Description

• Malignant neoplasm of cells native to the breast—epithelial, glandular, or stroma
• Types: ductal carcinoma in situ (DCIS), infiltrating ductal carcinoma, infiltrating lobular carcinoma, Paget disease, phyllodes tumor, inflammatory BC, angiosarcoma
• Molecular subtypes: luminal A (ER+/PR+/HER2−), triple negative (ER−/PR−/HER2−), luminal B (ER+/HER−), luminal B-like (ER+/HER2+), HER2-enriched (ER−/PR−/HER2+)

Epidemiology

Incidence
Estimated in 2023: ~297,790 new cases of invasive BC, ~55,720 DCIS; ~43,700 deaths from BC in U.S women; increased by ~0.5% per year since mid-2000s

Prevalence
>3.8 million BC survivors in the United States (1)

Etiology and Pathophysiology

• Genes such as BRCA1 and BRCA2 function as tumor suppressor genes, and mutation leads to cell cycle progression and limitations in DNA repair.
• Mutations in estrogen/progesterone induce cyclin D1 and c-Myc expression, leading to cell cycle progression.
• Additional tumors (33%) may cross talk with estrogen receptors and epidermal growth factor receptors (EGFRs), leading to similar abnormal cellular replication.

Genetics

• Criteria for additional risk evaluation/gene testing in affected BC individual
  • BC at age ≤50 years
  • BC at any age and
    • ≥1 family member with BC (≤50 years of age or in men) or ovarian/fallopian tube/primary peritoneal CA at any age
    • ≥2 family members with BC or pancreatic CA any age
    • Population at increased risk (e.g., Ashkenazi Jewish descent)
  • Triple-negative BC (ER−, PR−, HER2−)
  • Second primary BC (not recurrence of first), ovarian/fallopian tube/primary peritoneal CA
  • ≥1 family member with BC and CA of thyroid, adrenal cortex, endometrium, pancreas, central nervous system (CNS), diffuse gastric, aggressive prostate (Gleason score of >7), leukemia, lymphoma, sarcoma, dermatologic manifestations, and/or macrocephaly, gastrointestinal (GI) hamartomas
  • Male BC
• Criteria for additional risk evaluation/gene testing in unaffected BC individual
  • First- or second- relative with BC ≤45 years of age
  • ≥2 breast primaries in one individual
  • ≥1 ovarian/fallopian tube/primary peritoneal CA from same side of family
  • ≥2 with breast primaries on same side of family
  • ≥1 family member with BC and CA of thyroid, adrenal cortex, endometrium, pancreas, CNS, diffuse gastric, aggressive prostate, leukemia, lymphoma, sarcoma, dermatologic manifestations, and/or macrocephaly, GI hamartomas
  • Ashkenazi Jewish descent with BC/ovarian CA at any age
  • Male BC
• 5–10% of BCs are associated with genetic mutations and are thus hereditary.
  • BRCA1 and BRCA2 are inherited in an autosomal fashion and account for
  • Syndromes associated with BC: Cowden syndrome (PTEN), Li-Fraumeni syndrome (TP53), ataxia-telangiectasia (ATM), and Peutz-Jeghers (STK11), hereditary diffuse gastric CA (CDH1); other BC genes include PALB2 and CHEK2.

Risk Factors

• National Cancer Institute Breast Cancer Risk Assessment Tool. https://bcrisktool.cancer.gov
• Female sex; increased age
• Hormone replacement therapy (combination estrogen-progesterone and estrogen only agents [but not vaginal estrogen]) during perimenopause increases BC risk for 10 years after medication is discontinued.
• Age >65 years, biopsy confirmed atypical hyperplasia, DCIS, lobular carcinoma in situ (LCIS)
• BRCA mutation, Ashkenazi Jewish descent
• Personal or family history of BC at a younger age
• Postmenopausal
• History of radiation or diethylstilbestrol (DES) exposure (especially at a young age)
• Increased alcohol use
• Proliferative breast disease without atypia (fibroadenoma or ductal hyperplasia)
• Dense breasts (>50%)
• Reproductive factors
  • Nulliparous, no history of full-term pregnancy or breastfeeding
  • Early menarche (<12 years old), late menopause (>55 years old), first pregnancy at >35 years old
• Obesity
• Tall stature
• History of endometrial or ovarian CA

General Prevention

• Maintain healthy weight/body mass index (BMI)—obesity increases BC risk.
• Limit alcohol use—≤1 serving of alcohol per day is recommended.
• High serum 25-OH vitamin D levels correlate with lower BC risk; consider vitamin D supplementation.
• Medication: U.S. Preventive Services Task Force (USPSTF) recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors (AIs), to women who have a >3% risk for BC and low risk for adverse medication effects (B grade recommendation).
• Breast self-exams (BSEs): no longer recommended
• Clinical breast exam (CBE): USPSTF: insufficient evidence to assess clinical benefits and harms; American Cancer Society (ACS): no clear benefit
• Mammography (MMG):
  • USPSTF: Women should undergo biennial mammogram starting at age 40 years until age 74 years (B grade recommendation).
  • ACS: Women annual mammograms starting at age 45 to 54 years and then women >55 years old biennial mammograms or yearly screening if desired (1); age 40 to 44 years, optional mammograms yearly

Commonly Associated Conditions

• Li-Fraumeni and Cowden disease
• History of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and LCIS
• Obesity