Breast

Key points

Breast Anatomy and Lymphatic Drainage

Principal Blood Supply:
- The breast receives its principal blood supply from:
  - Perforating branches of the internal mammary artery.
  - Lateral branches of the posterior intercostal arteries.
  - Branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery.
Lymphatic Drainage:
- The axillary lymph nodes usually receive >75% of the lymph drainage from the breast.
- The rest flows through lymph vessels that accompany the perforating branches of the internal mammary artery and enter the parasternal (internal mammary) group of lymph nodes.

Breast Development and Benign Disorders

Breast Development:
- Initiated by a variety of hormonal stimuli, with major trophic effects being modulated by estrogen, progesterone, and prolactin.
Benign Breast Disorders:
- Related to the normal processes of reproductive life and involution.
- There is a spectrum of breast conditions that ranges from normal to disorder to disease (aberrations of normal development and involution classification).

Breast Cancer Risk and Screening

Breast Cancer Risk Calculation (Gail Model):
- To calculate breast cancer risk using the Gail model [ value of >1.7 is significant], a woman’s risk factors are translated into an overall risk score by multiplying her relative risks from several categories.
- This risk score is then compared with an adjusted population risk of breast cancer to determine the woman’s individual risk.
- This model is not appropriate for use in women with a known BRCA1 or BRCA2 mutation or women with lobular or ductal carcinoma in situ*.
Screening Recommendations:
- Routine use of screening mammography in women ≥50 years of age reduces mortality from breast cancer by 25%.
- MRI screening is recommended in women with BRCA mutations and may be considered in women with a greater than 20% to 25% lifetime risk of developing breast cancer.

Breast Cancer Diagnosis and Treatment

Diagnosis:
- Core-needle biopsy is the preferred method for the diagnosis of palpable or nonpalpable breast abnormalities.
Surgical Considerations:
- When a diagnosis of breast cancer is made, the surgeon should determine the clinical stage, histologic characteristics, and appropriate biomarker levels before initiating local therapy.
Sentinel Node Dissection:
- Preferred method for staging the regional lymph nodes in women with clinically node-negative invasive breast cancer.
- Axillary dissection may be avoided in women with one to two positive sentinel nodes who are treated with breast-conserving surgery, whole breast radiation, and systemic therapy.
Therapy Decisions:
- Local-regional and systemic therapy decisions for an individual patient with breast cancer are best made using a multidisciplinary treatment approach.
- The sequencing of therapies is dependent on patient and tumor-related factors, including breast cancer subtype.

Grave Signs of Breast Cancer (Described by Haagensen and Stout, 1943)

Edema of the skin of the breast
Skin ulceration
Chest wall fixation
Axillary lymph node > 2.5 cm in diameter
Fixed axillary lymph nodes

Modified Radical Mastectomy (Patey and Dyson, 1948)

Advocated by: Patey and Dyson, Middlesex Hospital, London.
Purpose: Management of advanced operable breast cancer.
Technique:
- Removal of breast and axillary lymph nodes.
- Preservation of the pectoralis major muscle.
- Removal of the pectoralis minor muscle to allow access to and clearance of axillary lymph node levels I to III.
Key Transition Acknowledgments:
1. Fewer patients were presenting with advanced local disease (with or without grave signs by Haagensen).
2. Extirpation of the pectoralis major muscle was not essential for local-regional control in stages I and II breast cancer.
3. Modified radical mastectomy and Halsted radical mastectomy did not consistently achieve local-regional control of stage III breast cancer.
Incorporation of Radiation Therapy:
- Integrated into the management of advanced breast cancer.
- Demonstrated improvements in local-regional control.

NSABP B-04 Trial (Early 1970s)

Purpose: To determine the impact of local and regional treatments on survival in operable breast cancer.
Enrollment: 1665 women, stratified by clinical assessment of axillary lymph nodes.
Randomization:
- Clinically node-negative women:
  1. Halsted radical mastectomy.
  2. Total mastectomy plus radiation therapy.
  3. Total mastectomy alone.
- Clinically node-positive women:
  - Halsted radical mastectomy.
  - Total mastectomy plus radiation therapy.
Key Findings:
- No differences in survival between the three groups of node-negative women.
- No differences in survival between the two groups of node-positive women.
- Overall survival equivalence persisted at 25 years of follow-up.

NSABP B-06 Trial

Type: Phase 3 study.
Randomization:
- 1851 patients were randomized to one of three groups:
  1. Total mastectomy.
  2. Lumpectomy alone.
  3. Lumpectomy with breast irradiation.
Key Findings:
- No difference in disease-free, distant disease-free, and overall survival among the three groups.
- Omission of radiation therapy led to significantly higher rates of ipsilateral breast tumor recurrence in those who received lumpectomy alone.
Trial Exclusions:
- Patients with palpable axillary lymph nodes were excluded.
Frozen Section Protocol:
- Patients randomized to breast-conserving surgery had frozen sections performed.
- If margins were involved on frozen section, the surgeon proceeded to perform a mastectomy.
- However, the patient was included in the analysis as having had a breast-conserving operation.
Local Recurrences:
- In B-06, local in-breast recurrences were regarded as "nonevents" in terms of disease-free survival.
Impact on Halstedian Concept:
- Both NSABP B-04 and B-06 trials refuted the Halstedian concept that cancer spread throughout a region of the breast to lymphatics and then on to distant sites.

Bernard Fisher's "Alternative Hypothesis"

Breast Cancer as a Systemic Disease:
- Proposed by: Bernard Fisher.
- Core Idea: Breast cancer is a systemic disease at diagnosis.
- Mechanism:
  - Tumor cells have access to both the blood and lymphatic systems.
  - Regional lymph nodes are markers of systemic disease, not barriers to cancer cell dissemination.
Host Factors and Metastasis:
- Host factors are crucial in the development of metastasis.
- Variations in local-regional treatment are unlikely to significantly impact survival.
Challenge to the Hypothesis:
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Overview Analysis:
  - Reported that avoiding recurrence in a conserved breast can avoid one breast cancer death over the next 15 years for every four recurrences avoided.
  - Implication: Not all breast cancer is systemic at presentation, suggesting that local-regional control does matter for survival in certain cases.

EBCTCG Overview Findings

Chemotherapy Regimens:
- Anthracycline-containing regimens are superior to cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).
- Addition of a taxane to an anthracycline-based regimen reduces breast cancer mortality by one-third.
Tamoxifen Therapy:
- Effective only in patients with estrogen receptor (ER) positive breast cancer.
- May decrease mortality from breast cancer by up to 30%.
Impact of Clinical and Pathologic Factors:
- Proportional reduction in risk was not significantly affected by standard clinical and pathologic factors such as:
  - Tumor size,
  - ER status,
  - Nodal status.
Implications for Adjuvant Therapy:
- Stratification of risk is crucial in determining adjuvant therapy decisions.
- Goal: Minimize toxicities of therapies in those unlikely to benefit while realizing substantial benefits in local-regional control and survival in those at higher risk.

Evolution of Breast Cancer Classification and Treatment

Early Randomized Clinical Trials:
- Treated all patients similarly, viewing breast cancer as a homogeneous disease.
Traditional Pathologic Determinants:
- Defined by: Conventional light microscopy and basic histologic techniques.
Advances in the 1980s:
- Immunohistochemistry:
  - Allowed assessment of the expression of individual tumor markers (most commonly proteins).
- DNA Assessment:
  - Initially assessed in terms of ploidy status.
DNA and Gene Expression Analysis:
- Breast cancer specimens interrogated at the DNA level by:
  - Labeling genes of interest and using fluorescent dyes to quantify gene abundance.
  - Comparing a large number of genes simultaneously in a single breast cancer specimen.
Gene Expression Arrays:
- Showed that breast cancers cluster according to their intrinsic gene expression patterns.
- Identified at least five intrinsic subtypes of breast cancer.
- These intrinsic subtypes correlate with breast cancer outcomes.
Current Classification:
- Breast cancers are now classified by molecular subtypes.
- Molecular subtypes are used for risk stratification and decision-making in terms of local-regional and systemic therapies.

Breast Disease and Cancer Consultation Statistics

Consultation with a Surgeon:
- 50% of American women will consult a surgeon regarding breast disease.
Breast Biopsy:
- 25% of women will undergo a breast biopsy for the diagnosis of an abnormality.
Breast Cancer Development:
- 12% of women will develop some variant of breast cancer.

Integration of Treatment Modalities

Progress Made:
- Integration of surgery, radiation therapy, and systemic therapy has advanced to:
  - Control local-regional disease.
  - Enhance survival.
  - Improve the quality of life for breast cancer survivors.

Role of Surgeons in Breast Care

Primary Physicians:
- Surgeons are traditionally the first physician consulted for breast care.
Importance of Comprehensive Training:
- Surgeons must be well trained in all aspects of breast care, including:
  - Embryologic development.
  - Growth and development.
  - Benign and malignant disease processes.
- Goal: Achieve optimal outcomes for patients and their families.

Breast Development and Anatomy

Embryological Development

Primary Tissue Bud:
- Develops from an ingrowth of ectoderm in the mesenchyme.
- Leads to the formation of 15 to 20 secondary buds.
Epithelial Cords:
- Develop from secondary buds, extending into surrounding mesenchyme.
- Major (lactiferous) ducts form and open into a shallow mammary pit.
Nipple Formation:
- Mesenchyme proliferation transforms the mammary pit into a nipple during infancy.
- Inverted nipple results from the failure of the pit to elevate above skin level (occurs in 4% of infants).

Infant and Puberty Stages

At Birth:
- Breasts in males and females are identical, only demonstrating major ducts.
- Breast enlargement and witch's milk (secretion) may occur due to maternal hormones crossing the placenta.
Puberty:
- Ovarian estrogen and progesterone stimulate breast enlargement, initiating proliferation of epithelial and connective tissue elements.
- Breasts remain incompletely developed until pregnancy.

Congenital and Rare Anomalies

Amastia: Rare, results from arrest in mammary ridge development during the sixth fetal week.
Poland's Syndrome:
- Includes hypoplasia or absence of the breast, costal cartilage and rib defects, hypoplasia of chest wall tissues, and brachysyndactyly.
Breast Hypoplasia: Can be iatrogenically induced before puberty by trauma, infection, or radiation therapy.
Symmastia: Rare anomaly with webbing between the breasts across the midline.
Accessory Nipples (Polythelia):
- Occurs in <1% of infants.
- May be associated with urinary and cardiovascular system abnormalities.
Supernumerary Breasts:
- Can occur along the mammary milk line.
- Most frequently found between the normal nipple location and the symphysis pubis.
Associated Syndromes:
- Turner's Syndrome: Ovarian agenesis and dysgenesis, may include polymastia.
- Fleischer's Syndrome: Displacement of nipples and bilateral renal hypoplasia, may include polymastia.
Accessory Axillary Breast Tissue: Uncommon and usually bilateral.

Anatomical Features

Posterior Surface:
- The breast rests on the fascia of the pectoralis major, serratus anterior, external oblique abdominal muscles, and the upper extent of the rectus sheath.
- Retromammary bursa: Identified between the investing fascia of the breast and the fascia of the pectoralis major muscles.
Axillary Tail of Spence:
- Extends laterally across the anterior axillary fold.
Quadrants:
- The upper outer quadrant contains a greater volume of tissue than other quadrants.
Breast Form and Variations:
- Conical form with a circular base measuring 10 to 12 cm in diameter.
- Nulliparous breast: Hemispheric configuration with distinct flattening above the nipple.
Changes with Pregnancy and Aging:
- Pregnancy and Lactation: Breast enlarges, increasing in volume and density.
- Senescence: Breast becomes flattened, flaccid, and more pendulous with decreased volume.

Axillary Lymph Node Groups

Six Recognized Groups:
1. Axillary Vein Group (Lateral):
  - Location: Medial or posterior to the axillary vein.
  - Number: 4 to 6 lymph nodes.
  - Function: Receives most lymph drainage from the upper extremity.
2. External Mammary Group (Anterior/Pectoral):
  - Location: Along the lower border of the pectoralis minor muscle, contiguous with the lateral thoracic vessels.
  - Number: 5 to 6 lymph nodes.
  - Function: Receives most lymph drainage from the lateral aspect of the breast.
3. Scapular Group (Posterior/Subscapular):
  - Location: Along the posterior wall of the axilla at the lateral border of the scapula, contiguous with the subscapular vessels.
  - Number: 5 to 7 lymph nodes.
  - Function: Receives lymph drainage from the lower posterior neck, posterior trunk, and posterior shoulder.
4. Central Group:
  - Location: Embedded in the fat of the axilla, immediately posterior to the pectoralis minor muscle.
  - Number: 3 to 4 sets of lymph nodes.
  - Function: Receives lymph drainage from the axillary vein, external mammary, and scapular groups, as well as directly from the breast.
5. Subclavicular Group (Apical):
  - Location: Posterior and superior to the upper border of the pectoralis minor muscle.
  - Number: 6 to 12 sets of lymph nodes.
  - Function: Receives lymph drainage from all other groups of axillary lymph nodes.
6. Interpectoral Group (Rotter's Lymph Nodes):
  - Location: Interposed between the pectoralis major and pectoralis minor muscles.
  - Number: 1 to 4 lymph nodes.
  - Function: Receives lymph drainage directly from the breast.
  - Pathway: Lymph fluid passes from this group directly into the central and subclavicular groups.

Lymphatic Drainage of the Breast

Lymphatic Plexus:
- Arises in: Interlobular connective tissue and walls of the lactiferous ducts.
- Communication: With the subareolar plexus of lymph vessels.
Efferent Lymph Vessels:
- Pathway:
  - Pass around the lateral edge of the pectoralis major muscle.
  - Pierce the clavipectoral fascia.
  - End in the external mammary (anterior, pectoral) group of lymph nodes.
  - Some lymph vessels may travel directly to the subscapular (posterior, scapular) group of lymph nodes.
  - From the upper part of the breast, a few lymph vessels pass directly to the subclavicular (apical) group of lymph nodes.
Lymph Drainage Distribution:
- Axillary lymph nodes receive >75% of lymph drainage from the breast.
- The remaining lymph drainage is primarily from the medial aspect of the breast.
- This drainage flows through lymph vessels accompanying the perforating branches of the internal mammary artery and enters the parasternal (internal mammary) group of lymph nodes.

Gynecomastia

Gynecomastia and Breast Cancer Risk

Cancer Predisposition:
- Gynecomastia generally does not predispose the male breast to cancer.
- Klinefelter's Syndrome (XXY):
  - Hypoandrogenic state where gynecomastia is usually evident.
  - Associated with an increased risk of breast cancer.

Gynecomastia Grading

Grade I:
- Mild breast enlargement without skin redundancy.
Grade IIa:
- Moderate breast enlargement without skin redundancy.
Grade IIb:
- Moderate breast enlargement with skin redundancy.
Grade III:
- Marked breast enlargement with skin redundancy and ptosis.

Pathophysiologic Mechanisms of Gynecomastia [Schwartz Table]

I. Estrogen Excess States

A. Gonadal Origin
1. True Hermaphroditism
2. Gonadal Stromal (Nongerminal) Neoplasms of the Testis
  - Leydig Cell (Interstitial)
  - Sertoli Cell
  - Granulosa-Theca Cell
3. Germ Cell Tumors
  - Choriocarcinoma
  - Seminoma, Teratoma
  - Embryonal Carcinoma
B. Nontesticular Tumors
1. Adrenal Cortical Neoplasms
2. Lung Carcinoma
3. Hepatocellular Carcinoma
C. Endocrine Disorders
D. Diseases of the Liver (Nonalcoholic and Alcoholic Cirrhosis)
E. Nutrition Alteration States

II. Androgen Deficiency States

A. Senescence
B. Hypoandrogenic States (Hypogonadism)
1. Primary Testicular Failure
  - Klinefelter’s Syndrome (XXY)
  - Reifenstein’s Syndrome
  - Rosewater-Gwinup-Hamwi Familial Gynecomastia
  - Kallmann Syndrome
  - Kennedy’s Disease with Associated Gynecomastia
  - Eunuchoidal State (Congenital Anorchia)
  - Hereditary Defects of Androgen Biosynthesis
  - Adrenocorticotropic Hormone Deficiency
2. Secondary Testicular Failure
  - Trauma
  - Orchitis
  - Cryptorchidism
  - Irradiation
C. Renal Failure

III. Pharmacologic Causes

IV. Systemic Diseases with Idiopathic Mechanisms

ANDI Classification of Benign Breast Disorders

Classification of Benign Breast Disorders

Category	Conditions
Nonproliferative Disorders of the Breast	- Cysts and apocrine metaplasia
	- Duct ectasia
	- Mild ductal epithelial hyperplasia
	- Calcifications
	- Fibroadenoma and related lesions
Proliferative Breast Disorders Without Atypia	- Sclerosing adenosis
	- Radial and complex sclerosing lesions ??? risk
	- Ductal epithelial hyperplasia
	- Intraductal papillomas
Atypical Proliferative Lesions	- Atypical lobular hyperplasia
	- Atypical ductal hyperplasia

Cancer Risk Associated with Benign Breast Disorders and In Situ Carcinoma of the Breast

Abnormality	Relative Risk
Nonproliferative lesions of the breast	No increased risk
Sclerosing adenosis	No increased risk
Intraductal papilloma	No increased risk
Florid hyperplasia	1.5 to 2-fold
Atypical lobular hyperplasia	4-fold
Atypical ductal hyperplasia	4-fold
Ductal involvement by cells of atypical ductal hyperplasia	7-fold
Lobular carcinoma in situ	10-fold
Ductal carcinoma in situ	10-fold

Benign Breast Conditions by Reproductive Years

Early Reproductive Years (Age 15–25 years)

Fibroadenomas:
- Common in younger women aged 15 to 25 years.
- Typically grow to 1 or 2 cm in diameter and then stabilize.
- Classification:
  - Small fibroadenomas (≤1 cm): Normal.
  - Larger fibroadenomas (≤3 cm): Disorders.
  - Giant fibroadenomas (>3 cm): Disease.
  - Multiple fibroadenomas (more than five lesions in one breast): Disease (very uncommon).
Mammographic Screening:
- Sometimes identifies asymptomatic fibroadenomas in older screened populations.
Adolescent Breast Hypertrophy:
- Etiology is unknown.
- Spectrum ranges from limited to massive stromal hyperplasia (gigantomastia).
Nipple Inversion:
- Disorder of development of the major ducts, preventing normal protrusion of the nipple.
- Can lead to mammary duct fistulas:
  - Cause: Nipple inversion predisposes to major duct obstruction.
  - Result: Leads to recurrent subareolar abscess and mammary duct fistula.

Later Reproductive Years (Age 25–40 years)

Cyclical Mastalgia and Nodularity:
- Associated with premenstrual enlargement of the breast.
- Normal: Physiologic discomfort and lumpiness with the menstrual cycle.
- Disorder: Painful nodularity that persists for >1 week of the menstrual cycle is considered a disorder.
Epithelial Hyperplasia of Pregnancy:
- Papillary projections may cause bilateral bloody nipple discharge.

Involution of the Breast

Lobular Epithelium Involution:
- Dependent on the specialized stroma around it.
- Disorders: Integrated involution of stroma and epithelium is not always seen, leading to common disorders.
Microcysts and Macrocysts:
- Rapid stroma involution can leave alveoli, forming microcysts (precursors of macrocysts).
- Macrocysts:
  - Common and often subclinical.
  - Typically do not require specific treatment.
Sclerosing Adenosis:
- Considered a disorder of both proliferative and involutional phases of the breast cycle.
Duct Ectasia and Periductal Mastitis:
- Duct Ectasia: Involves dilated ducts.
- Periductal Mastitis:
  - Leads to periductal fibrosis.
  - May result in nipple retraction.
Epithelial Hyperplasia:
- About 60% of women ≥70 years exhibit some degree of epithelial hyperplasia.
- Atypical Proliferative Diseases:
  - Include ductal and lobular hyperplasia.
  - Display some features of carcinoma in situ.
  - Women with atypical ductal or lobular hyperplasia have a fourfold increase in breast cancer risk.

Radial Scars and Complex Sclerosing Lesions

Characterization:
- Central sclerosis with varying degrees of epithelial proliferation, apocrine metaplasia, and papilloma formation.
Classification:
- Radial Scars: Lesions up to 1 cm in diameter.
- Complex Sclerosing Lesions: Larger lesions beyond 1 cm.
Origin:
- Arise at sites of terminal duct branching.
- Characteristic histologic changes radiate from a central area of fibrosis.
Histologic Features:
- Larger complex sclerosing lesions exhibit greater disturbance of structure with:
  - Papilloma formation
  - Apocrine metaplasia
  - Occasionally sclerosing adenosis.
Diagnostic Challenges:
- Distinguishing between a radial scar and invasive breast carcinoma can be difficult, especially based on core-needle biopsy.
- Imaging features of a radial scar can be similar to those of invasive cancer, often necessitating:
  - Vacuum-assisted biopsy or
  - Surgical excision to exclude the possibility of carcinoma.

Atypical Ductal Hyperplasia (ADH) & DCIS

Histological Appearance:
- Similar to low-grade ductal carcinoma in situ (DCIS).
- Composed of monotonous round, cuboidal, or polygonal cells enclosed by basement membrane with rare mitoses.
Size-Based Classification:
- ADH: Lesions up to 2 or 3 mm in size.
- DCIS: Lesions larger than 3 mm.
Diagnostic Considerations:
- Core-needle biopsy may not be sufficient for diagnosis; excisional biopsy is often required for proper classification.
Risk and Counseling:
- Individuals diagnosed with ADH are at increased risk for breast cancer.
- They should be counseled on risk reduction strategies appropriately.

Atypical Lobular Hyperplasia (ALH) and Lobular Carcinoma In Situ (LCIS)

Atypical Lobular Hyperplasia (ALH)

Characteristics:
- Results in minimal distention of lobular units.
- Cells are similar to those seen in LCIS (Lobular Carcinoma In Situ).

Lobular Carcinoma In Situ (LCIS)

Diagnosis:
- Identified when small monomorphic cells distend the terminal ductal lobular unit.
- Acini are full and distended while maintaining the overall lobular architecture.
Classic LCIS:
- Not associated with specific mammographic or palpable abnormalities.
- Often an incidental finding noted on breast biopsy.
- Management:
  - Not treated with excision.
  - Patients are at risk for developing invasive breast cancer in either breast.
  - Counseling on appropriate risk reduction strategies is essential.
Pleomorphic LCIS:
- Variant of LCIS.
- May present with calcifications or other suspicious mammographic changes, prompting the need for a biopsy.
- Diagnostic Challenges:
  - Can be difficult to distinguish from high-grade DCIS (Ductal Carcinoma In Situ).
  - Some suggest managing pleomorphic LCIS similarly to DCIS, with attention to margins and consideration of radiation therapy in breast-conserving treatment.

Diagnostic Tools

E-cadherin Staining:
- Immunohistochemical staining for E-cadherin can help differentiate between LCIS and DCIS.
- Lobular neoplasias (ALH and LCIS): Lack of E-cadherin expression.
- Ductal lesions: Majority will show E-cadherin reactivity.

Treatment of Recurrent Subareolar Sepsis

Condition	Suitable for Fistulectomy	Suitable for Total Duct Excision
Abscess Size and Location	Small abscess localized to one segment	Large abscess affecting >50% of the areolar circumference
Recurrence Pattern	Recurrence involving the same segment	Recurrence involving a different segment
Nipple Inversion	Mild or no nipple inversion	Marked nipple inversion
Patient Preference	Patient unconcerned about nipple inversion	Patient requests correction of nipple inversion
Patient Age	Younger patient	Older patient
Discharge from Other Ducts	No discharge from other ducts	Purulent discharge from other ducts
Previous Procedures	No prior fistulectomy	Recurrence after fistulectomy

Gail Model Overview

Purpose: The Gail model is used to calculate the cumulative risk of breast cancer by incorporating multiple risk factors, including:
- Age
- Age at menarche
- Age at first live birth
- Number of breast biopsy specimens
- History of atypical hyperplasia
- Number of first-degree relatives with breast cancer
Output: The model provides a 5-year risk and lifetime risk of developing breast cancer.
Access: A software program incorporating the Gail model is available from the National Cancer Institute.
Recent Modification: The model has been modified to more accurately assess risk in African American women.

Relative Risk Estimates for the Gail Model

Variable	Relative Risk
Age at Menarche (years)
- ≥14	1.00
- 12–13	1.10
- ≤11	1.21
Number of Biopsy Specimens/History of Benign Breast Disease, Age <50 years
- 0	1.00
- 1	1.70
- ≥2	2.88
Number of Biopsy Specimens/History of Benign Breast Disease, Age ≥50 years
- 0	1.02
- 1	1.27
- ≥2	1.62
Age at First Live Birth (years)
<20 years
- 0 first-degree relatives with history of breast cancer	1.00
- 1 first-degree relative with history of breast cancer	2.61
- ≥2 first-degree relatives with history of breast cancer	6.80
20–24 years
- 0 first-degree relatives with history of breast cancer	1.24
- 1 first-degree relative with history of breast cancer	2.68
- ≥2 first-degree relatives with history of breast cancer	5.78
25–29 years
- 0 first-degree relatives with history of breast cancer	1.55
- 1 first-degree relative with history of breast cancer	2.76
- ≥2 first-degree relatives with history of breast cancer	4.91
≥30 years
- 0 first-degree relatives with history of breast cancer	1.93
- 1 first-degree relative with history of breast cancer	2.83
- ≥2 first-degree relatives with history of breast cancer	4.17

Claus Model for Breast Cancer Risk Assessment

Development:
- Based on data from the Cancer and Steroid Hormone Study (a case-control study of breast cancer).
- Developed by Claus et al.
Key Features:
- Focus on Family History:
  - Incorporates more detailed information about family history compared to the Gail model.
  - Provides individual estimates of breast cancer risk based on the presence of first- and second-degree relatives with breast cancer and their age at diagnosis.
- Excludes Other Risk Factors:
  - Unlike the Gail model, it excludes other risk factors such as age at menarche, age at first live birth, etc.
Comparison with Gail Model:
- Claus Model:
  - Includes: More detailed family history.
  - Excludes: Other risk factors.
- Gail Model:
  - Includes: Age, age at menarche, age at first live birth, number of breast biopsy specimens, history of atypical hyperplasia, number of first-degree relatives with breast cancer.
Risk Assessment:
- Provides estimates of breast cancer risk according to decade of life.
- Focuses on high-penetrance breast cancer susceptibility genes.
Exclusion of Certain Risk Factors:
- Diet, use of oral contraceptives, lactation: Less consistently associated with breast cancer, therefore excluded.
- Radiation exposure: Rare in the general population, thus excluded from both the Gail and Claus models.
Other Models:
- Some models include mammographic breast density in assessing breast cancer risk.

BRCAPRO Model for Breast and Ovarian Cancer Risk Assessment

Limitations of the Gail and Claus Models:
- Gail Model and Claus Model do not account for the risk associated with mutations in the breast cancer susceptibility genes BRCA1 and BRCA2.
BRCAPRO Model:
- Type: Mendelian model.
- Purpose: Calculates the probability that an individual is a carrier of a mutation in one of the breast cancer susceptibility genes BRCA1 or BRCA2.
- Inputs: Based on family history of breast and ovarian cancer.
Risk Calculation:
- Probability of Mutation:
  - The model calculates the probability that an individual carries a BRCA1 or BRCA2 mutation.
- Probability of Developing Cancer:
  - Derived from the mutation probability, using age-specific incidence curves for both mutation carriers and noncarriers.
Clinical Use:
- Challenges:
  - Requires comprehensive input of all family history information regarding breast and ovarian cancer.
  - This complexity can make the use of the BRCAPRO model challenging in clinical settings.

Tyrer-Cuzick Model for Breast Cancer Risk Assessment

Purpose:
- Combines family history information with individual risk factors to assess breast cancer risk.
Key Features:
- Family History:
  - Calculates the probability that an individual carries a mutation in one of the breast cancer susceptibility genes.
- Personal Risk Factors:
  - Adjusts the risk based on factors including:
    - Age at menarche
    - Parity
    - Age at first live birth
    - Age at menopause
    - History of atypical hyperplasia or LCIS
    - Height
    - Body mass index (BMI)
Application:
- Risk Communication:
  - Once the model has been utilized, the assessed risk must be communicated to the individual.
  - This risk should be put into context with competing risks and medical comorbidities.
- Discussion of Options:
  - The information can then be used to discuss available options for managing risk with the individual.

Breast Cancer Risk and Hormone Replacement Therapy (HRT)

Increased Risk with Hormone Replacement Therapy:
- Threefold to fourfold higher risk of breast cancer after >4 years of use of HRT.
- No significant reduction in coronary artery or cerebrovascular risks associated with HRT.
Collaborative Group on Hormonal Factors in Breast Cancer:
- Study Overview:
  - Combined and reanalyzed data from 52,705 women with breast cancer and 108,411 women without breast cancer.
- Findings:
  - Increased risk of breast cancer with every use of estrogen replacement therapy.
  - Increased risk was noted among current users but not past users.
  - Risk increased with the duration of use of hormone replacement therapy.
WHI Study (Cheblowski et al.):
- Reported that estrogen + progesterone increased the incidence of breast cancer.
Million Women Study:
- Confirmed the findings of the WHI study.
- Increased risk was substantially greater for the combined estrogen + progesterone replacement therapy compared to other types of hormone replacement therapy.

Screening Mammography Recommendations for Average-Risk Women

Key Organizations and Guidelines

U.S. Preventive Services Task Force (USPSTF):
- Recommendation:
  - Biennial screening mammography for women aged 50 to 74 years.
- Guidelines Application:
  - Applies to asymptomatic women aged >40 years who:
    - Do not have preexisting breast cancer.
    - Were not previously diagnosed with a high-risk breast lesion.
    - Are not at high risk due to known genetic mutations or history of chest radiation at a young age.
American Cancer Society (ACS):
- Updated Guidelines (October 2015):
  - Annual screening mammography starting at 45 years of age.
  - Women aged 45 to 54 years: Screened annually.
  - Women aged 55 years and older: Transition to biennial screening or continue annual screening based on preference.
  - Women aged 40 to 44 years: Have the opportunity to begin annual screening.
  - Screening should continue as long as overall health is good and life expectancy is 10 years or longer.
- Clinical Breast Examination:
  - Not recommended for average-risk women at any age.
National Comprehensive Cancer Network (NCCN):
- Recommendation:
  - Annual screening mammography starting at 40 years of age.
  - Includes annual clinical breast exams and breast awareness.

High-Risk Women Definition (According to USPSTF, ACS, NCCN)

Personal history of breast cancer.
History of chest radiation at a young age.
Confirmed or suspected genetic mutation known to increase breast cancer risk.

Controversy of Screening Mammography in Women <50 Years of Age

Challenges:
1. Breast density:
  - Greater in younger women, reducing the sensitivity of mammography.
2. False-positive test findings:
  - More common, leading to unnecessary biopsies.
3. Lower incidence of breast cancer:
  - Younger women are less likely to have breast cancer, so fewer benefit from screening.
U.S. Perspective:
- The benefits of screening mammography for women aged 40 to 49 years generally outweigh the risks.
- Targeting mammography to higher-risk women can improve the balance of risks and benefits.

American Cancer Society (ACS) and MRI Screening

MRI Screening:
- Recommended for women with a 20% to 25% or greater lifetime risk based on risk assessment tools.
- Eligible Individuals:
  - BRCA mutation carriers.
  - Individuals with a family member with a BRCA mutation who have not been tested themselves.
  - Individuals who received radiation to the chest between the ages of 10 and 30 years.
  - Individuals with a history of Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley Ruvalcaba syndrome.
  - Those with a first-degree relative with one of the above syndromes.
Advantages of MRI:
- Extremely sensitive screening tool.
- Not limited by breast density as mammography is.
Disadvantages of MRI:
- Moderate specificity, leading to more false-positive events.
- Increased need for biopsy due to false positives.

Tamoxifen Therapy Recommendations and Risks

Indications for Tamoxifen Therapy:

Recommended for women who meet any of the following criteria:
- Gail relative risk of 1.66% or higher.
- Age 35 to 59 years.
- Women over the age of 60.
- Diagnosis of:
  - Lobular Carcinoma In Situ (LCIS).
  - Atypical ductal hyperplasia.
  - Atypical lobular hyperplasia.

Associated Risks of Tamoxifen:

Deep Vein Thrombosis (DVT):
- Occurs 1.6 times as often in women taking tamoxifen.
Pulmonary Emboli:
- Occurs 3.0 times as often in women taking tamoxifen.
Endometrial Cancer:
- Occurs 2.5 times as often in women taking tamoxifen.
- Increased risk is primarily for early-stage cancers in postmenopausal women.
Cataracts:
- Cataract surgery is required almost twice as often among women taking tamoxifen.

Gail Model for Tamoxifen Use:

Gail et al. developed a model to account for:
- The underlying risk of breast cancer.
- Comorbidities to determine the net risk-benefit ratio of tamoxifen use for chemoprevention.

Classification of Invasive Breast Cancers

General Classification

Special-Type Cancer:
- To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features.
Invasive Ductal Carcinoma of No Special Type (NST):
- About 80% of invasive breast cancers are classified as invasive ductal carcinoma of no special type (NST).
- Generally, these cancers have a worse prognosis compared to special-type cancers.

Foote and Stewart Classification:

Paget's Disease of the Nipple
Invasive Ductal Carcinoma:
- Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST).
- 80% of invasive breast cancers.
Medullary Carcinoma:
- 4% of invasive breast cancers.
Mucinous (Colloid) Carcinoma:
- 2% of invasive breast cancers.
Papillary Carcinoma:
- 2% of invasive breast cancers.
Tubular Carcinoma:
- 2% of invasive breast cancers.
Invasive Lobular Carcinoma:
- 10% of invasive breast cancers.
Rare Cancers:
- Includes adenoid cystic, squamous cell, and apocrine carcinomas.

Medullary Carcinoma Characteristics

Microscopic Features:

Lymphoreticular Infiltrate:
- Dense infiltrate composed predominantly of lymphocytes and plasma cells.
Nuclei Characteristics:
- Large pleomorphic nuclei that are poorly differentiated.
- Show active mitosis.
Growth Pattern:
- Sheet-like growth pattern with minimal or absent ductal or alveolar differentiation.

Associated Features:

Ductal Carcinoma In Situ (DCIS):
- Approximately 50% of medullary carcinomas are associated with DCIS.
- DCIS is characteristically present at the periphery of the cancer.
Hormone Receptor Status:
- <10% of medullary carcinomas demonstrate hormone receptors.

Mucinous Carcinoma (Colloid Carcinoma)

General Characteristics:

Prevalence:
- Accounts for 2% of all invasive breast cancers.
Typical Presentation:
- Often presents as a bulky tumor in the older population.

Defining Features:

Extracellular Pools of Mucin:
- Surround aggregates of low-grade cancer cells.
Cut Surface:
- Glistening and gelatinous in quality.
Fibrosis:
- Variable; when abundant, it imparts a firm consistency to the cancer.

Hormone Receptor Status:

>90% of mucinous carcinomas display hormone receptors.

Lymph Node Metastases:

Occur in 33% of cases.

Survival Rates:

5-year survival rate: 73%.
10-year survival rate: 59%.

Diagnostic Considerations:

Mucinous Component:
- Cancer cells may not be evident in all microscopic sections.
- Analysis of multiple sections is essential to confirm the diagnosis.

Papillary Carcinoma of the Breast

Prevalence: Accounts for 2% of all invasive breast cancers.

Typical Presentation: Generally presents in the seventh decade of life and occurs disproportionately in nonwhite women.

Tumor Size and Structure:

Typically small, rarely exceeding 3 cm in diameter.
Characterized by papillae with fibrovascular stalks and multilayered epithelium.

Hormone Receptor Status: 87% of papillary carcinomas express estrogen receptor (based on SEER database findings).

Prognosis:

Show a low frequency of axillary lymph node metastases.
5-year and 10-year survival rates are similar to those for mucinous and tubular carcinoma.

Tubular Carcinoma of the Breast