Breast Cancer

Overview

Epidemiology

• Breast cancer is the most common cancer in women.
• Accounts for 29% of all malignant diseases among women in the United States
• Incidence: 125 cases per 100,000 women
• Risk increases with age, with 90% of cases occurring in women > 40 years of age
• Male breast cancer accounts for < 1% of total cases.
• An important cause of death in women:
  • United States: the 2nd leading cause of cancer-related deaths
  • Developing countries: the leading cause of cancer-related deaths
• Early detection and improved treatments have reduced death rates.

Risk factors

Unmodifiable factors that increase the risk:

• Family history:
  • Breast cancer in 1st- or 2nd-degree relatives (mother, grandmother, sister)
  • Ashkenazi Jewish descent
• Hormonal influences: long hormone exposure due to early menarche and/or late menopause
• Genetic mutations (examples):
  • BRCA1 (on chromosome 17q)
  • BRCA2 (on chromosome 13q)
  • p53 (on chromosome 17)
• Increasing age
• Breast cancer on the contralateral side

Modifiable risk factors:

• Lifestyle factors that increase the risk: 
  • High-fat diet
  • Obesity (especially after menopause)
  • Heavy alcohol use
  • Tobacco
• Hormonal influences that increase the risk:
  • Higher age at 1st delivery (> 30 years of age)
  • Nulliparity
  • Hormone replacement therapy after menopause (> 5 years)
• Hormonal influences that decrease risk: breastfeeding for at least 6 months

Mnemonics:

“BReast-CAncer 1 and 2” = Mutated genes are the BRCA1 and BRCA2 genes.

Histologic classification

Non-invasive:

• Ductal carcinoma in situ (DCIS)
• Lobular carcinoma in situ (LCIS)

Invasive:

• Infiltrating ductal (most common)
• Infiltrating lobular
• Ductal/lobular
• Mucinous/colloid
• Tubular
• Medullary 
• Micropapillary

Other clinical forms:

• Paget’s disease of the breast
• Inflammatory carcinoma

Molecular classification

Based on expression of:

• Estrogen receptors (ERs)
• Progesterone receptors (PRs)
• Human epidermal growth factor receptor 2 (HER2)
• Cell proliferation regulator/protein (Ki-67)

Molecular types:

• Luminal A: 
  • ER positive, HER2 negative
  • PR positive, low Ki-67 (low proliferation)
  • Favorable prognosis
• Luminal B: 
  • ER positive, HER2 negative/positive
  • PR positive, high Ki-67 (high proliferation)
  • Worse prognosis than luminal A
• HER2 amplified: 
  • Overexpress HER2
  • ER negative, PR negative
  • Grows faster than luminal cancers
• Basal-like or triple-negative breast cancers (TNBCs): 
  • Negative for ER, PR, and HER2
  • More common in African American women

Pathophysiology

Familial breast cancer

• 25%–30% of breast cancers are associated with susceptibility genes.
• Tumor suppressor genes (TSGs):
  • Most significant susceptibility genes for familial breast cancer
  • Autosomal dominant inheritance of risk, which occurs with loss-of-function mutations
• TSG mutations:
  • BRCA1 (on chromosome 17q21) and BRCA2 (on chromosome 13q12.3) mutations (familial breast and ovarian cancer):
    • 80%–90% of single gene familial breast cancers
    • At-risk population: strong family history, certain ethnic groups (Ashkenazi Jewish descent)
    • Associated with poorly differentiated cancer
  • TP53 (Li-Fraumeni syndrome)
  • PTEN (Cowden syndrome)
  • STK11 (Peutz-Jeghers syndrome)
  • CDH1 (hereditary diffuse gastric cancer syndrome)
  • PALPB2 (hereditary breast cancer)
• Normally functioning TSGs induce cell cycle arrest and deoxyribonucleic acid (DNA) repair in the setting of DNA damage.
• Impaired function of TSGs → ↑ DNA damage → ↑ oncogenic mutations

Sporadic breast cancer

• Tumor progression:
  • Breast cancer occurs from malignant transformation of secretory epithelial cells that are part of the normal breast epithelium (2 layers):
    • Basal myo-epithelial layer
    • Luminal epithelial layer
  • Early genetic mutations cause proliferative epithelial replacement.
  • Additional genetic events + hormone signaling → increased and abnormal overgrowth (hyperplasia, precursor lesion(s)) → carcinoma in situ → eventually invasive ductal carcinoma
  • The morphology and clinical behavior depend on the molecular type.
• In the luminal type (ER positive/HER2 negative):
  • Up to 65% of breast malignancies
  • Estrogen exposure (major factor):
    • ↑ Growth factors (e.g., transforming growth factor ɑ)
    • Stimulate epithelial cell proliferation (puberty, menses, pregnancy), increasing the risk of malignant transformation
    • ↑ Age and ↑ estrogen exposure with more menstrual cycles → ↑ breast cancer risk
  • ER-positive precursor lesions: flat atypia and atypical ductal and lobular hyperplasia (more associated with luminal A)
• In the HER2-positive/amplified type:
  • Up to 20% of breast cancers
  • Associated with amplification of the HER2 gene (chromosome 17q)
  • HER2 (also called ERBB2): protein that promotes proliferation, and opposes apoptosis
  • Used to have a poor outcome but with biologic therapy (trastuzumab), prognosis has improved
  • No definite precursor lesion
• In TNBCs:
  • 15% of breast cancers
  • Basal-like: have markers characterizing the basal myoepithelial cells
  • Associated with genomic instability from defects in DNA repair
  • Possible precursor lesion: cells with TP53 mutations

Clinical Presentation

Clinical findings

In areas with established breast cancer screening: Most cases of cancer are diagnosed by having an abnormal mammogram.

Symptoms:

• Patient feels a lump/mass.
• Skin changes (dimpling, erythema, thickening)
• Nipple changes (appearance, discharge)

Signs:

• Firm or hard mass with poorly defined margins, fixed or immovable (on its own not enough to distinguish malignancy)
• Location: 
  • Highest frequency: upper outer quadrant (50% of cases)
  • Lowest frequency: lower inner quadrant (5%)
• Possible to have multifocal/multiple foci in the same quadrant 
• Possible to have different quadrants of the breasts affected (multicentric)
• Contralateral breast also affected by the tumor in 5%–10% of cases

Metastasis

• Presentation depends on organ(s) involved
• Most common sites: 
  • Bone (back or leg pain)
  • Liver (jaundice, abdominal pain, nausea, abnormal liver tests)
  • Lungs (shortness of breath, cough, abnormal chest imaging)

Non-invasive Breast Cancer

DCIS

• Proliferation of cytologically malignant cells within the mammary ductal system, with no invasion of the surrounding stroma
• ⅓ develop invasive cancer in 5 years
• Frequently detected by mammography

LCIS

• Proliferation of malignant cells within the lobules, growing in an incohesive manner
• Mucin-positive signet cell rings usually noted
• Loss of cellular adhesion also observed (from dysfunction of E-cadherin)
• Rarely with calcifications (incidence not changed by mammography)

Comparison DCIS versus LCIS

Invasive Breast Cancer

Infiltrating ductal carcinoma

• Most common invasive breast cancer (76% of all breast carcinomas)
• Mostly unilateral
• Gross appearance: 
  • Firm, fibrous, “rock-hard” mass with irregular stellate shape
  • Often 2–3 cm in size
• Microscopic findings (Nottingham Histologic Score):
  • Well differentiated (grade 1): tubular/cribriform pattern, small uniform nuclei, low proliferative rate
  • Moderately differentiated (grade 2): cells in clusters or single infiltrating cells, nuclear polymorphism, + mitotic figures
  • Poorly differentiated (grade 3): ragged nest pattern, large irregular nuclei, high proliferative rate

Infiltrating lobular carcinoma

• 2nd most common invasive breast cancer (5%–10%)
• Gross appearance: 
  • May not have a mass lesion 
  • Difficult to palpate or detect by mammography
• Microscopic findings:
  • Incohesive infiltrating tumor cells (often with signet ring cells)
  • Staining with E-cadherin (negative in infiltrating lobular carcinoma): helps distinguish from infiltrating ductal carcinoma
• Metastatic pattern: involves the peritoneum, retroperitoneum, leptomeninges, ovaries/uterus, and gastrointestinal tract
• Heterozygous germline mutations in CDH1: increased risk of lobular carcinoma

Tubular carcinoma

• ≤ 2% of invasive breast cancers
• Microscopic findings: well-formed tubules; associated with low-grade DCIS
• Good prognosis, metastasis rare

Mucinous/colloid carcinoma

• 1%–2% of invasive breast cancers
• More common in older patients 
• Favorable prognosis
• Gross appearance: soft, circumscribed, pale gray-blue gelatin
• Microscopic findings: clusters of tumor cells within lakes of mucin

Medullary carcinoma

• More frequently found in BRCA1 carcinomas
• Occurs in younger patients
• Better prognosis than other poorly differentiated carcinomas
• Microscopic findings: 
  • Well circumscribed, with areas of necrosis and hemorrhage
  • Sheets of large cells, pleomorphic nuclei with prominent nucleoli
  • Marked lymphoplasmacytic infiltrate

Micropapillary carcinoma

• Rare but aggressive cancer
• High propensity for lymphovascular invasion and lymph node metastasis
• Microscopic findings: Clusters of cells float within an empty stromal space.

Paget’s disease of the breast

• 1%–4% of cases
• Appearance: 
  • Unilateral eczematous, erythematous patches on the nipple, and nipple retraction
  • In > 50%, palpable mass present (often invasive carcinoma, ER negative and overexpress HER2)
• Those without a mass: Most have DCIS.
• Paget’s cells: large, round, malignant cells in the epidermis 

Inflammatory carcinoma

• Characterized by dermal lymphovascular invasion of tumor cells
• Appearance:
  • Breast skin erythema and thickening
  • Breast skin resembles orange peel (peau d’orange).
• Poor prognosis 

Diagnosis

Clinical and diagnostic tools

• Breast exam 
• Screening mammography:
  • May offer screening starting at age 40 years.
  • Signs of a malignant finding:
    • Soft-tissue mass or density
    • Clustered microcalcifications
    • Spiculated high-density mass (most specific for invasive cancer)
  • The presence of a breast lump with a negative mammogram still warrants further investigation.
• Ultrasonography:
  • Complementary test to mammography
  • Benefit: 
    • No radiation exposure
    • Differentiates solid (such as a benign fibroadenoma or cancer) from fluid-filled cystic (such as a benign cyst) lesions
  • Disadvantage: highly operator dependent, not suited for screening on its own
  • Signs of malignant finding:
    • Internal calcifications
    • Hypoechoic
    • Shadowing
    • Spiculated margins
• Magnetic resonance imaging (MRI):
  • Screening for women at high risk for breast cancer
  • Benefit: high soft-tissue contrast, very high sensitivity
  • Disadvantage: low specificity, no detection of microcalcifications
  • Signs of malignant finding:
    • Spiculated mass
    • Enhancing internal septa
    • Heterogenous internal enhancement
• Biopsy (confirms diagnosis):
  • Fine-needle aspiration: small sample, with a false-negative rate of 10%
  • Core needle biopsy (recommended): larger sample, and allows for immunohistochemical testing 

Post-diagnostic tools

• Breast cancer receptor testing:
  • When cancer is confirmed, determine ER/PR receptor expression:
    •  If > 1% of the tumor cells stain positive (on immunohistochemistry or IHC) for ER/PR → hormone receptor positive 
    • ER/PR-positive carcinoma is suitable for endocrine therapy → better prognosis
  • Overexpression of HER2 receptor:
    • Detected by IHC or fluorescence in situ hybridization (FISH) 
    • HER2 positive → treatment with trastuzumab (HER2 antibody)
• Additional imaging (for metastatic breast cancer):
  • Bone scan: for patients with bone pain or elevated alkaline phosphatase
  • Computed tomography (CT) of the chest: for patients with pulmonary symptoms
  • CT of the abdomen and pelvis or MRI: for patients with abnormal pain and/or examination, elevated liver enzymes/alkaline phosphatase
  • Positron emission tomography-CT (PET-CT): for whole-body screening for metastasis (stage III or higher)
• Tumor markers: 
  • CA 15-3, CA 27.29, and carcinoembryonic antigen (CEA)
  • Biochemical markers are not specific for breast cancer relapse.
  • Used to monitor treatment response of patients with metastatic disease
• Genetic testing:
  • United States Preventive Services Task Force recommends the use of approved familial risk assessment tools for the following:
    • A personal or family history of breast, ovarian, tubal, or peritoneal cancer
    • Ancestry associated with BRCA1 or 2 mutations
    • Positive assessment indicates the need for genetic counseling and testing.
  • Other expert groups have varying recommendations.

Staging

Overview of breast cancer staging

• Based on the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) 8th edition
• Includes the tumor, node, metastasis (TNM) staging system and incorporates biologic factors for prognostic staging
• Information included in staging:
  • Tumor
  • Node
  • Metastasis
  • ER status
  • PR status
  • HER2 status
  • Histologic grade
  • Recurrence score (Oncotype Dx) considered
• Anatomic stage grouping relies on TNM.
• Prognostic stage grouping:
  • Relies on TNM, ER/PR/HER2, grade
  • Primary prognostic staging system for those who receive neoadjuvant treatment or for those who do not undergo surgery

TNM staging

Categories

• Early-stage non-metastatic breast cancer: stage I, IIA, a subset of stage IIB (T2N1)
• Locally advanced non-metastatic breast cancer: subset of stage IIB (T3N0), stage IIIA–IIIC
• Metastatic breast cancer: stage IV

Management and Prognosis

DCIS

• Surgery: breast-conserving surgery (BCS) (e.g., lumpectomy) or mastectomy
• Radiation therapy (RT) considered in those with high risk of recurrence
• Endocrine therapy for ER-positive DCIS (for 5 years):
  • Tamoxifen:
    • ER antagonist
    • Option for all women
  • Aromatase inhibitors (e.g., anastrozole):
    • Inactivates aromatase, reducing peripheral conversion of androgens to estrogens
    • Alternative for post-menopausal women

Early-stage cancer

• Surgery:
  • BCS or mastectomy
  • Axillary LN assessment performed with sentinel lymph node biopsy (if positive, axillary dissection is done)
• RT in most cases (if BCS is done and for those at risk for local recurrence)
• Adjuvant or systemic therapy given in addition to surgery:
  • Endocrine therapy:
    • For hormone receptor (ER/PR)–positive patients
    • Aromatase inhibitors or tamoxifen
  • HER2-targeted therapy: 
    • For HER2-positive cancers
    • Trastuzumab +/- pertuzumab
  • Chemotherapy (doxorubicin + cyclophosphamide, then paclitaxel): 
    • For TNBCs (≥ 0.5 cm)
    • For HER2-positive cancers (> 1 cm) 
    • For hormone receptor–positive cancers (with high-risk features: ≥ 2-cm size, + LNs, high-grade lesions) 

Locally advanced breast cancer

• Neoadjuvant systemic therapy:
  • HER2-directed therapy + chemotherapy: for HER2-positive cancer
  • Chemotherapy given 1st for hormone receptor–positive cancer 
  • Chemotherapy given for TNBCs
• Surgery (BCS or mastectomy + LN assessment) follows neoadjuvant therapy.
• Adjuvant therapy:
  • Given if there was no neoadjuvant therapy (similar principles as early-stage cancer)
  • For those who had neoadjuvant therapy: 
    • Endocrine therapy or HER2-directed therapy continued as indicated
    • Chemotherapy use is dictated by clinical status and tumor characteristics.
• RT

Metastatic breast cancer

• Systemic therapy:
  • Aromatase inhibitors with/without chemotherapy for ER-positive cancers
  • Trastuzumab with chemotherapy for HER2-positive cancers
  • Chemotherapy for receptor-negative cancers
  • Immunotherapy (immune checkpoint inhibitors)
• RT for palliation

Prognosis

• 10-year survival:
  • Stage 0 (DCIS): 97%
  • Stage I: 87%
  • Stage II: 65%
  • Stage III: 40%
  • Stage IV: 5%
• With distant metastasis, there is no cure.

Differential Diagnosis

• Fibroadenoma: benign breast tumors that arise in young women. Diagnosis is based on the physical finding of a mobile, non-tender breast mass. Some fibroadenoma are asymptomatic, small in size, and should be treated conservatively. Other fibroadenoma grow rapidly in size, are symptomatic, and should be surgically excised.
• Fat necrosis of the breast: a benign condition caused by trauma to the breast, which may go unnoticed, leading to adipocyte necrosis and calcification. Patients may present with a solid, painless mass with or without skin changes. Fat necrosis of the breast can mimic malignancy and definitive diagnosis is by imaging and biopsy. 
• Mastitis: inflammation of the mammary gland tissue that can be lactational or non-lactational. Mastitis is most common in women of childbearing age. Patients usually present with high fever, chills, fatigue, malaise, and myalgia. Analgesics and antibiotics are given as part of the management.
• Breast abscess: a breast mass associated with mastitis. Breast abscess presents as a unilateral and fluctuant mass, accompanied by fever, and a painful, erythematous, and edematous breast. History, physical findings, and needle aspiration (revealing purulent contents) help differentiate a breast abscess. Treatment includes incision and drainage, with antibiotics.
• Intraductal papillomas: abnormal growths with a papillary configuration of the breast stroma and epithelium within a breast duct. The most common presenting feature is bloody or serous nipple discharge. Core needle biopsy confirms the diagnosis.
• Simple breast cyst: round or oval fluid-filled masses from the terminal duct lobular unit. A cyst is felt as a palpable mass that can cause pain. Ultrasonography shows a cyst as a well-circumscribed, anechoic mass with no solid components.