoplasmic reticulum
(merocrine secretion).
○​ Lipid component: forms as free lipid droplets in the cytoplasm
(apocrine secretion).
●​ Colostrum:
○​ Milk released in the first few days after parturition.
○​ Low lipid content, high antibody content.
○​ Antibodies from lymphocytes and plasma cells in connective
tissues.
●​ Mature Milk:
○​ Colostrum production decreases.
○​ Lipid-rich milk is released.
●​ Lymphatic Drainage Pathway:
○​ Plexus in interlobular connective tissue and lactiferous duct walls
communicates with subareolar plexus.
○​ Efferent vessels pass around lateral edge of pectoralis major,
pierce clavipectoral fascia, and end in external mammary group.
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 SURGERY — BREAST

○​ Some vessels go directly to subscapular group. LACTATION

○​ Some from upper breast go directly to subclavicular group.
●​ Postpartum: decreased estrogen and progesterone allows full prolactin
○​ 75% of lymph from medial breast drains via perforating branches
action.
of internal mammary artery to parasternal (internal mammary)
●​ Milk production and release: neural reflex arcs from nipple-areola
nodes.
complex.
●​ Lactation maintenance: regular stimulation of neural reflexes, prolactin
secretion, and milk letdown.
●​ Oxytocin release: auditory, visual, and olfactory stimuli, contraction of
myoepithelial cells, milk expulsion.
●​ Weaning:
○​ Decreased prolactin and oxytocin.
○​ Dormant milk causes pressure, leading to epithelial atrophy.
SENESCENCE
●​ Menopause:
○​ Decreased estrogen and progesterone.
○​ Involution of ducts and alveoli.
○​ Increased density of fibrous connective tissue.
○​ Breast tissue replaced by adipose tissue.
GYNECOMASTIA
PHYSIOLOGY OF THE BREAST
●​ Gynecomastia: Enlarged male breast.
BREAST DEVELOPMENT AND FUNCTION
●​ Physiologic Gynecomastia: Occurs in neonates (placental estrogens),
●​ Hormonal Control of Breast Development and Function: adolescence (estradiol excess), and senescence (testosterone decline).
○​ Initiated by estrogen, progesterone, prolactin, oxytocin, thyroid ●​ Gynecomastia Characteristics:
hormone, cortisol, and growth hormone. ○​ Ductal structures enlarge, elongate, and branch with increased
○​ Estrogen: ductal development. epithelium.
○​ Progesterone: epithelial differentiation and lobular development. ○​ Puberty: often unilateral, ages 12-15.
○​ Prolactin: primary stimulus for lactogenesis, upregulates ○​ Senescence: usually bilateral.
hormone receptors, stimulates epithelial development. ○​ Diagnosis: at least 2 cm diameter breast tissue in non-obese
●​ Hypothalamic-Pituitary-Ovarian Axis: male.
○​ Hypothalamus secretes GnRH. ○​ Mammography and ultrasonography differentiate breast tissues.
○​ Anterior pituitary secretes LH and FSH. ○​ Dominant masses, firmness, irregularity, asymmetry suggest
○​ Ovaries release estrogen and progesterone. breast cancer (especially in older men).
○​ Positive and negative feedback loops regulate hormone secretion. ●​ Gynecomastia and Cancer:
○​ Generally does not predispose to male breast cancer.
○​ Klinefelter's syndrome (XXY) with gynecomastia has increased
breast cancer risk.
Grade Enlargement Skin Redundancy

Grade I Mild None

Grade IIa Moderate None

Grade IIb Moderate (+)

Grade III Marked (+) with ptosis

●​ Pathophysiologic Mechanisms (Table 17-1):
○​ Estrogen excess: testicular/nontesticular tumors, nutritional
alterations, endocrine disorders (hyper/hypothyroidism), hepatic
disease.
○​ Androgen deficiency: decreased testosterone, elevated
testosterone-binding globulin, primary/secondary testicular failure
(Klinefelter's, trauma, orchitis, cryptorchidism), renal failure.
○​ Pharmacologic: estrogenic drugs (digitalis, estrogens, anabolic
●​ Female Neonate and Puberty: steroids, marijuana), drugs enhancing estrogen synthesis (hCG),
○​ Neonate: low estrogen and progesterone due to drugs inhibiting testosterone (cimetidine, ketoconazole, phenytoin,
hypothalamic-pituitary axis sensitivity to negative feedback. spironolactone, antineoplastic agents, diazepam), idiopathic
○​ Puberty: decreased sensitivity to negative feedback, increased mechanisms (reserpine, theophylline, verapamil, tricyclic
sensitivity to positive feedback from estrogen, increased GnRH, antidepressants, furosemide).
FSH, and LH, leading to increased estrogen and progesterone ○​ Idiopathic causes.
and menstrual cycle onset.
●​ Menstrual Cycle and Breast Changes:
○​ Increased breast size and density, followed by engorgement and
epithelial proliferation.
○​ Engorgement subsides and epithelial proliferation decreases with
menstruation.
PREGNANCY, LACTATION, AND SENESCENCE
PREGNANCY AND BREAST CHANGES
●​ Dramatic increase in estrogen and progestins.
●​ Breast enlargement due to ductal and lobular epithelial proliferation.
●​ Areolar skin darkens.
●​ Montgomery's glands become prominent.
●​ First and second trimesters: minor duct branching and development.
●​ Third trimester: fat droplets accumulate, colostrum fills alveolar and
ductal spaces.
●​ Late pregnancy: prolactin stimulates milk fat and protein synthesis.

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●​ Benign, self-limited.
●​ Treatment: anti-inflammatories, warm compresses, excision if persistent.
COMMON BENIGN DISORDERS AND DISEASES OF THE BREAST
●​ Benign breast disorders and diseases:
○​ Encompass a wide range of clinical and pathologic entities.
○​ Require in-depth understanding for:
■​ Clear explanations to affected women.
■​ Appropriate treatment.
■​ Avoidance of unnecessary long-term follow-up.
ABERRATIONS OF NORMAL DEVELOPMENT AND INVOLUTION
●​ Basic principles:
○​ Related to normal processes of reproductive life and involution.
○​ Spectrum of conditions: normal to disorder to disease.
○​ Encompasses all aspects of the breast condition.
■​ Horizontal component: pathogenesis.
■​ Vertical component: degree of abnormality.
●​ ANDI classification:
○​ Defines along a spectrum: normal, mild abnormality (disorder),
●​ Refeeding Gynecomastia: Resumption of pituitary gonadotropin
severe abnormality (disease).
secretion after pituitary shutdown.
○​ Indicates the period during which the condition develops.
●​ Senescent Gynecomastia: Decreased testosterone, elevated
testosterone-binding globulin, reduced free testosterone, usually in men
aged 50-70.
●​ Treatment:
○​ Androgen deficiency: testosterone administration.
○​ Medication-induced: discontinue medication.
○​ Endocrine defects: specific therapy.
○​ Progressive/unresponsive: surgical therapy (excision,
liposuction, subcutaneous mastectomy).
○​ Danazol: may be successful, but significant androgenic side
effects.
INFECTIOUS AND INFLAMMATORY DISORDERS OF THE BREAST
●​ Infections of the Breast:
○​ Postpartum most common.
○​ Non-lactational: intrinsic (breast abnormality) or extrinsic
(adjacent structure infection).
EARLY REPRODUCTIVE YEARS
BACTERIAL INFECTION
●​ Fibroadenomas:
●​ S. aureus, Streptococcus most frequent.
○​ Predominantly seen in younger women (15-25 years).
●​ S. aureus: abscesses (point tenderness, erythema, hyperthermia), often
○​ Usually grow to 1-2 cm, then stable, but may grow larger.
in first few weeks of breastfeeding.
○​ Classification by size:
●​ Abscess types:
■​ ≤1 cm: normal.
○​ Subcutaneous
■​ ≤3 cm: disorder.
○​ Subareolar
■​ 3 cm (giant fibroadenomas): disease.
○​ Interlobular (periductal)
○​ Multiple fibroadenomas (more than five): disease.
○​ Retromammary
○​ Asymptomatic fibroadenomas sometimes found in older women
●​ Treatment: antibiotics (penicillin or cephalosporin) and repeated
due to mammographic screening.
ultrasound-guided aspiration, surgery if unresolved.
●​ Adolescent breast hypertrophy:
●​ Streptococcus: diffuse superficial involvement, local wound care, IV
○​ Precise etiology unknown.
antibiotics.
○​ Spectrum of changes: limited to massive stromal hyperplasia
●​ Chronic infections: cultures for acid-fast bacilli, anaerobes, aerobes,
(gigantomastia).
fungi, long-term antibiotics.
●​ Nipple inversion:
●​ Abscess cavity wall biopsy: rule out cancer if antibiotics/drainage
○​ Disorder of major duct development.
ineffective.
○​ Prevents normal nipple protrusion.
●​ Puerperal infections: less common now.
●​ Mammary duct fistulas:
●​ Epidemic puerperal mastitis: virulent S. aureus, breastfeeding stopped,
○​ Arise when nipple inversion predisposes to major duct
antibiotics, surgery.
obstruction.
●​ Nonepidemic puerperal mastitis: nipple fissuring, milk stasis,
○​ Leads to recurrent subareolar abscess and mammary duct fistula.
retrograde infection, emptying breast, antibiotics.
●​ Zuska's disease (recurrent periductal mastitis): recurrent retroareolar LATER REPRODUCTIVE YEARS
infections/abscesses, smoking risk factor, antibiotics, incision/drainage, ●​ Cyclical mastalgia and nodularity:
debridement/resection. ○​ Usually associated with premenstrual breast enlargement.
MYCOTIC INFECTION ○​ Considered normal.
○​ Pronounced mastalgia and severe painful nodularity: viewed
●​ Rare, usually blastomycosis/sporotrichosis.
differently than physiologic discomfort and lumpiness.
●​ Infant oral fungi, mammary abscesses near nipple, bloody pus, antifungal
○​ Painful nodularity persisting >1 week of menstrual cycle: disorder.
agents.
●​ Epithelial hyperplasia of pregnancy:
●​ Candida: erythematous, scaly lesions, topical nystatin.
○​ Papillary projections may cause bilateral bloody nipple discharge.
HIDRADENITIS SUPPURATIVA
INVOLUTION
●​ Chronic inflammation, Montgomery/sebaceous glands, chronic acne
predisposition. ●​ Lobular epithelium involution: dependent on specialized stroma.
●​ Nipple-areola/axilla, mimics other conditions. ●​ Integrated stroma and epithelium involution not always seen.
●​ Treatment: antibiotics, incision/drainage, excision, skin grafts. ●​ Stroma involutes too quickly: alveoli remain, forming microcysts
(precursors of macrocysts).
MONDOR’S DISEASE
●​ Macrocysts: common, often subclinical, no specific treatment needed.
●​ Thrombophlebitis of superficial chest/breast veins.
●​ Sclerosing adenosis: disorder of both proliferative and involutional
●​ Tender, cord-like structure, acute pain.
phases.
●​ Lateral thoracic, thoracoepigastric, superficial epigastric veins.
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 SURGERY — BREAST

●​ Duct ectasia (dilated ducts) and periductal mastitis: important Fibrocystic Disease ●​ Nonspecific term, used inappropriately.
components of ANDI. ●​ Synonyms: fibrocystic changes, cystic mastopathy,
●​ Periductal fibrosis: sequela of periductal mastitis, may result in nipple etc.
retraction. ●​ Refers to spectrum of histopathologic changes,
●​ Epithelial hyperplasia: ~60% of women ≥70 years exhibit some degree. should be diagnosed/treated specifically.
●​ Atypical proliferative diseases: ductal and lobular hyperplasia (some
features of carcinoma in situ).
●​ Atypical ductal or lobular hyperplasia: fourfold increase in breast PATHOLOGY OF PROLIFERATIVE DISORDERS WITHOUT ATYPIA
cancer risk. ●​ Includes: sclerosing adenosis, radial scars, complex sclerosing lesions,
ductal epithelial hyperplasia, intraductal papillomas.
Condition Characteristics & Features
Sclerosing Adenosis ●​ Childbearing/menopausal years, no malignant
potential.
●​ Proliferative (ductal proliferation) and involutional
(stromal fibrosis, epithelial regression) changes.
●​ Distorted lobules, often with microcysts, may
present as mass.
●​ Benign calcifications common.
●​ Management: observation if imaging/pathology
concordant.
Radial Scars/Complex ●​ Central sclerosis, epithelial proliferation, apocrine
Sclerosing Lesions metaplasia, papilloma formation.
●​ Radial scar: <1cm.
●​ Complex sclerosing lesion: >1cm, more structural
disturbance.
●​ Distinguishing from invasive carcinoma can be
challenging (biopsy/excision).
Ductal Hyperplasia ●​ Mild: 3-4 cell layers above basement membrane.
●​ Moderate: 5+ cell layers.
●​ Florid: >70% of duct lumen, increased cancer risk.
Intraductal Papillomas ●​ Major ducts, usually premenopausal, <0.5cm (up to
5cm).
●​ Nipple discharge (serous/bloody) common.
●​ Pinkish tan, friable, stalk.
○​ Small painful movable nodule directly beneath
the areola
●​ Rarely malignant, no increased cancer risk (unless
with atypia).
●​ Multiple papillomas (younger women): susceptible
PATHOLOGY OF NONPROLIFERATIVE DISORDERS
to malignant transformation.
●​ Histologic differentiation: benign, atypical, malignant.
●​ Page classification: nonproliferative, proliferative without atypia,
proliferative with atypia. PATHOLOGY OF ATYPICAL PROLIFERATIVE DISEASES
●​ Nonproliferative disorders: 70% of benign conditions, no increased ●​ Some features of carcinoma in situ, but not fully developed.
cancer risk. Condition Characteristics & Features
●​ Includes: cysts, duct ectasia, periductal mastitis, calcifications,
Atypical Ductal ●​ Similar to low-grade DCIS.
fibroadenomas.
Hyperplasia (ADH) ●​ Monotonous round/cuboidal/polygonal cells,
Condition Characteristics & Features basement membrane, rare mitoses.
Breast Macrocysts ●​ Involutional disorder, often multiple. ●​ ADH: ≤2-3mm, DCIS: >3mm.
●​ Diagnosis difficult on core biopsy, often needs
Duct Ectasia ●​ Dilated subareolar ducts, palpable, nipple
excision.
discharge.
●​ Increased breast cancer risk.
●​ Haagensen: ectasia → stagnation → ulceration →
inflammation → fibrosis → retraction. Lobular Neoplasia ●​ Spectrum: atypical lobular hyperplasia (ALH) to
●​ Alternative theory: mastitis → duct weakening → lobular carcinoma in situ (LCIS).
dilatation. ●​ ALH: minimal lobular distention, cells similar to
●​ Problems: nipple discharge, retraction, LCIS.
inflammatory masses, abscesses. ●​ LCIS: monomorphic cells distend terminal ductal
lobular unit, acini full, lobular architecture
Calcifications ●​ Most benign, from
maintained.
secretions/debris/trauma/inflammation.
●​ Classic LCIS: no specific mammographic/palpable
●​ Cancer-associated: microcalcifications (<0.5mm,
abnormality, incidental finding.
variable shape/density), fine linear branching.
●​ Pleomorphic LCIS: calcifications/suspicious
Fibroadenomas ●​ Abundant stroma, normal cellular elements. mammographic changes.
●​ Hormonal dependence (lactate in pregnancy, ●​ Classic LCIS: no excision, risk reduction strategies.
involute postmenopause). ●​ Pleomorphic LCIS: difficult to distinguish from
Adenomas ●​ Well-circumscribed, benign epithelium, sparse high-grade DCIS, may be managed like DCIS
stroma. (margins, radiation).
●​ Types: tubular (young, nonpregnant), lactating ●​ E-cadherin staining: LCIS/ALH lack expression,
(pregnancy/postpartum). ductal lesions express it.

Hamartomas ●​ Discrete tumors, 2-4cm, firm, sharply

circumscribed.
Adenolipomas ●​ Sharply circumscribed, fatty tissue, normal
lobules/ducts.

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 SURGERY — BREAST

PATHOLOGY OF ATYPICAL PROLIFERATIVE DISEASES RISK ASSESSMENT MODELS

●​ Average lifetime risk for US women: 12%.
Condition Characteristics & Management
●​ Risk decreases with age (e.g., 50 years: 11%, 70 years: 7%).
Cysts ●​ Firm movable mass ●​ Models needed due to interacting risk factors.
●​ Image before needle biopsy. ●​ Gail Model:
○​ Anechoic mass with regular borders ○​ Factors:
●​ Fine Needle Aspiration: 21-gauge needle, 10mL ■​ Age
syringe, aspirate to dryness if fluid not bloody, ■​ Menarche age
discard fluid. ■​ First live birth age
●​ Palpate after aspiration. ■​ Breast biopsies
●​ Most aspirated under ultrasound guidance. ■​ Atypical hyperplasia history
●​ If residual mass: core biopsy. ■​ Family history.
●​ Bloody fluid: cytology. ○​ Predicts cumulative risk by decade.
●​ Complex cyst: concern for malignancy. ○​ Risk score: relative risks multiplied, compared to population risk.
●​ Pneumocystogram: inject air, repeat mammogram. ○​ Output: 5-year and lifetime risk.
Fibroadenomas ●​ Most self-limiting. ○​ Paget: National Cancer Institute.
●​ Many go undiagnosed, so a more conservative ○​ Modified for African American and Asian/Pacific Islander women.
approach is reasonable ○​ Revised model: includes weight and mammographic density,
●​ Ultrasound + core biopsy for diagnosis. excludes menarche age.
○​ Well-circumscribed solid (hypoechoic) mass Variable Relative Risk
●​ Young women (<25): core biopsy may not be
Age at menarche (years)
needed if ultrasound pathognomonic.
●​ Options for those > 2 cm: surgical removal, ≥14 1.00
cryoablation, vacuum-assisted biopsy, observation. 12–13 1.10
●​ Many decrease in size, especially <3cm.
<12 1.21
Sclerosing Disorders ●​ Sclerosing adenosis: mimics cancer, needs
Number of biopsy specimens/history of benign breast disease,
excisional biopsy.
age <50 y
●​ Radial scars/complex sclerosing lesions:
stereotactic biopsy, difficult to differentiate from 0 1.00
cancer, larger biopsy (vacuum-assisted or 1 1.70
excisional).
●​ Discordance: if core biopsy benign but imaging ≥2 2.88
suspicious. Number of biopsy specimens/history of benign breast disease,
Periductal Mastitis ●​ Aspiration: 21-gauge needle, culture for anaerobes. age ≥50 y
●​ Antibiotics: cover polymicrobial infection. 0 1.02
●​ Purulent material: repeated ultrasound-guided
1 1.27
aspiration.
●​ Surgery: drainage or definitive surgery. ≥2 1.62
●​ Subareolar abscess: usually unilocular. Age at first live birth (years)
●​ Fistulectomy: preferred for localized abscess +
<20 y
fistula.
●​ Total duct excision: for diffuse sepsis or multiple 0 first-degree relatives with history of breast cancer 1.00
fistulas. 1 first-degree relative 2.61
●​ Antibiotics after fistula excision.
≥2 first-degree relatives 6.80
Nipple Inversion ●​ Congenital more common than from duct ectasia.
20–24 y
●​ Complications: altered sensation, necrosis,
fibrosis/retraction. 0 first-degree relatives 1.24
●​ Surgery: divide subareolar ducts for permanent
1 first-degree relative 2.68
correction.
≥2 first-degree relatives 5.78
25–29 y
RISK FACTORS FOR BREAST CANCER
HORMONAL AND NONHORMONAL RISK FACTORS 0 first-degree relatives 1.55

●​ Risk Factors for Breast Cancer: 1 first-degree relative 2.76

Hormonal Factors ≥2 first-degree relatives 4.91
Increased Risk Protective Factors ≥30 y
Increased estrogen exposure Reduced estrogen exposure 0 first-degree relatives 1.93
Increasing menstrual cycles Decreasing menstrual cycles 1 first-degree relative 2.83
●​ Early menarche ●​ Exercise
≥2 first-degree relatives 4.17
●​ Nulliparity ●​ Longer lactation
●​ Late menopause
●​ Claus Model:
Older age at first live birth ○​ From Cancer and Steroid Hormone Study.
Obesity ○​ Factors: family history (first- and second-degree relatives).
○​ Estimates risk by decade.
Non-Hormonal
○​ Excludes: diet, oral contraceptives, lactation, radiation.
Radiation exposure (esp during ●​ Other Models:
adolescence) ○​ Account for mammographic density.
Alcohol consumption (increases ●​ BRCAPRO Model:
estradiol levels) ○​ Mendelian model, calculates BRCA1/2 mutation probability.
○​ Uses family history of breast/ovarian cancer.
High-fat diet (increased estrogen
○​ Predicts breast/ovarian cancer risk based on mutation probability.
levels)
○​ Challenging to use: requires extensive family history.

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 SURGERY — BREAST

●​ Tyrer-Cuzick Model: ○​ Raloxifene: 76% of tamoxifen efficacy, less endometrial cancer,

○​ Combines family history and individual risk factors. no effect on LCIS/DCIS.
○​ Calculates mutation probability, adjusts for personal factors ●​ Aromatase inhibitors (AIs): more effective than tamoxifen for
(menarche, parity, birth age, menopause, hyperplasia/LCIS contralateral breast cancer.
history, height, BMI). ●​ MAP.3 trial: exemestane vs. placebo, 65% reduction in invasive cancer.
●​ Risk assessment results: communicate to individual, consider other ●​ IBIS II trial: anastrozole vs. placebo, 50% reduction.
risks/comorbidities, discuss risk management options. ●​ ASCO: tamoxifen for pre/postmenopausal, raloxifene/exemestane
RISK MANAGEMENT for postmenopausal at increased risk.
●​ Breast cancer risk influences medical decisions: hormone therapy, RISK-REDUCING SURGERY
mammography/MRI screening, tamoxifen use, prophylactic mastectomy. ●​ Prophylactic mastectomy: reduces risk by >90% (retrospective study).
POSTMENOPAUSAL HORMONE REPLACEMENT THERAPY ●​ BRCA mutation study: benefit depends on risk: 40% risk adds 3 years of
life, 85% risk adds >5 years.
●​ Used for estrogen deficiency symptoms (hot flashes, night sweats,
●​ Domchek et al.: risk-reducing mastectomy effective in BRCA carriers.
osteoporosis, cognitive changes).
●​ Risk-reducing salpingo-oophorectomy: reduces ovarian/breast cancer,
●​ Combined estrogen/progesterone: standard for women with intact
reduces mortality.
uterus (unopposed estrogen increases uterine cancer risk).
●​ Bilateral prophylactic mastectomy: reduces incidence, limited data on
●​ Concerns about prolonged estrogen exposure and cardiovascular effects
survival benefit, cosmetic issues.
led to large trials.
●​ Women's Health Initiative (WHI): showed increased breast cancer risk BRCA MUTATIONS
(3-4x after >4 years), no significant reduction in coronary/cerebrovascular ●​ Up to 5% of breast cancers due to inherited germline mutations (BRCA1,
risks. BRCA2).
●​ Collaborative Group: increased risk with any estrogen replacement ●​ Autosomal dominant inheritance, varying penetrance.
therapy, increased risk with current use, increased risk with longer use. Feature BRCA1 BRCA2
●​ WHI: estrogen + progesterone increased breast cancer incidence.
Location Chromosome arm 17q Chromosome arm 13q
●​ Million Women Study: confirmed increased risk, greater with combined
estrogen + progesterone. Inheritance Autosomal dominant with high Autosomal dominant with high
penetrance (50% of children penetrance (50% of children of
BREAST CANCER SCREENING of carriers inherit the trait) carriers inherit the trait)
●​ Mammography (≥50 years): reduces mortality by 25%. Function Transcription, cell-cycle Not well defined; some role in
●​ Debate about screening harms. control, and DNA damage DNA damage response
●​ Conflicting recommendations: USPSTF, ACS, NCCN. repair pathways
●​ High-risk definition: personal history, chest radiation, genetic mutation. Mutation carrier 85% 85%
●​ USPSTF: biennial mammography 50-74 years. risk of breast
●​ ACS: annual mammography at 45, 45-54 annual, 55+ biennial or annual, cancer
offer annual 40-44, continue as long as health and 10+ year life Mutation carrier 40% 20% (lower)
expectancy, no clinical breast exam for average risk. risk of ovarian
●​ NCCN: annual mammography ≥40, annual clinical breast exam, breast cancer
awareness. Characteristics Invasive ductal carcinomas Invasive ductal carcinomas
●​ UK expert panel: screening reduces mortality by ~20%, 11% of breast cancer
overdiagnosis, but screening should continue. Poorly differentiated Well differentiated
●​ Mammography <50: controversial (reduced sensitivity/specificity, lower
Hormone receptor negative or More likely to express hormone
incidence). triple receptor negative: ER(-), receptors
●​ US: benefits in 40-49 outweigh risks, targeted screening for high-risk PR (-), HER2 (-) or basal
women. phenotype
●​ Family history: abnormal mammography 3x more likely to be cancer in Distinguishing Early age of onset compared Early age of onset compared
women 40-49. clinical features with sporadic cases with sporadic cases
●​ Mammographic density: independent risk factor, incorporation into
Higher prevalence of bilateral Higher prevalence of bilateral
models promising. breast cancer breast cancer
●​ Ultrasonography: for dense breasts, no data on mortality reduction.
Associated Ovarian cancer (primarily) Ovarian
●​ MRI: ACS recommends for ≥20-25% lifetime risk, BRCA mutation, cancers Colon cancer Colon cancer
untested family member with mutation, chest radiation 10-30 years, Prostate cancer Prostate cancer
Li-Fraumeni/Cowden/Bannayan-Riley-Ruvalcaba syndrome, or Pancreatic cancer
first-degree relative with these syndromes. Gallbladder cancer
●​ MRI: high sensitivity, moderate specificity (more false positives). Bile duct cancer
Stomach cancers
CHEMOPREVENTION Melanoma
●​ Tamoxifen: first drug shown to reduce breast cancer incidence. ●​ Risk-Reducing Surgery
●​ No mortality effect (trials not powered for it). ○​ Prophylactic mastectomy
●​ Adverse events: ○​ Risk-reducing salpingo-oophorectomy
○​ Endometrial cancer
EPIDEMIOLOGY OF BREAST CA
○​ Thromboembolic events
●​ General Statistics:
○​ Cataracts
○​ Breast cancer: most common cancer in women, leading cause of
○​ Vasomotor disturbances.
cancer death in women 20-59
●​ Tamoxifen recommendation:
○​ 2018 estimates: 266,120 new cases, 40,920 deaths.
○​ Gail risk ≥1.66%
○​ 30% of new cancers in women, 14% of cancer deaths.
○​ Age 35-59 or >60
○​ Lifetime risk: 1 in 8 US women (2004).
○​ LCIS or Atypical hyperplasia
●​ Trends:
●​ Tamoxifen risks:
○​ 1970s: 1 in 13 lifetime risk.
○​ DVT 1.6x
○​ 1980: 1 in 11 lifetime risk.
○​ PE 3x
○​ Mid-1940s: increasing incidence.
○​ Endometrial cancer 2.5x
○​ 2000: incidence decreased 2-3% per year.
○​ Cataract surgery ~2x
○​ 1973-1980: ~1% annual increase.
●​ Gail model:
○​ 1980-1987: 4% increase.
○​ Accounts for risk and comorbidities to determine tamoxifen
○​ Increased incidence primarily in women ≥55, paralleled
risk/benefit.
mammogram increase.
●​ Tamoxifen vs. Raloxifene.
○​ Decreased regional metastasis, decreased mortality.
○​ Raloxifene: similar breast cancer reduction, better adverse event
profile.
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 SURGERY — BREAST

●​ Survival Rates: ○​ Metastatic foci implantation: after primary cancer >0.5cm (~27th
○​ 1960-1963: 63% 5-year survival (White), 46% (African American). doubling).
○​ 1981-1983: 78% 5-year survival (White), 64% (African American). ○​ 10 years post-treatment: distant metastases most common death
○​ 2002-2008: 92% 5-year survival (White), 78% (African American). cause.
●​ Global Variation: ○​ Metastases may appear 20-30 years after primary treatment.
○​ 10-fold variation in incidence across countries. ○​ ER-negative: earlier recurrence (3-5 years).
○​ Highest mortality: Cyprus, Malta (29.6/100,000). ○​ ER-positive: slower recurrence beyond 5 years.
○​ Lowest mortality: Haiti (2.0/100,000). ○​ Common sites:
○​ US mortality: 19.0/100,000. ■​ Bone
○​ Less industrialized nations: lower incidence (except Japan). ■​ Lung
○​ US: Mormons, Seventh Day Adventists, American Indians, Alaska ■​ Pleura
Natives, Hispanic/Latina, Japanese/Filipino (Hawaii) have ■​ Soft tissue
below-average incidence. Nuns and Ashkenazi Jewish women ■​ Liver.
have above-average incidence. ○​ Brain metastases: less frequent overall, may be seen earlier with
●​ Recent Trends: systemic therapies.
○​ 1990s: incidence increased in most countries (~0.5% annually). ■​ Risk factors:
○​ China/East Asia: increases up to 3-4% annually. ●​ Triple-negative
○​ Past decade: incidence decline (attributed to decreased HRT use). ●​ HER2-positive (post-chemo/HER2 therapy).
●​ Geographic/Lifestyle/Ethnic Variation:
○​ Asia/Africa: lower incidence/mortality.
○​ Industrialized/Westernized: higher burden.
○​ Lower incidence: young childbearing, multiple pregnancies,
prolonged lactation.
○​ Higher mortality in underdeveloped nations: lack of
screening/treatment.
○​ Asian Americans: increased incidence/mortality with Western
lifestyles.
●​ US Disparities:
○​ African Americans/Hispanic/Latina: higher poverty, less insurance,
barriers to screening/treatment, delayed diagnosis, increased
mortality.
○​ Hispanic: language barriers.
○​ Treatment inequities: less systemic therapy, sentinel node
dissection, reconstruction.
○​ Comorbidities contribute.
○​ Unexplained unevenness in treatment. DIAGNOSIS OF BREAST CANCER
●​ Racial/Ethnic Ancestry: ●​ Presenting signs and symptoms (not all are present in every case):
○​ African Americans: lower lifetime risk, higher mortality, younger ○​ Lump in breast (∼30% of cases).
age distribution, higher ER-negative tumors, similar patterns in ○​ Breast enlargement or asymmetry.
West Africa. ○​ Nipple changes (retraction, discharge).
○​ Increased male breast cancer in African Americans/Africans. ○​ Ulceration or erythema of breast skin.
●​ Untreated Breast Cancer (1805-1933): ○​ Axillary mass.
○​ Median survival: 2.7 years. ○​ Musculoskeletal discomfort.
○​ 5-year survival: 18%. ●​ Up to 50% of women with breast complaints have no physical signs.
○​ 10-year survival: 3.6%. ●​ Breast pain is usually associated with benign disease.
○​ 15-year survival: 0.8%. ●​ Misdiagnosis:
○​ 95% died of breast cancer. ○​ Accounts for most malpractice claims for diagnostic errors.
○​ ~75% developed breast ulceration. ○​ Accounts for largest number of paid claims.
○​ Longest survival: 19 years. ○​ Litigation often involves younger women (≤45 years).
NATURAL HISTORY OF BREAST CA ○​ Physical examination and mammogram may be misleading in
●​ Primary Breast Cancer: younger women.
○​ 80% show productive fibrosis. ○​ Young women with palpable mass and equivocal mammogram:
○​ Desmoplastic response: entraps/shortens Cooper's ligaments ultrasound and biopsy to avoid delay.
→ skin retraction. EXAMINATION
○​ Peau d'orange: localized edema from disrupted lymph drainage. ●​ Inspection:
○​ Skin invasion → ulceration → satellite nodules. ○​ Arms at sides (Fig. 17-18A).
○​ Size correlates with disease-free/overall survival, closely ○​ Arms raised (Fig. 17-18B).
associated with axillary node involvement. ○​ Hands on hips (with and without pectoral muscle contraction).
○​ Recurrence: ○​ Record: symmetry, size, shape, edema (peau d'orange),
■​ ~20% local-regional nipple/skin retraction, erythema.
■​ >60% distant ○​ Arms extended forward, leaning forward: accentuate skin
■​ ~20% both retraction.
●​ Axillary Lymph Node Metastases: ●​ Palpation:
○​ Cancer cells shed into lymphatics → regional nodes (especially ○​ Supine position (Fig. 17-18C).
axillary). ○​ Palpate all quadrants: sternum to latissimus dorsi, clavicle to
○​ Nodes: soft → firm/hard → conglomerate mass → fixed to upper rectus sheath.
axilla/chest wall. ○​ Palmar aspect of fingers, avoid grasping/pinching.
○​ Sequential involvement: level I → II → III. ○​ Cup/mold breast to check for retraction.
○​ ~95% of breast cancer deaths involve distant metastases. ○​ Systematic search for lymphadenopathy.
○​ Node status: major prognostic factor. ○​ Axillary examination (Fig. 17-18D): support arm/elbow, assess all
■​ Node-negative: <30% recurrence risk. three levels of axillary nodes.
■​ Node-positive: up to 75% recurrence risk. ○​ Palpate supraclavicular and parasternal sites.
●​ Distant Metastases: ○​ Diagram (Fig. 17-19): record location, size, consistency, shape,
○​ ~20th cell doubling: neovascularization. mobility, fixation, other characteristics of mass/lymphadenopathy.
○​ Cancer cells shed into venous blood → lungs/vertebral column.

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 SURGERY — BREAST

IMAGING TECHNIQUES ●​ Intraductal papillomas: small filling defects surrounded by contrast.

●​ Cancers: irregular masses or multiple intraluminal filling defects.
MAMMOGRAPHY
ULTRASONOGRAPHY
●​ Conventional mammography: 0.1 cGy radiation dose per study.
●​ Chest radiography: 25% of mammography dose. ●​ Second most frequent breast imaging method (after mammography).
●​ No increased breast cancer risk from screening mammography radiation. ●​ Resolves equivocal mammographic findings.
●​ Screening mammography: detects unexpected cancer in asymptomatic ●​ Defines cystic masses.
women, supplements history and physical exam. ●​ Demonstrates echogenic qualities of solid abnormalities.
○​ Two views: craniocaudal (CC) and mediolateral oblique (MLO). ●​ Guides fine-needle aspiration, core-needle biopsy, needle localization.
○​ MLO: images most breast tissue, including upper outer quadrant ●​ Highly reproducible, high patient acceptance.
and axillary tail of Spence. ●​ Does not reliably detect lesions ≤1 cm.
○​ CC: better visualization of medial breast, greater compression. ●​ Can image regional lymph nodes.
●​ Diagnostic mammography: evaluates abnormal findings (mass, nipple ●​ Axillary node examination:
discharge). ○​ Sensitivity: 35-82%.
○​ May use additional views: 90° lateral, spot compression. ○​ Specificity: 73-97%.
○​ 90° lateral + CC: triangulate abnormality location.
○​ Spot compression: small device over abnormality, minimizes
motion artifact, improves definition, separates tissues, decreases
radiation.
○​ Magnification (×1.5) with spot compression: resolves
calcifications and mass margins.
○​ Guides interventional procedures (needle localization, biopsy).
●​ Mammographic features suggesting cancer:
○​ Solid mass (with/without stellate features).
○​ Asymmetric tissue thickening.
○​ Clustered microcalcifications (fine, stippled calcium: ~50% of
nonpalpable cancers, important in younger women). MAGNETIC RESONANCE IMAGING
●​ Screening mammography impetus: Health Insurance Plan study and
●​ Detects additional breast lesions while evaluating mammographic
Breast Cancer Detection Demonstration Project (33% mortality reduction
abnormalities.
after 72).
●​ Low probability of cancer diagnosis by MRI if mammography and
●​ Mammography more accurate than clinical exam for early cancers: 90%
physical exam are negative.
true-positive rate.
●​ Uses:
●​ Nonpalpable cancers: 20% with axillary node metastases (vs. 50% with
○​ Screening high-risk women (strong family history, genetic
palpable cancers).
mutations): mammography limited by breast density in younger
●​ NCCN guidelines:
women.
○​ ≥20 years: breast exam every 3 years.
○​ Evaluating contralateral breast in newly diagnosed cancer: 5.7%
○​ ≥40 years: yearly exam and mammogram.
show contralateral cancer.
○​ ≥50 years: screening reduces mortality by 20-25%.
○​ Detecting additional tumors in the index breast
●​ UK review: 11% of cancers diagnosed via screening are overdiagnosis,
(multifocal/multicentric disease): may alter surgical decisions.
but screening still confers significant benefit.
○​ Surgical treatment planning: identifies additional disease,
●​ <50 years: controversial due to reduced sensitivity/specificity and lower
assesses extent.
incidence; targeted screening for high-risk women.
●​ No decrease in reoperation rates with MRI + mammography + ultrasound
●​ Risk assessment models available to estimate risk and assess screening
vs. standard imaging.
benefits/risks.
●​ MRI associated with increased mastectomy rates, questionable clinical
●​ Screen film mammography replaced xeromammography (lower
significance of additional disease detected.
radiation, similar image).
●​ Alliance trial: randomizing patients to MRI vs. standard imaging to assess
●​ Digital mammography: manipulates contrast, useful in dense breasts
local-regional recurrence in triple-negative and HER2-positive cancers.
and women <50.
●​ Requires dedicated breast coils.
●​ DMIST trial: digital and screen film have similar accuracy, digital more
●​ BIRADS lexicon assigned to each exam.
accurate in women <50, dense breasts, pre/perimenopausal.
●​ Digital breast tomosynthesis (3D): alternative to 2D, overcomes
superimposition and density limitations.
○​ STORM trial: higher cancer detection, fewer false positives than
2D.
○​ Multiple projection images reconstructed to allow visual review of
thin breast sections.
○​ In 2011, approved by FDA in combination with standard digital
mammography for screening.
○​ Total radiation dose is twice of digital mammography but still
below the FDA limit.
○​ STORM-2: synthetic 2D-3D mammography similar cancer
detection as 2D-3D but reduces radiation exposure.
●​ Contrast-enhanced digital mammography (CEDM):
○​ Approved by FDA in 2001.
○​ Uses iodinated contrast.
○​ Detects cancers similar to MRI.
○​ Advantages over MRI: compression limits motion, decreased
cost/time, option for MRI-incompatible patients.
DUCTOGRAPHY
●​ Primary Indication: nipple discharge, especially bloody. ●​ MRI-only abnormality: focused ultrasound needed.
●​ Radiopaque contrast injected into major ducts, mammography. ●​ If not seen on mammogram/ultrasound: MRI-guided biopsy.
●​ Procedure: ●​ Useful scenarios:
○​ Duct gently dilated. ○​ Nodal metastasis without identifiable primary tumor.
○​ Small, blunt cannula inserted into nipple ampulla (sterile ○​ Assessing neoadjuvant therapy response.
conditions). ○​ Selecting patients for partial breast irradiation.
○​ Supine patient, 0.1-0.2 mL dilute contrast injected. ○​ Evaluating treated breast for recurrence.
○​ CC and MLO mammograms obtained (no compression).
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 SURGERY — BREAST

BREAST BIOPSY Stage Description

NONPALPABLE LESIONS Stage 0 Cancer cannot be felt by hand
●​ Image-guided biopsy frequently required. Stage I Cancer < 2 cm and has not spread outside the breast
●​ Ultrasound localization: for masses.
Stage II Cancer > 2 cm but < 5 cm and/or spread into the armpit LN
●​ Stereotactic techniques: for no mass (microcalcifications, architectural
distortion). Stage IIIA Cancer is > 5 cm and has spread to armpit LN
●​ Mammography + ultrasound/stereotactic localization + FNA: ~100%
Stage IIIB Cancer has spread to chest wall or has ulcerated, skin nodules
accuracy. and peau d’orange
●​ FNA: cytologic evaluation.
Stage IIIC Cancer has spread above or below the clavicle
●​ Core-needle: tissue architecture analysis, invasive cancer determination.
○​ Preferred: single surgical procedure planned based on results. Stage IV Cancer has read to other organs
○​ Advantages: low complication rate, minimal scarring, lower cost.

PALPABLE LESIONS
●​ FNA or core biopsy in outpatient setting.
●​ FNA: 1.5-in, 22-gauge needle, 10-mL syringe.
○​ Syringe holder recommended.
○​ Needle in mass, suction applied, moved back and forth, cellular
material collected.
○​ Air-dried and ethanol-fixed slides prepared.
○​ Sensitivity and specificity approach 100% if clinically and
mammographically suspicious.
●​ Core-needle: 14-gauge needle (e.g., Tru-Cut), automated devices
available.
●​ Vacuum-assisted core biopsy: 8-10 gauge needles, image guidance,
4-12 samples, specimen radiographed for microcalcifications,
radiopaque marker placed.
●​ Tissue specimens in formalin, processed to paraffin blocks.
●​ Low false-negative rate for core-needle, but sampling error possible.
●​ Clinical, radiographic, and pathologic findings should agree.
●​ Discrepancy: multidisciplinary review, consider image-guided/open
biopsy.
BREAST CANCER STAGING AND BIOMARKERS
BREAST CANCER STAGING
●​ Clinical stage: physical exam of skin, breast tissue, regional lymph nodes
(axillary, supraclavicular, internal mammary).
●​ Clinical axillary node assessment accuracy: 33%.
●​ Ultrasound (US): more sensitive than physical exam for axillary node
involvement.
●​ FNA/core biopsy: definitive diagnosis of suspicious nodes.
●​ Pathologic stage: combines findings from primary tumor and regional
lymph node pathology.
●​ Distant metastasis prediction after 10+ levels I/II axillary node resection.
●​ TNM (tumor, nodes, metastasis) system: frequently used.
●​ AJCC: modified TNM to include anatomic and biologic factors.
○​ Tumor size correlates with axillary node metastasis.
○​ Tumor size, node metastasis: associated with disease-free
survival.
●​ Number of involved nodes: important predictor of 10/20-year survival.
●​ Internal mammary node biopsy: not routine, but targeted biopsy used
with sentinel node dissection.
●​ AJCC 8th edition: Staging based on internal mammary sentinel nodes.
●​ Internal mammary drainage: more frequent in central/medial cancers.
●​ Supraclavicular node metastasis: no longer stage IV, scalene/
supraclavicular biopsy not indicated.

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 SURGERY — BREAST

○​ FDA approved for use in stage-1 or stage- 2, node negative,

ER-positive or ER-negative breast cancers to identify patients
with high or low risk of recurrence
STEROID HORMONE RECEPTOR PATHWAY
●​ Hormones (estrogens, metabolites, progesterone): role in
development/progression.
●​ Breast cancer risk: related to estrogen exposure.
●​ Postmenopausal hormone therapy (estrogen + progesterone): 26%
increased risk vs. placebo.
●​ Hormone receptor-positive tumors: longer survival than
receptor-negative.
●​ ER/PR negative tumors: not candidates for hormonal therapy.
●​ ER/PR positive tumors: higher endocrine therapy response.
●​ ER/PR status: now immunohistochemical, can be measured in archived
tissue, FNA, or core biopsy.
●​ ER/PR testing: all primary invasive cancers.
●​ ER/PR status: determine in pre/postmenopausal patients to identify
endocrine therapy candidates.
GROWTH FACTOR RECEPTORS AND GROWTH FACTORS
●​ EGFR overexpression: correlates with ER-negative status and p53
overexpression.
●​ HER2 overexpression: associated with mutated TP53, Ki67
overexpression, ER-negative status.
●​ HER2: ErbB family, ligand binding causes homodimerization and tyrosine
phosphorylation.
●​ Tyrosine phosphorylation: signal transduction, changes in cell behavior.
●​ Ligand binding to one receptor: heterodimerization,
transphosphorylation, transactivation.
●​ HER2/neu: may function as a co-receptor, modulates other EGFR family
signaling.
○​ Prognostic and predictive factor.
●​ HER2/neu overexpression: enhanced growth, proliferation, invasion,
metastasis.
○​ Poorly differentiated tumors, high proliferation, positive nodes,
decreased hormone receptor expression, increased recurrence/
death risk.
●​ HER2/neu testing: all invasive breast cancers (immunohistochemical or
FISH).
BIOMARKERS ●​ HER2/ERBB2 activation: not recommended for clinical decisions due to
●​ Risk factor biomarkers: associated with increased risk (familial high false negative rate.
clustering, germline abnormalities, proliferative disease with atypia, ●​ HER2 amplification/overexpression: candidates for anti-HER2/neu
mammographic density). therapy.
●​ Exposure biomarkers: subset of risk factors, measure carcinogen ●​ Trastuzumab (Herceptin): monoclonal antibody against HER2.
exposure (DNA adducts). ●​ Trastuzumab: active in HER2/neu overexpressing metastatic breast
●​ Surrogate endpoint biomarkers: biologic alterations between initiation cancer.
and development (histologic changes, proliferation indices, genetic ●​ Adjuvant trastuzumab: effective in early-stage breast cancer with
alterations). chemotherapy (40-50% recurrence reduction, ~33% mortality reduction).
●​ Prognostic biomarkers: information on outcome, irrespective of therapy.
●​ Predictive biomarkers: information on therapy response.
●​ Candidate biomarkers/targets:
○​ Steroid hormone receptor pathway.
○​ Growth factors/receptors (HER2/neu, EGFR, transforming growth
factor, platelet-derived growth factor, insulin-like growth factor
family).
○​ Proliferation indices (PCNA, Ki-67).
○​ Angiogenesis indices (VEGF, angiogenesis index).
○​ mTOR signaling pathway.
○​ Tumor suppressor genes (p53).
○​ Cell cycle, cyclins, cyclin-dependent kinases.
○​ Proteasome. INDICES OF PROLIFERATION
○​ COX-2 enzyme.
●​ PCNA: nuclear protein, increases in G1, peaks at G1/S, decreases
○​ PPARs.
through G2.
○​ Apoptosis indices/modulators (bcl-2, bax:bcl-2 ratio).
●​ PCNA staining: outlines proliferating compartments.
●​ 21-gene expression assay
●​ PCNA expression: correlates with flow cytometry cell cycle distribution
○​ A recurrence score is generated, and those patients with high
and bromodeoxyuridine/Ki67 uptake.
recurrence scores are likely to benefit from chemotherapy,
●​ PCNA/Ki67: positively correlated with p53 overexpression, high S-phase
whereas those with low recurrence scores benefit most from
fraction, aneuploidy, high mitotic index, high histologic grade; negatively
endocrine therapy and may not require chemotherapy
correlated with ER content.
○​ In the 21-gene expression assay, studies have shown:
●​ Ki67: included in IHC4 panel (ER, PR, HER2, Ki67), similar prognostic
■​ Low recurrence score (0 to 10) have a low rate of
information to 21-Gene Recurrence Score.
local-regional and distant recurrence (98.7%) and very
●​ Ki67: interest as biomarker, reproducibility issues.
good overall survival at 5 years (98%) with endocrine
therapy alone without chemotherapy INDICES OF ANGIOGENESIS
●​ MammaPrint ●​ Angiogenesis: necessary for growth/invasion, promotes progression.
○​ The MammaPrint assay uses a 70-gene expression profile to ●​ VEGF: binds to tyrosine kinase receptors.
assess the risk of distant metastasis.
11
 SURGERY — BREAST

●​ VEGF overexpression: correlated with increased microvessel density

and recurrence in node-negative cancer.
●​ Angiogenesis index: microvessel density (CD31) + thrombospondin + p53
expression.
●​ VEGF/angiogenesis index: prognostic and predictive significance.
●​ Bevacizumab: monoclonal antibody to VEGF, FDA approved (metastatic,
with paclitaxel), approval revoked in 2011 due to inconsistent results.
INDICES OF APOPTOSIS
●​ Apoptosis alterations (p53-dependent/independent): prognostic and
predictive biomarkers.
●​ Bcl-2 family: regulates apoptosis, some members inhibit, others promote.
●​ Bcl-2: oncogene, inhibits apoptosis.
●​ Bax: death-signal protein, induced by stress/growth factor deprivation,
requires wild-type p53/AP-1/fos.
●​ Bax/bcl-2 ratio: intracellular regulatory mechanism (bax-bax homodimers
stimulate, bax-bcl-2 heterodimers inhibit).
●​ Bcl-2 overexpression, decreased bax/bcl-2 ratio: high histologic grade,
node metastasis, reduced survival.
●​ Decreased bax expression: node metastasis, poor chemo response,
decreased survival.
●​ Other biomarkers: preclinical testing.
COEXPRESSION OF BIOMARKERS
●​ Optimal therapy: accurate prognosis and prediction of response.
●​ Key markers: ER, PR, HER2/neu.
●​ Clinicians: use staging and ER/PR/HER2/neu to assess prognosis and
assign therapy.
●​ Clinicopathologic factors: separate patients into prognostic groups.
●​ Other indices/programs: Nottingham Prognostic Index, PREDICT.

●​ Combined prognostic factors: up to 70% of early breast cancer patients

receive unnecessary/ineffective chemotherapy.
●​ Individual biomarkers: predict prognosis/response, but don't improve
accuracy.
●​ Prognostic indices: combine biomarker predictive power with
clinicopathologic factors.
●​ High-throughput gene expression assays: detailed patient stratification.
●​ Oncotype DX: 21-gene RT-PCR, node-negative, ER-positive, generates
recurrence score (high score: chemo benefit, low score: endocrine
BREAST CANCER PROGNOSIS
benefit).
●​ TAILORx: validates 21-gene assay, low score (0-10): low recurrence, ●​ The 5-year relative survival by race was:
good survival with endocrine therapy alone. ○​ 90.4% for white women
●​ Recurrence score: alters treatment recommendations. ○​ 78.7% for black women
●​ The 5-year survival rate for patients with:
BREAST CANCER THERAPY
○​ Localized disease (61% of patients) was 98.6%
●​ Before diagnostic biopsy, the surgeon must consider the possibility that ○​ Regional disease (32% of patients) was 84.4%
a suspicious mass or mammographic finding may be breast cancer. ○​ Distant metastatic disease (5% of patients) was 24.3%
●​ Once a diagnosis of breast cancer is made, the type of therapy is
determined by
○​ Stage of the disease
○​ Biologic subtype
○​ General health status of the individual
●​ Laboratory tests and imaging studies are performed based on the initial
stage
●​ Before therapy is initiated, the patient and the surgeon must share a clear
perspective on the planned course of treatment.
●​ Before initiating local therapy, determine the following:
○​ Clinical stage
○​ Histologic characteristics
○​ Appropriate biomarker levels.

SURGICAL TECHNIQUES IN BREAST CANCER THERAPY

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●​ Preoperative lymphoscintigraphy: not required.

●​ Radioactive colloid injection:
○​ Breast parenchyma, subareolar, or subdermal.
○​ 0.5 mCi (same-day) or 2.5 mCi (day before).
○​ Subdermal: near tumor or subareolar.
●​ Blue dye injection:
○​ Breast parenchyma or subareolar.
○​ Avoid subdermal (tattooing, necrosis).
●​ Nonpalpable cancers: injection guided by ultrasound/mammography.
●​ Previous biopsy: injections around cavity, not into it.
●​ Isosulfan blue dye: urine color change, allergy risk (1 in 10,000),
anaphylaxis possible, antihistamine/steroid/H-2 antagonist prophylaxis.
●​ Radioactive colloid: safe, low radiation exposure.
●​ Pregnancy: SLN dissection with radioactive colloid only.
●​ Procedure:
○​ Gamma counter: identifies SLN location.
○​ 3-4 cm incision: lower axilla.
○​ Dissect through subcutaneous tissue and axillary fascia.
○​ Identify blue lymphatic channels.
○​ Gamma probe: pinpoints SLN.
○​ 10-second in vivo count.
○​ SLN removal, 10-second ex vivo count.
○​ Pathology: permanent/frozen section.
○​ "10% rule": harvest all blue nodes and nodes >10% of SLN ex
vivo count.
○​ Gamma counter: measure residual radioactivity, search for more
SLNs if counts high.
○​ <10% of SLN ex vivo count: stop search.
EXCISIONAL BIOPSY WITH NEEDLE LOCALIZATION ○​ ~98% positive SLNs recovered with 4 SLNs.
●​ Excisional biopsy: complete lesion removal with normal tissue margin. ●​ NSABP B-32: false-negative rate influenced by tumor location, biopsy
●​ Past practice: consent for mastectomy if biopsy confirmed cancer. type, number of SLNs.
●​ Current practice: consider local therapy options (lumpectomy vs. ○​ Lateral breast tumors: higher false-negative rate.
mastectomy), nodal assessment (SLN dissection). ○​ Excisional biopsy before SLN: higher false-negative rate.
●​ Needle-core biopsy: preferred diagnostic method. ○​ More SLNs removed: lower false-negative rate (17.7% to 10% to
●​ Excisional biopsy: reserved for discordant needle biopsy/imaging/exam 6.9% with 2, 3 SLNs).
findings. ●​ Internal mammary node drainage on lymphoscintigraphy: worse distant
●​ Incision placement: disease-free survival.
○​ Circumareolar: subareolar lesions, near nipple-areolar complex. BREAST CONSERVATION
○​ Elsewhere: along skin tension lines, concentric with nipple-areolar ●​ Resection of primary cancer with normal tissue margin.
complex. ●​ Adjuvant radiation therapy.
○​ Lower breast: radial incisions. ●​ Regional lymph node assessment.
○​ Distant tumor: biopsy incision separate from mastectomy incision. ●​ Resection names: segmental mastectomy, lumpectomy, partial
○​ Upper breast: avoid radial incisions (scar contracture, nipple mastectomy, wide local excision, tylectomy.
displacement). ●​ BCT preferable for stage I/II: equivalent survival to mastectomy,
○​ Lower breast: avoid curvilinear incisions (nipple displacement). preserves breast.
●​ Post-excision: ●​ BCT: oncologically equivalent to mastectomy.
○​ Specimen X-ray: confirm excision with margins. ●​ BCT advantages:
○​ Specimen orientation: sutures, clips, dyes. ○​ Quality of life
○​ Additional margins: if lesion near margins on X-ray. ○​ Aesthetic outcomes
○​ Additional shavings: confirm complete excision. ■​ Preserves shape, skin, sensation
○​ Hemostasis: electrocautery, ligatures. ○​ Psychological benefit.
○​ Cosmesis: absorbable sutures for defect approximation. ●​ Standard for stage 0, I, II invasive cancer.
○​ Skin closure: running subcuticular, absorbable monofilament. ●​ DCIS: resection and radiation, no node assessment.
○​ Drainage: usually not required. ●​ Lumpectomy incision: curvilinear (upper breast), radial (lower breast).
●​ Needle/seed localization: ●​ Skin excision: only if direct tumor involvement.
○​ Preoperative mammography visit: wire/seed placement. ●​ Margin width controversy: SSO/ASTRO consensus: "no tumor on ink"
○​ Sonography: in imaging suite or OR. for invasive I/II with whole-breast irradiation.
○​ Wire/seed placement: near lesion. ●​ Increasing margin width doesn't affect local recurrence if inked margin is
○​ Excision: guided by wire/seed, with margin. negative.
○​ Specimen radiography: confirm complete excision. ●​ Specimen X-ray: confirm lesion excision.
SENTINEL LYMPH NODE DISSECTION ●​ Specimen orientation: surgeon's responsibility.
●​ Used for clinically node-negative early breast cancers. ●​ Additional margins: as needed for negative margin.
●​ Accurate for larger tumors (T3 N0), but most have axillary metastases. ●​ ER/PR/HER2 requests: to pathologist.
●​ Accurate for axillary staging after chemotherapy in clinically ●​ Surgeon's responsibility: complete cancer removal.
node-negative disease. ●​ Negative margins: minimize local recurrence, enhance cure.
●​ Tan et al.: 93% sensitivity, 7% false-negative rate, 94% negative ●​ Mastectomy: if negative margins unattainable with re-excision.
predictive value, 95% accuracy. ●​ SLN: before primary tumor removal.
●​ Not recommended: ●​ Oncoplastic surgery: at segmental mastectomy or later, improves
○​ Inflammatory breast cancer aesthetics (reshaping, tissue rearrangement, flaps, reduction).
○​ Biopsy-proven metastasis ●​ Oncoplastic candidates:
○​ DCIS without mastectomy ○​ Resection extent
○​ Prior axillary surgery. ○​ Tumor location
●​ Safe in pregnancy (radioisotope alone). ○​ Breast size
●​ Incidence of lymphedema and sensory loss for SLN is significantly ○​ Body habitus.
lower than the standard axillary treatment ●​ Oncoplastic prime considerations:
●​ Combined gamma probe and blue dye: more accurate than either alone. ○​ Significant skin resection.

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○​ Large parenchyma resection. ○​ Lymphedema:

○​ Tumor between nipple and inframammary fold. ■​ ~20%, up to 50-60% with radiation
○​ Excision may malposition nipple. ■​ Risk factors:
●​ Extensive node dissection
●​ Radiation,
●​ Positive nodes
●​ Obesity
■​ Treatment:
●​ Physical therapy
●​ Compression sleeves
●​ Complex decongestive therapy.
MASTECTOMY AND AXILLARY DISSECTION NONSURGICAL BREAST CANCER THERAPIES
●​ Reasons for mastectomy preference:
○​ Less concern about cosmesis.
○​ Avoids radiation.
○​ Unfavorable cosmetic result with excision.
○​ Extensive microcalcifications.
○​ Large cancers in subareolar/central breast.
○​ Multicentric cancers.
Type of Mastectomy Description
Skin-sparing mastectomy ●​ Removes all breast tissue, nipple-areola
complex, prior biopsy scars; recurrence rate
<6-8% (comparable to standard mastectomy).
Total (simple) mastectomy ●​ Removes all breast tissue, nipple-areola
complex, skin.
Extended simple ●​ Removes all breast tissue, nipple-areola
mastectomy complex, skin, level I axillary nodes.
Modified radical ("Patey") ●​ Removes all breast tissue, nipple-areola
mastectomy complex, skin, levels I, II, III axillary nodes;
pectoralis minor divided (can be left in situ). RADIATION THERAPY
●​ Used for all breast cancer stages.
Halsted radical ●​ Removes all breast tissue, skin, nipple-areola
●​ Adjuvant radiation:
mastectomy complex, pectoralis major/minor, levels I, II, III
axillary nodes. Clinical Scenario Radiation Recommendation

Radical mastectomy ●​ Nearly eliminated due to systemic DCIS and early-stage Previously described
chemotherapy, hormonal therapy, and radiation. Mastectomy with positive Chest wall radiation
surgical margins
Nipple-areolar sparing ●​ Used especially for risk-reducing mastectomy.
mastectomy Metastatic disease (≥4 axillary Chest wall and supraclavicular radiation
nodes) or premenopausal with
Eligibility Factors for ●​ Tumor >2-3 cm from areola, smaller breast, 1-3 positive nodes
Nipple-Areolar Sparing minimal ptosis, no periareolar incisions, BMI Advanced local-regional Radiation reduces recurrence risk
Mastectomy <40, no tobacco, no prior irradiation, no (IIIA/IIIB)
collagen vascular disease.
IIIA/IIIB Recommendations
- After neoadjuvant chemo and Radiation to breast and supraclavicular nodes
MODIFIED RADICAL MASTECTOMY segmental mastectomy
●​ Preserves pectoralis major, removes levels I, II, III axillary nodes. - After neoadjuvant chemo and Radiation to chest wall and supraclavicular
●​ Patey's contribution: removed pectoralis minor for level III access, mastectomy nodes
preserved pectoralis major and lateral pectoral nerve. - After segmental Radiation to chest wall and supraclavicular
●​ Anatomic boundaries: latissimus dorsi laterally, sternum medially, mastectomy/mastectomy and nodes
subclavius superiorly, 2-3 cm below inframammary fold inferiorly. adjuvant chemo
●​ Skin flap thickness: 7-8 mm (skin + tela subcutanea). EBCTCG Findings Improved local-regional control and survival
●​ Procedure: with mastectomy and post-mastectomy
○​ Skin flaps developed. radiation (1-3 positive nodes)
○​ Pectoralis major fascia and breast tissue elevated. Note: EBCTCG data predates routine sentinel
○​ Axillary dissection: lymph node dissection, likely higher disease
■​ Identify axillary vein, clear it anteriorly/inferiorly. volume in earlier trials
■​ Clear level I nodes (lateral, subscapular), preserve ○​ Multidisciplinary team discussion: risks/benefits of
thoracodorsal bundle. post-mastectomy radiation (1-3 positive nodes).
■​ Clear level II nodes (central), preserve long thoracic nerve ●​ Partial Breast Irradiation (APBI):
of Bell. ○​ For breast-conserving surgery patients.
●​ Permanent disability with a winged scapula and ○​ Delivery methods: brachytherapy, external beam (3D
shoulder weakness will follow denervation of the conformal/IMRT).
serratus anterior muscle ○​ Promising results in low-risk, but use should be based on
■​ Patey: divided and removed pectoralis minor. guidelines or clinical trials.
■​ Current practice: divide pectoralis minor tendon, leave CHEMOTHERAPY ADJUVANT
muscle intact.
CHEMOTHERAPY
■​ Clear level III nodes (apical) medially to costoclavicular
ligament. ●​ Reduces recurrence and death in women ≤70 with stage I, IIA, IIB.
○​ Breast and axillary contents removed. ●​ ≥70 years: limited data, no definitive recommendations.
●​ Complications: ●​ Not recommended: negative nodes, ≤0.5 cm tumors.
○​ Seroma: most frequent (up to 30%), reduced by closed suction ●​ 0.6-1.0 cm tumors: consider unfavorable prognostic features
drainage. ○​ Vessel invasion
○​ Wound infection: infrequent, usually from skin flap necrosis, treat ○​ High nuclear/histologic grade
with cultures, debridement, antibiotics. ○​ HER2 overexpression
○​ Hemorrhage: rare, treat with exploration and drainage. ○​ Negative hormone receptors
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●​ ASCO guidelines: consider for ●​ Fulvestrant/anastrozole/both neoadjuvant

○​ Positive nodes ○​ Secondary resistance and crosstalk between ER and
○​ HER2-positive PI3K/Akt/mTOR: leads to evaluation of PI3K inhibitors with
○​ Adjuvant! Online mortality >10% endocrine therapy.6
○​ Grade 3 node-negative >5mm ●​ Phase 2 trial: letrozole +/- everolimus, combination had better
○​ Triple-negative response.
○​ Lymphovascular invasion ●​ LORLEI study: evaluating taselisib (PI3K inhibitor) with letrozole.7
○​ >15% 10-year distant relapse risk. ●​ CDK 4/6 inhibitors (palbociclib): shown to reduce Ki67 with
●​ NCCN: recommends for unfavorable prognostic features. anastrozole, suggesting increased efficacy.8
Condition Recommended Treatment ●​ Neoadjuvant: observe tumor response, may define adjuvant therapy
benefit.
Hormone receptor-negative, Adjuvant chemotherapy
>1 cm ●​ Trials comparing neoadjuvant chemo/endocrine therapy:
genomic/proteomic analysis for personalized approach.
Node-negative, hormone Antiestrogen ± chemotherapy
receptor-positive, T1 ANTIESTROGEN THERAPY

Special types (tubular, Antiestrogen TAMOXIFEN

mucinous, medullary), >1 cm ●​ Binds to estrogen receptors, blocks estrogen uptake in breast tissue.
Node-positive or special Chemotherapy; if hormone receptor-positive, also ●​ Clinical response: >60% ER-positive, <10% ER-negative.
type >3 cm antiestrogen ●​ Early Breast Cancer Trialists' Collaborative Group: 5 years tamoxifen
Stage IIIA Preoperative chemotherapy (anthracycline/ taxane), reduces mortality by ~1/3, reduces contralateral cancer risk by 39%.
then surgery, then radiation (especially for ●​ Carry-over effect: mortality benefit continues after stopping tamoxifen.
ER-negative) ●​ Side effects:
ER-positive Stage IIIA Less responsive to chemotherapy; consider ○​ Bone pain
neoadjuvant endocrine therapy or primary ○​ Hot flashes
endocrine therapy ○​ Nausea
○​ Vomiting
○​ Fluid retention
○​ Thrombotic events (<3%)
○​ Cataracts.
●​ Stockholm trial: 5 years tamoxifen reduces locoregional recurrence and
distant metastasis in postmenopausal ER-positive, increased endometrial
cancer.
●​ NSABP B14: 10 years vs. 5 years, no additional benefit beyond 5 years
(terminated early).
●​ ATLAS trial: 10 years vs. 5 years, reduced recurrence and mortality,
NEOADJUVANT (PREOPERATIVE) CHEMOTHERAPY benefit seen 10-15 years.
●​ NCI Milan trials (1970s): T3/T4 cancers, surgery between chemo courses, ●​ aTTom study: corroborated ATLAS.
82% local control, 25% 5-year disease-free survival. ●​ Extended letrozole after tamoxifen: improves disease-free survival
●​ NSABP B-18: operable II/III, chemo before or after surgery, no survival (node-positive only).
difference, more lumpectomies, less node positivity with neoadjuvant. ●​ Tamoxifen for ER-positive DCIS: decreases ipsilateral recurrence and
●​ Meta-analyses: neoadjuvant and adjuvant chemo equivalent for OS. contralateral cancer risk, not recommended after bilateral
●​ Increased local-regional recurrence with neoadjuvant if only mastectomy.
radiation without surgery. ●​ Increasingly limited to premenopausal women due to aromatase
○​ Local-regional recurrence driven by biology/stage, not chemo inhibitors.
timing. AROMATASE INHIBITORS
●​ Allows observation of tumor response. ●​ First-line adjuvant therapy for postmenopausal women.1
●​ Stable/progressive tumors: consider new regimen. ●​ Third-generation: anastrozole, letrozole, exemestane.2
●​ Pathologic complete response (pCR): improved survival. ●​ 5 years of AIs reduce recurrence by 30%, 10-year mortality by 15% vs.
●​ MD Anderson: residual cancer burden (RCB) predicts relapse-free tamoxifen.
survival. ●​ Additional 5 years letrozole after 5 years tamoxifen/AI, improved breast
●​ Progression during neoadjuvant: poorest survival. cancer-free interval, no improvement in disease-free survival.
●​ FDA: supports neoadjuvant platform and pCR as endpoint for ●​ Beneficial for:
accelerated approval. ○​ Node-positive
●​ NCCN: neoadjuvant chemo (anthracycline/taxane +/-), then surgery, then ○​ Post-chemo
radiation. ○​ Prior tamoxifen.
●​ HER2-positive: add trastuzumab/pertuzumab preoperatively. ●​ Less endometrial cancer than tamoxifen,
●​ Inoperable IIIA/IIIB: neoadjuvant chemo to decrease burden, then ●​ SE: Osteoporosis, Joint pain.
surgery, then radiation. ●​ Endocrine therapy for node-negative/positive, hormone
NEOADJUVANT ENDOCRINE THERAPY receptor-positive.
●​ Initially for elderly women unsuitable for surgery/chemo.1 ●​ Metastatic Breast Cancer:
●​ ER-positive tumors don't respond to chemo as readily as ER-negative ○​ Postmenopausal, ER-positive, HER2-negative:
(pCR rate ~3x lower). ■​ Anastrozole/letrozole
●​ As age increases, chemo benefit decreases, consider ER, grade, type, ■​ Exemestane
proliferation. ■​ Tamoxifen/toremifene
●​ ER-rich tumors: may benefit more from neoadjuvant endocrine therapy.2 ■​ Fulvestrant
●​ Shrinks tumors, enabling breast-conserving surgery in those needing ■​ Megestrol acetate
mastectomy, long-term recurrence data lacking.3 ■​ Fluoxymesterone
●​ Tamoxifen/anastrozole/both in postmenopausal ER-positive ■​ Ethinyl estradiol.
operable/locally advanced, anastrozole had higher breast-conserving ○​ First-line: AI or palbociclib + letrozole.
surgery rate. ○​ Abemaciclib: approved with fulvestrant or alone after endocrine
●​ Invasive lobular cancers: poor chemo response, may respond better to progression.
endocrine therapy.4 ○​ Premenopausal, stage IV, ER-positive: tamoxifen or ovarian
●​ Aromatase inhibitors suppression/ablation + AI +/- CDK4/6 inhibitor.
○​ Had similar response and breast conservation as chemo, lower ●​ PI3K/mTOR Pathway:
toxicity. ○​ Involved in secondary endocrine resistance.
○​ Higher response and breast conservation than tamoxifen. ○​ BOLERO-2: exemestane + everolimus improved PFS after AI
progression.4
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○​ Tamoxifen + everolimus: improved PFS.

○​ Letrozole + temsirolimus: no PFS improvement.
○​ Trials evaluating adjuvant mTOR/CDK 4/6 inhibitors ongoing.
●​ Endocrine Therapy Response:
○​ Objective response/stable disease: "clinical benefit", consider
further endocrine therapy at progression.
○​ De novo progression: low benefit from subsequent endocrine
therapy, consider chemo.
●​ ESR1 Mutations:
○​ Associated with aromatase inhibitor resistance.
○​ 20-30% incidence, uncommon in primary cancers.
○​ Trials evaluating SERDs ongoing.
ABLATIVE ENDOCRINE THERAPY
●​ Past: adrenalectomy/hypophysectomy (rarely used now).
●​ Premenopausal: ovarian ablation (oophorectomy/radiation) or
suppression (GnRH agonists - goserelin/leuprolide).
●​ Goserelin + tamoxifen vs. CMF: endocrine better relapse-free survival.
●​ SOFT/TEXT trials: exemestane + suppression better than tamoxifen +
suppression (ovarian suppression with triptorelin, oophorectomy, or
radiation).
●​ SOFT: tamoxifen + suppression not better than tamoxifen alone, benefit
in high-risk women, no benefit without chemo.
●​ Ovarian suppression + AI: consider in high-risk premenopausal (age <40,
positive nodes) needing chemo.
ANTI-HER2 THERAPY
●​ HER2 testing: recommended for all new breast cancer diagnoses.
●​ Trastuzumab: initially for metastatic, then adjuvant trials (NSABP, NCTG).
●​ Joint analysis: improved 3-year disease-free survival, reduced mortality.
●​ Anthracycline numerically superior but more toxicity.
○​ 1 year trastuzumab: standard.
○​ 2 years: more effective, more toxicity.
○​ 6 months vs. 12 months: 6 months not non-inferior.
●​ Trastuzumab: added to taxane chemo, not usually with anthracyclines.
●​ Neoadjuvant trastuzumab + chemo: increased pathologic complete
response.
●​ Lapatinib: inferior to trastuzumab, combination not better than
trastuzumab alone.
●​ T-DM1: for metastatic, previously treated with trastuzumab/taxane.
●​ Pertuzumab: approved with trastuzumab/docetaxel for metastatic (no
prior HER2 therapy) and neoadjuvant (>2cm or node-positive).
○​ Pertuzumab + trastuzumab + docetaxel increased pathologic
complete response.
●​ Pertuzumab: approved with trastuzumab/chemo in adjuvant setting for
high risk HER2 amplified (APHINITY trial).
●​ Neratinib: improved 2-year disease-free survival after adjuvant
trastuzumab.
●​ HER2 mutations: ~2%, usually ER-positive, more in pleomorphic
lobular, predict response/resistance.
●​ Neratinib for HER2-mutated metastatic: 36% clinical benefit.

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