Etiology

• second most common malignant disease in women

• Postmenopausal

• Incidence increases with age.

• 50% of breast cancers are diagnosed in women ≥ 65 years of age.

second leading cause of cancer death in women in the US

• Hormonal risk factors

• Individual risk factors

1. Increased exposure to endogenous estrogen

2. Exogenous estrogen intake

• First viable pregnancy after 35 years of age

• Nulliparity and/or absence of breastfeeding [5]

• Early menarche and/or late menopause

• Obesity in postmenopausal women (lipocytes convert androstenedione to estrone)

• Hormone replacement therapy after menopause

• Hormonal contraception

Invasive lobular carcinoma is commonly associated with hormone replacement therapy.

• Sex: female

• Age: advanced age (most commonly in women ≥ 65 years)

• Ethnicity

  • Individuals of European descent are at highest risk.

  • African Americans are at increased risk for triple-negative breast cancer.

• Lifestyle

  • Low-fiber and high-fat diet

  • Smoking

  • Alcohol consumption

• Positive medical history

  • Breast cancer in the contralateral breast

  • Breast conditions with cellular atypia (e.g., fibrocystic change, fibroadenoma)

  • Endometrial cancer , ovarian, or colorectal cancer

  • Radiation therapy during childhood

1. Mutations

2. Genetic conditions

• Positive family history (e.g., in first-degree relatives)

• Tumor suppressor genes

  • BRCA1 and BRCA2: BRCA are tumor suppressor genes that code for a DNA repair protein.

    • Autosomal-dominant mutation

    • Associated with an increased risk for breast cancer and ovarian cancer

    • 5–10% of breast cancer cases are hereditary; BRCA mutations account for most of these.

    • BRCA-positive women develop breast cancer earlier than women without the mutation.

    • An estimated 55–60% of women with BRCA1-positive status will develop invasive breast cancer before the age of 70; the number is 45% in BRCA2-positive women.

    • Men with breast cancer are often positive for BRCA2.

  • PTEN, RB1, CDH1

• Oncogenes (e.g., RAS)

• Mutations responsible for receptor overexpression

  • Estrogen/progesterone receptors

  • ERBB2 (HER2/neu)

• Li-Fraumeni syndrome: autosomal dominant mutation of the p53 tumor suppressor gene

  • Pathophysiology

    • One abnormal copy of the TP53 gene is inherited.

    • If the second allele is somatically mutated or deleted (loss of heterozygosity), it results in unregulated cell proliferation and cancer.

  • Clinical features: multiple malignancies at an early age

    • Breast cancer

    • Osteosarcoma

    • Leukemia, lymphoma

    • Brain tumors

    • Adrenocortical carcinoma

• Others:

  • Peutz-Jeghers syndrome

  • Klinefelter syndrome