Breast Cancer


Most commonly diagnosed cancer (CA) in women and the second most common cause of CA death for U.S. women. Females have a ~2.6% or 1 in 39 chance of dying from breast cancer in the United States.


  • 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 breast cancer (BC), angiosarcoma



  • Estimated new female DCIS: 49,290; invasive BC: 281,550 in 2021
  • Estimated deaths in 2021: females 43,600
  • Incidence rates of BC have increased by 0.5% per year in recent years.

There are >3.8 million breast cancer survivors in US.

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 factors receptors (EGFR), leading to similar abnormal cellular replication.


  • 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 ovarian/fallopian tube/primary peritoneal CA
      • ≥2 family members with BC or pancreatic CA
      • Population at increased risk (e.g., Ashkenazi Jew with BC or ovarian CA at any age)
    • Triple-negative BC (ER−, PR−, HER2−)
    • Two BC primaries
    • Ovarian/fallopian tube/primary peritoneal CA
    • ≥1 family member with BC and CA of thyroid, adrenal cortex, endometrium, pancreas, central nervous system, diffuse gastric, aggressive prostate (Gleason >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-degree 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 w/ 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 Jew with BC/ovarian CA at any age
    • Male BC
    • Known BC susceptibility gene mutation in a family member
  • BRCA1 and BRCA2 are inherited in an autosomal fashion and account for 5–10% of female and 5–20% male CAs; 15–20% familial BCs
    • Mutations higher in Ashkenazi Jewish descent
    • Mutation in BRCA raises risk to 45–65% from 7% at age 70 years.

Risk Factors

  • National Cancer Institute BC Risk calculator:
  • Hormone replacement therapy (combination estrogen-progesterone and estrogen only agents [but not vaginal estrogen]) during perimenopause increases breast cancer risk for 10 years after medication is discontinued.
  • Relative risk (RR) >4.0:
    • Age >65 years
    • Biopsy confirmed atypical hyperplasia
    • BRCA mutation
    • DCIS
    • Lobular carcinoma in situ (LCIS)
    • Personal history of early-onset BC (<40 years)
    • ≥2 first-degree relatives diagnosed at an early age
  • RR 2.1 to 4.0:
    • Personal history of BC (40+ years)
    • Postmenopausal
    • History of radiation
    • First-degree relative of BC
  • RR 1.1 to 2.0:
    • Alcohol use
    • Ashkenazi Jewish descent
    • Diethylstilbestrol exposure
    • Early menarche (<12 years old)
    • Late menopause (>55 years old)
    • High socioeconomic status
    • First pregnancy at >30 years
    • Proliferative breast disease without atypia (fibroadenoma or ductal hyperplasia)
    • Dense breasts (>50%)
    • Nulliparous/no history of full-term pregnancy
    • No history of breastfeeding
    • History of obesity
    • History of endometrial or ovarian CA
    • Hormone replacement therapy
    • Recent oral contraceptive pill use
    • Tall height
  • Patients with 20–25% lifetime risk should receive an annual MRI beginning at age 30 years:
    • BRCA mutation
    • First-degree relative with BRCA mutation
    • History of radiation age 10 to 30 years
    • Li-Fraumeni or Cowden syndrome or first-degree relative with the same
  • Patients with 15–20% lifetime risk:
    • Personal history of BC, DCIS, LCIS, atypical ductal hyperplasia, atypical lobular hyperplasia
    • History of dense or unevenly dense breasts

General Prevention

  • Maintain healthy weight—obesity increases BC risk; physical activity and healthy diet are key.
  • Limit alcohol use—≥1 serving of alcohol per day is recommended.
  • High serum 25-OH vitamin D levels correlate with lower breast cancer risk; consider vitamin D supplementation.
  • Medication: The U.S. Preventative Services Task Force (USPSTF) recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects (B recommendation).
    • The National Cancer Institute Risk Assessment Tool can be used to determine risk.
    • Greater risk was defined as >3% where the risk of medication harms are low.
  • Breast self-exams (BSE): American Cancer Society no longer recommend routine monthly BSE.
  • Clinical breast exam (CBE):
    • USPSTF: insufficient evidence to assess clinical benefits and harms
    • American Cancer Society (ACS): no clear benefit or structured guidelines in average-risk women (1)
  • Mammography:
    • USPSTF: women should undergo biennial mammogram starting at age 50 until age 74
    • American Cancer Society: Women should have annual mammograms starting at age 45 to 54, then women 55 and over should have biennial mammograms or can continue yearly screening if desired (1).
      • Women ages 40 to 44 have the choice to begin annual screening mammograms if desired.

Commonly Associated Conditions

  • Genetic syndromes and mutations such as BRCA1, BRCA2, Li-Fraumeni, and Cowden disease
  • History of high-risk breast lesions such as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and LCIS
  • Obesity

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