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Breast Cancer

Oncology and Hematology | Part 4 – Oncology: Solid Tumors · Part 4 – Oncology: Solid Tumors · Chapter 84

Key Clinical Points

  1. Breast cancer is the most common nonskin cancer in women; ~310,000 new cases expected in US women in 2024.
  2. 5-year relative survival is 91% due to advances in screening, diagnosis, and treatment.
  3. 70% of cases occur in women ≥55 years; median age of diagnosis is 63.
  4. Molecular subtypes include Luminal A, Luminal B, HER2-positive, and Basal-like (TNBC).
  5. Screening mammography reduces mortality by ~20–25% in women ≥50 years.
  6. Tamoxifen reduces risk of invasive cancer in high-risk women; aromatase inhibitors reduce risk by ~50% in postmenopausal women.
  7. Prophylactic mastectomy reduces risk by ~90% in individuals with germline mutations.
  8. Neoadjuvant therapy is indicated for HER2-positive tumors ≥2 cm or node-positive disease.
  9. Complete pathologic response (pCR) to neoadjuvant therapy correlates with better outcomes.
  10. Routine imaging of other types or blood studies do not improve outcomes in asymptomatic survivors.

DEFINITION & OVERVIEW

• Prevalence: Most common nonskin malignancy in women globally. • Incidence (2024): ~310,000 invasive breast cancer cases; ~56,000 DCIS cases. • Mortality: ~42,250 annual deaths in the US. • Survival: 5-year relative survival rate of 91%. • Staging (AJCC 8th edition): ◦ Stage I-II: Early-stage disease confined to breast/ipsilateral nodes ◦ Stage III: Locally advanced disease ◦ Stage IV: Metastatic disease (M1) • Metastatic Sites: Lung, bone, liver, brain. • Molecular Subtypes: Luminal A, Luminal B, HER2+, and Basal-like (TNBC).

1.1 Epidemiology & Survival Statistics

• Demographics: Incidence highest in non-Hispanic whites; mortality highest in non-Hispanic blacks. • Survival by Stage: ◦ Stage I: >99% survival (all races) ◦ Stage II: 75-93% survival ◦ Stage III: 29-75% survival ◦ Stage IV: <30% survival • Table 84-1: Shows 5-year relative survival rates by stage and race. ◦ Stage I: >99% for all groups. ◦ Stage II: 93% (All), 89% (Black). ◦ Stage III: 75% (All), 64% (Black). ◦ Stage IV: 29% (All), 20% (Black).

EPIDEMIOLOGY & RISK FACTORS

• Primary Factors: Female gender and aging (70% of cases in women ≥55 years). • Modifiable Risks: ◦ Postmenopausal obesity ◦ Alcohol consumption ◦ Radiation exposure during adolescence • Benign Breast Disease: ◦ Atypical hyperplasia: 4-5x risk ◦ LCIS: 7-12x risk • Non-genetic Risk Factors: ◦ Early menarche (<12 years) ◦ Late menopause (>55 years) ◦ Nulliparity or late first pregnancy (>30 years) ◦ Prolonged hormone replacement therapy (HRT) use ◦ Oral contraceptive use • Genetic Risk Factors: ◦ BRCA1/2: 50-80% lifetime risk of breast cancer; 30% ovarian cancer risk ◦ TP53 (Li-Fraumeni syndrome) ◦ PALB2, ATM, STK11 (Peutz-Jehers), PTEN (Cowden)

2.2 Genetic Testing Criteria

• Testing Recommended for: ◦ Patients with breast cancer diagnosed ≤65 years ◦ Ashkenazi Jewish ancestry ◦ Multiple primaries or specific subtypes (e.g., TNBC, lobular with gastric cancer history) ◦ Family history of early-onset/male breast cancer, ovarian/pancreatic/prostate cancer

ETIOLOGY & PATHOPHYSIOLOGY

• Molecular Subtypes: ◦ Luminal A: ER+/PR+, low Ki67, favorable prognosis ◦ Luminal B: ER+/PR-, high Ki67, intermediate prognosis ◦ HER2+: ER-/PR-, HER2 overexpression, responsive to anti-HER2 therapy ◦ Basal-like/TNBC: ER-/PR-/HER2-, poor prognosis, chemotherapy-sensitive • Lobular Cancers: ER+, HER2-, E-cadherin loss, propensity for serosal metastases (omentum, pleura). • Special Types: Mucinous and medullary subtypes have favorable outcomes with local therapy. • In Situ Pathology: ◦ DCIS: Confined to ducts; 30% risk of progression to invasive cancer if untreated. ◦ LCIS: Incidental finding with 25-30% risk of subsequent invasive disease in either breast.

CLINICAL FEATURES

• Presentations: ◦ Breast lump, skin/nipple changes, palpable nodes ◦ Asymptomatic findings on mammography (masses, microcalcifications) ◦ <10% present with de novo metastatic disease • Screening Findings: ◦ Mammography increases DCIS/LCIS detection. ◦ High breast density correlates with increased risk. ◦ 3% of newly diagnosed cases have unsuspected contralateral disease.

DIFFERENTIAL DIAGNOSIS

• DCIS vs. Invasive Ductal Carcinoma: Invasion beyond basement membrane. • LCIS vs. Invasive Lobular Carcinoma: Risk marker vs. malignant progression. • Metastatic Mimics: Inflammatory breast cancer, Paget's disease. • Subtype-specific presentations: Metaplastic, mucinous, medullary cancers.

DIAGNOSTIC APPROACH

  1. Initial finding → Screening imaging (mammography, ultrasound, MRI if indicated)
  2. Suspicious lesion → Diagnostic biopsy (core needle or excisional)
  3. Axillary lymph node evaluation → Imaging-guided biopsy
  4. Biomarker testing: ER/PR (≥1% staining), HER2 (IHC and FISH), Ki67, genomic assays (Oncotype DX, MammaPrint)
  5. Staging → Clinical (c) or pathologic (p) staging with TNM system incorporating molecular data

Flowchart 1: Evaluation of Breast Lesions • Pathway A (Clinical Finding): Suspicious clinical finding → Diagnostic breast imaging → ◦ If Negative/benign → Follow-up exam → ◦ If Resolved → Routine follow-up screening mammogram as indicated ◦ If Uncertain or clinical suspicion persists → Refer to experienced breast diagnostician ◦ If Confirmed suspicious finding (e.g., "Suspicious microcalcifications" or "Suspicious mass") → Biopsy • Pathway B (Screening): Screening breast imaging → No suspicious breast finding → Routine follow-up screening mammogram as indicated • Pathway C (Screening to Diagnosis): Screening breast imaging → Suspicious breast finding → Diagnostic breast imaging → ◦ If Confirmed suspicious finding → Biopsy

Flowchart 2: Evaluation of Prior History Patients • Pathway A (Non-specific/Resolved): Clinical symptom → History, physical exam → Suspicious history or clinical finding → Nondiagnostic → Follow-up evaluation → Resolved → Routine follow-up • Pathway B (Persistent Non-malignant): Clinical symptom → History, physical exam → Suspicious history or clinical finding → Nondiagnostic → Follow-up evaluation → Uncertain or persists → Continue follow-up no rule out noncancer etiology; further workup if indicated • Pathway C (Potential Malignancy): Clinical symptom → History, physical exam → Suspicious history or clinical finding → Confirmed suspicious finding → Biopsy if possible → ◦ If Benign → Routine follow-up ◦ If Other cancer or infection → Further evaluation and treatment as appropriate ◦ If Positive for metastasis → Re-evaluate duration, stage, [PgR, HER2, PIK3CA, AKT1, MET, NGS]"

MANAGEMENT & TREATMENT

  1. Surgery: Lumpectomy + radiotherapy
  2. Surgery: Mastectomy (consider if multifocal disease, prior chest radiation, or BRCA mutations)
  3. Radiation: Tailored by age/tumor size/nodal status
  4. Radiation options: Whole breast radiotherapy (WBR), hypofractionated regimens, or partial breast irradiation
  5. Systemic therapy: Endocrine therapy for ER+/PR+ disease (tamoxifen or aromatase inhibitors)
  6. Systemic therapy: Chemotherapy for high-risk patients
  7. Systemic therapy: Targeted therapies (trastuzumab, pertuzumab) for HER2+
  8. Systemic therapy: PARP inhibitors (olaparib) for BRCA-mutated cancers
  9. Systemic therapy: CDK4/6 inhibitors (abemaciclib, ribociclib) with endocrine therapy
  10. Neoadjuvant chemotherapy: Tumor size ≥2 cm
  11. Neoadjuvant chemotherapy: Node-positive disease
  12. Neoadjuvant chemotherapy: HER2+ tumors
  13. Prevention: Tamoxifen (~30% risk reduction in high-risk women)
  14. Prevention: Aromatase inhibitors (~50% risk reduction in postmenopausal women)
  15. Prevention: Prophylactic mastectomy (~90% risk reduction in BRCA mutation carriers)

Note on Neoadjuvant Therapy: • Complete pathologic response (pCR) to neoadjuvant therapy correlates with better outcomes.

Note on Prevention: • Tamoxifen reduces risk of invasive breast cancer in high-risk women; aromatase inhibitors reduce risk by ~50% in postmenopausal women. • Prophylactic mastectomy reduces risk by ~90% in individuals with germline mutations.

COMPLICATIONS & PROGNOSIS

• Prognosis by Subtype: ◦ Luminal A: Best survival ◦ TNBC: Worst prognosis without pCR to neoadjuvant therapy • Long-term Complications: ◦ Endocrine therapy: hot flashes, arthralgias, bone loss ◦ Chemotherapy: cardiotoxicity, neuropathy, secondary leukemia • Survivorship Care: ◦ Annual imaging for ipsilateral/contralateral disease ◦ No benefit from routine blood tests or imaging in asymptomatic survivors.

SPECIAL POPULATIONS

• Pregnancy: Management similar to non-pregnant patients, with consideration for fetal safety. • BRCA Carriers: ◦ Prophylactic bilateral mastectomy recommended ◦ Oophorectomy for ovarian cancer risk reduction.

KEY PEARLS & HIGH-YIELD POINTS

• DCIS: Not curable without treatment (30% progression risk). • LCIS: A risk marker, not a malignancy. • TNBC: Poor response to hormonal therapy; may benefit from immunotherapy. • AIs: Contraindicated in premenopausal women without ovarian suppression. • pCR: Predicts better outcomes in neoadjuvant settings.

Reference Tables

TABLE 83-14 Staging Thymic Tumors

Harrison's 22e, p.632

MASAOKA STAGE DEFINITION
I Grossly and microscopically encapsulated
IIB Macroscopic invasion into surrounding tissue excluding
pericardium, lung, and great vessels
IVA Pleural or pericardial dissemination
WHO
A Tumor with few lymphocytes
B1 Tumor with features of normal epithelial cells with
vesicular nuclei and distinct nucleoli and an abundant
population of lymphocytes. Also known as cortical
thymoma, lymphocyte-rich thymoma
B3 Well-differentiated thymic carcinoma with mild atypia
84 Breast Cancer
Nancy E. Davidson

TABLE 84-1 Five-Year Breast Cancer Relative Survival Rate (%) by Stage at Diagnosis and Race/Ethnicity in United States…

Harrison's 22e, p.635

STAGE ALL WHITE BLACK AIAN HISPANIC API
I >99 >99 >99 >99 >99 >99
93 93 89 93 92
III 75 77 64 72 74 77
29 31 20 35 29