Etiology

The etiology of the majority of invasive breast cancers is unknown, but the following factors are thought to have a role.

Genetic factors

It is estimated that 5% to 10% of breast cancers are linked to inherited genetic mutations.[11][12][13] BRCA1 and BRCA2 mutations are the most common inherited genetic mutation found in breast cancer.[13][14][15] The estimated cumulative lifetime risk of breast cancer (up to age 80 years) is reported to be 72% and 69% for BRCA1 and BRCA2 mutation carriers, respectively.[15] However, these mutations affect <0.1% of the general population, with variable penetrance.[16]

Other genetic mutations associated with breast cancer include: CHEK2, PALB2, ATM, NBN, BARD1, RAD51C, RAD51D, CDH1 (hereditary diffuse gastric cancer), NF1 (neurofibromatosis type 1), PTEN (Cowden syndrome), STK11 (Peutz-Jeghers syndrome), and TP53 (Li-Fraumeni syndrome).[17]

Hormonal factors

Prospective trials have demonstrated the correlation between increased levels of endogenous sex hormones and a significant elevation in the risk of breast cancer.[18][19]

Women exposed to exogenous estrogen and progestin (e.g., via hormone replacement therapy or hormonal contraception) have an increased risk of breast cancer.[20][21][22]

Pathophysiology

Malignant cells of the breast result from a cascade of genetic events involving the uncontrolled expression of endogenous growth factors and signaling pathways.[23] Among those implicated are the steroid hormone family, especially estrogens, the ErbB family, myc family, PI3K/AKT signaling pathway, NFkappaB, PDGFR, Src, and IGF. The diversity of pathways associated with the pathogenesis of breast cancer has led to innovations in the targeted therapy of this disease. Furthermore, most malignant cells maintain their expression of steroid hormone receptors and subsequent hormonal dependence, enabling the use of hormonal manipulation as a mechanism for treating breast cancer.

Germline mutations that increase the risk of breast and other cancers have been identified. These include mutations in homologous recombination DNA repair genes, such as BRCA1, BRCA2, and PALB2, and in tumor suppressor genes, such as the TP53 gene (associated with Li-Fraumeni syndrome).[24][25][26][27]​​ Recognition of these mutations has led to new targeted drug therapy strategies.

Classification

The World Health Organization (WHO) classification of tumors of the breast (5th edition)

The WHO classifies breast neoplasms into the following categories:[2]

  • Epithelial tumors:

    • Microinvasive carcinoma.

  • Invasive breast carcinoma:

    • Invasive carcinoma of no special type (NST)

    • Invasive lobular carcinoma

    • Tubular carcinoma

    • Cribriform carcinoma

    • Mucinous carcinoma

    • Carcinoma with medullary features

    • Carcinoma with apocrine differentiation

    • Carcinoma with signet ring differentiation

    • Invasive micropapillary carcinoma

    • Metaplastic carcinoma of NST

    • Rare types.

  • Epithelial-myoepithelial tumors:

    • Pleomorphic adenoma

    • Adenomyoepithelioma

    • Adenoid cystic carcinoma.

  • Precursor lesions:

    • Ductal carcinoma in situ

    • Lobular neoplasia

    • Atypical lobular hyperplasia.

  • Intraductal proliferative lesions:

    • Usual ductal hyperplasia

    • Columnar cell lesions (including flat epithelial atypia)

    • Atypical ductal hyperplasia.

  • Papillary lesions:

    • Intraductal papilloma

    • Intraductal papillary carcinoma

    • Encapsulated papillary carcinoma

    • Solid papillary carcinoma.

  • Benign epithelial proliferations:

    • Sclerosing adenosis

    • Apocrine adenosis

    • Microglandular adenosis

    • Radial scar/complex sclerosing lesion

    • Adenomas.

  • Mesenchymal tumors:

    • Nodular fasciitis

    • Myofibroblastoma

    • Desmoid-type fibromatosis

    • Inflammatory myofibroblastic tumor

    • Benign vascular lesions

    • Pseudoangiomatous stromal hyperplasia

    • Granular cell tumor

    • Benign peripheral nerve sheath tumors

    • Lipoma

    • Liposarcoma

    • Angiosarcoma

    • Rhabdomyosarcoma

    • Osteosarcoma

    • Leiomyoma

    • Leiomyosarcoma.

  • Fibroepithelial tumor:

    • Fibroadenoma

    • Phyllodes tumor

    • Hamartoma.

  • Tumors of the nipple:

    • Nipple adenoma

    • Syringomatous tumor

    • Paget disease of the nipple.

  • Malignant lymphoma:

    • Diffuse large B-cell lymphoma

    • Burkitt lymphoma

    • T-cell lymphoma

    • Extranodal marginal-zone B-cell lymphoma of MALT type

    • Follicular lymphoma.

  • Metastatic tumors

  • Tumors of the male breast:

    • Gynecomastia

    • Carcinoma.

  • Clinical patterns:

    • Inflammatory carcinoma

    • Bilateral breast carcinoma.

Molecular subtypes

Breast cancer can be classified into subtypes based on gene expression profiling.

Subtype guides therapy and informs prognosis. Subtypes are: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)+, normal-breast-like, and basal type.

BRCA1 mutations are associated with basal type tumors. Basal type and HER2+ tumors are associated with a shorter disease-free survival; luminal A tumors are associated with a longer disease-free survival.[3]

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