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breast cancer

Tuesday 30 September 2003

breast carcinomas, mammary carcinoma, breast cancers, mammary carcinomas

Definition: Mammary malignant tumors. See also : mammary carcinomas

Breast cancer, rather than constituting a monolithic entity, comprises heterogeneous tumors with different clinical characteristics, disease courses, and responses to specific treatments.

Tumor-intrinsic features, including classical histological and immunopathological classifications as well as more recently described molecular subtypes, separate breast tumors into multiple groups.

Tumor-extrinsic features, including microenvironmental configuration, also have prognostic significance and further expand the list of tumor-defining variables.

A better understanding of the features underlying heterogeneity, as well as of the mechanisms and consequences of their interactions, is essential to improve targeting of existing therapies and to develop novel agents addressing specific combinations of features.

To understand how such variation arises, it is instructive to examine the normal architecture of the breast environment.

Each lobe arises from multiple lobules, which connect to a common terminal interlobular duct.

These ducts then continue to their outlet at the nipple. Histologically, lobules and ducts are lined by a single layer of luminal epithelial cells, surrounded by transversely oriented myoepithelial cells.

These structures are separated from the surrounding tissue, or stroma, by a basement membrane, the breach of which distinguishes invasive carcinoma from carcinoma in situ.

The surrounding stroma comprises ECM, discrete cells (e.g., fibroblasts, immune cells, and adipocytes), and organized structures (e.g., blood vessels), each of which contributes to the overall configuration of the local microenvironment.

Classical pathology has segregated breast tumors into multiple categories, based on their overall morphology and structural organization.

The most common type observed and reported is invasive ductal carcinoma, not otherwise specified (IDC NOS; about 75% of cases), while invasive lobular carcinoma (ILC) represents the next most frequent histologic type of breast tumor (about 10% of cases).

Together, these two categories and combinations thereof make up the vast majority (about 90%) of breast cancers, while the remainder are categorized as medullary, neuroendocrine, tubular, apocrine, metaplastic, mucinous (A and B), inflammatory, comedo, adenoid cystic, and micropapillary types.

Interestingly, histologic type is linked to prognosis. While IDC NOS, ILC, apocrine, and medullary carcinomas have similar 10-year survival rates, adenoid cystic, medullary, mucinous, and tubular carcinomas exhibit relatively better overall outcomes.

However, the rarity of specific non-ILC/non-IDC tumors (known as “special types”) has resulted in a relative paucity of in-depth characterization of larger cohorts of such cases, and thus the details of how membership in these groups interacts with other factors contributing to tumor heterogeneity are not well understood.

Immunohistochemical classification

The presence of specific markers in breast cancer has long been recognized to both define subtypes with differential overall prognosis and to identify tumors susceptible to targeted treatments.

The chief markers assessed are estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (HER2).

Expression of the first two is assayed almost exclusively by immunohistochemistry (IHC)-based methods, which report levels of the corresponding proteins, while HER2 assays combine IHC and FISH approaches.

Ambiguous IHC-derived HER2 results are subjected to FISH testing for genomic amplification of HER2; cases in which the overall ratio of copies of the HER2 gene to those of its chromosome is greater than 2.2 are reported as HER2+.

ER status is utilized to identify tumors that may respond to anti-estrogen (endocrine) therapy, including ER antagonists or aromatase inhibitors, which target ER-dependent signaling.

PR status, generally correlated with ER status, has less clinical significance. PR status does not appear to predict relative benefit from specific types of endocrine therapy, and overall, ER+/PR+ cases may not receive additional benefit from endocrine therapy compared with ER+/PR– cases.

HER2+ cases are treated with targeted therapies such as the monoclonal antibody trastuzumab, which binds to HER2, mediates antibody-dependent cytotoxicity, and disrupts HER2-dependent signaling.

There is currently no standard targeted therapy for cases assessed as ER– and HER– by IHC, although this represents an intensive area of research.

Combinations of these markers allow for the assignment of individual cases to specific categories, namely:
- ER+ (ER+/HER2–)
- HER2+ (ER–/HER2+)
- triple negative (TN; ER–/PR–/HER2–)
- triple positive (ER+/PR+/HER2+).

From a prognostic viewpoint, ER+ tumors exhibit the best overall outcome.

Following the advent of HER2-targeted therapies, HER2+ tumors, previously associated with poor outcome, now exhibit an improved overall outcome when treated with such therapies.

TN tumors, on the other hand, are linked to the worst prognosis among the subtypes, while triple-positive cases appeared to have a prognosis intermediate between those of ER+ and HER2+ cases prior to the introduction of HER2-targeted treatments.


- mammary adenoid cystic carcinoma
- mammary adenosquamous carcinoma, low grade
- mammary apocrine carcinoma
- mammary cribriform carcinoma
- mammary infiltrating ductal carcinoma
- mammary glycogen rich clear cell carcinoma
- mammary histiocytoid carcinoma
- mammary infiltrating lobular carcinoma
- mammary inflammatory carcinoma
- mammary lipid rich carcinoma
- mammary low grade adenosquamous carcinoma
- mammary medullary carcinoma
- mammary metaplastic carcinoma
- mammary invasive micropapillary carcinoma
- mammary mucinous carcinoma
- mammary neuroendocrine carcinoma, low grade
- mammary neuroendocrine carcinoma, NOS
- mammary neuroendocrine carcinoma, high grade
- mammary oncocytic carcinoma
- mammary carcinoma with osteoclast-like giant cells
- mammary Paget disease
- mammary secretory sarcinoma (secretory breast carcinoma)
- mammary signet ring carcinoma (variant of lobular)
- mammary small cell carcinoma
- mammary tubular carcinoma
- mammary tubulolobular carcinoma

Breast cancer susceptibility

See : breast cancer susceptibility

- MAP3K1
- LSP1
- 10q23.32-q25.3 locus (17171685)

Molecular biology

- allelotypes
- expression profiling
- proteomics: 11721633

Gene expression profiling

Gene expression profiling with breast carcinomas has allowed further classification of these tumors into 5 distinct subtypes with unique clinical outcomes:
- luminal A
- luminal B
- HER2-overexpression
- basal-like
- normal-like.

Immunohistochemical classification

Subsequent studies have shown that breast carcinomas can also be divided into 5 similar subgroups using immunohistochemical (IHC) analysis with a limited panel of molecular markers (including estrogen receptor, progesterone receptor, HER2, CK5/6, and epidermal growth factor receptor).

These subgroups have distinguishing features closely associated with subtypes defined by gene expression profiling, including distinct clinical outcomes.

Comparative genomic hybridization (16457699)

CGH revealed approximately 20 regions of recurrent increased DNA sequence copy number in breast tumors. These regions are predicted to encode dominantly acting genes that may play a role in tumor progression or response to therapy.

Amplified regions

- 1q32.1 amplification (66%) (16457699)
- 8p12 amplification
- 8q24.3 amplification (79%): MYC (MIM.190080) (16457699)
- 11q13 amplification: CCND1 (MIM.168461) and EMS1 (MIM.164765)
- 12q13 amplification
- 16p13.3 amplification (57%)
- 17q12 amplification: ERBB2 (MIM.164870)
- 20q13 amplification (18%)

In breast cancer, ERBB2, CCND1 and EMS1 amplification and overexpression are associated with decreased life expectancy, whereas MYC amplification has been associated with lymph node involvement, advanced stage, and an increased rate of relapse.

20q13 gains in greater than 25% of cancers of the ovary, colon, head and neck, brain, and pancreas.

Amplified genes

- HER2 amplification
- MDM2 amplification
- CCND1 amplification
- ESR1 amplification


- 1p
- 4p
- 5q
- 8p12-p23
- 11q
- 13q > RB1 (26%) (16457699)
- 14q
- 16q
- 17p
- 17q


- hypermethylation and hypomethylation of CpG islands (16575877)




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- Bergamaschi A, Kim YH, Wang P, Sorlie T, Hernandez-Boussard T, Lonning PE, Tibshirani R, Borresen-Dale AL, Pollack JR. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer. 2006 Nov;45(11):1033-40. PMID: 16897746

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