Breast cancer classification divides

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

into categories according to different schemes criteria and serving a different purpose. The major categories are the

histopathological Histopathology (compound of three Greek language, Greek words: 'tissue', 'suffering', and ''-logy, -logia'' 'study of') is the light microscope, microscopic examination of Tissue (biology), tissue in order to study the manifestations of dis ...

type, the

grade Grade most commonly refers to: * Grading in education, a measurement of a student's performance by educational assessment (e.g. A, pass, etc.) * A designation for students, classes and curricula indicating the number of the year a student has reach ...

of the tumor, the

stage Stage, stages, or staging may refer to: Arts and media Acting * Stage (theatre), a space for the performance of theatrical productions * Theatre, a branch of the performing arts, often referred to as "the stage" * ''The Stage'', a weekly Brit ...

of the tumor, and the expression of

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s and

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

s. As knowledge of cancer cell biology develops these classifications are updated. The purpose of classification is to select the best treatment. The effectiveness of a specific treatment is demonstrated for a specific breast cancer (usually by randomized, controlled trials). That treatment may not be effective in a different breast cancer. Some breast cancers are aggressive and life-threatening, and must be treated with aggressive treatments that have major adverse effects. Other breast cancers are less aggressive and can be treated with less aggressive treatments, such as lumpectomy. Treatment

algorithm In mathematics and computer science, an algorithm () is a finite sequence of Rigour#Mathematics, mathematically rigorous instructions, typically used to solve a class of specific Computational problem, problems or to perform a computation. Algo ...

s rely on breast cancer classification to define specific subgroups that are each treated according to the best evidence available. Classification aspects must be carefully tested and validated, such that confounding effects are minimized, making them either true

prognostic Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) o ...

factors, which estimate disease outcomes such as disease-free or overall survival in the absence of therapy, or true predictive factors, which estimate the likelihood of response or lack of response to a specific treatment. Classification of breast cancer is usually, but not always, primarily based on the

histological Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...

appearance of tissue in the tumor. A variant from this approach, defined on the basis of

physical exam In a physical examination, medical examination, clinical examination, or medical checkup, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally consists of a series of questions ...

findings, is that

inflammatory breast cancer Inflammatory breast cancer (IBC) is one of the most aggressive types of breast cancer. It can occur in women of any age (and, extremely rarely, in men, see male breast cancer). It is referred to as "inflammatory" due to its frequent presentation w ...

(IBC), a form of ductal carcinoma or malignant cancer in the ducts, is distinguished from other

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoder ...

s by the

inflamed Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', ''d ...

appearance of the affected breast, which correlates with increased cancer aggressivity.

Schemes or aspects

Overview

Breast cancers can be classified by different schemata. Each of these aspects influences treatment response and prognosis. Description of a breast cancer would optimally include all of these classification aspects, as well as other findings, such as signs found on

. A full classification includes histopathological type,

(TNM), receptor status, and the presence or absence of genes as determined by

DNA testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

: * Histopathology. Although breast cancer has many different histologies, the considerable majority of breast cancers are derived from the epithelium lining the ducts or lobules, and are classified as

mammary ductal carcinoma Invasive carcinoma of no special type (invasive carcinoma NST), invasive breast carcinoma of no special type (IBC-NST), invasive ductal carcinoma (IDC), infiltrating ductal carcinoma (IDC) or invasive ductal carcinoma, not otherwise specified (NOS ...

. ''

Carcinoma in situ Carcinoma ''in situ'' (CIS) is a group of abnormal cells. While they are a form of neoplasm, there is disagreement over whether CIS should be classified as cancer. This controversy also depends on the exact CIS in question (e.g., cervical, skin, b ...

'' is proliferation of cancer cells within the epithelial tissue without invasion of the surrounding tissue. In contrast, ''invasive carcinoma'' invades the surrounding tissue. Perineural and/or lymphovascular space invasion is usually considered as part of the histological description of a breast cancer, and when present may be associated with more aggressive disease. * Grade. Grading focuses on the appearance of the breast cancer cells compared to the appearance of normal breast tissue. Normal cells in an organ like the breast become differentiated, meaning that they take on specific shapes and forms that reflect their function as part of that organ. Cancerous cells lose that differentiation. In cancer, the cells that would normally line up in an orderly way to make up the milk ducts become disorganized. Cell division becomes uncontrolled. Cell nuclei become less uniform. Pathologists describe cells as well differentiated (low-grade), moderately differentiated (intermediate-grade), and poorly differentiated (high-grade) as the cells progressively lose the features seen in normal breast cells. Poorly differentiated cancers have a worse prognosis. * Stage. The TNM classification for staging

is based on the size of the cancer where it originally started in the body and the locations to which it has travelled. These cancer characteristics are described as the size of the tumor (T), whether or not the tumor has spread to the

lymph nodes A lymph node, or lymph gland, is a kidney-shaped Organ (anatomy), organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphoc ...

(N) in the armpits, neck, and inside the chest, and whether the tumor has metastasized (M) (i.e. spread to a more distant part of the body). Larger size, nodal spread, and metastasis have a larger stage number and a worse prognosis. The main stages are: ** Stage 0 which is in situ disease or Paget's disease of the nipple. Stage 0 is a pre-cancerous or marker condition, either

ductal carcinoma in situ Ductal carcinoma ''in situ'' (DCIS), also known as intraductal carcinoma, is a pre-cancerous or non-invasive cancerous lesion of the breast. DCIS is classified as Breast cancer classification#Stage, Stage 0. It rarely produces symptoms or a ...

(DCIS) or lobular carcinoma in situ (LCIS). ** Stages 1–3 are within the breast or regional lymph nodes. ** Stage 4 is a

metastatic cancer Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

Metastatic breast cancer Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary l ...

has a less favorable prognosis. * Receptor status. Cells have

receptors Receptor may refer to: *Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...

on their surface and in their

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

and

nucleus Nucleus (: nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucleu ...

. Chemical messengers such as

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

s bind to receptors, and this causes changes in the cell. Breast cancer cells may or may not have many different types of receptors, the three most important in the present classification being:

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

(ER),

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...

(PR), and

HER2/neu Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The ...

. Cells with or without these receptors are called ER positive (ER+), ER negative (ER-), PR positive (PR+), PR negative (PR-), HER2 positive (HER2+), and HER2 negative (HER2-). Cells with none of these receptors are called basal-like or triple negative. HER2-low has some HER2 proteins on the cell surface, but not enough to be classified as HER2-positive. Trastuzumab deruxtecan is the first approved therapy by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) targeted to people with the HER2-low breast cancer subtype. * DNA-based classification. Understanding the specific details of a particular breast cancer may include looking at the cancer cell

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

by several different laboratory approaches. When specific DNA mutations or gene expression profiles are identified in the cancer cells this may guide the selection of treatments, either by targeting these changes, or by predicting from these alterations which non-targeted therapies are most effective. * Other classification approaches. ** Computer models such as Adjuvant can combine the various classification aspects according to validated

s and present visually appealing graphics that assist in treatment decisions. ** The USC/Van Nuys prognostic index (VNPI) classifies

(DCIS) into dissimilar risk categories that may be treated accordingly. ** The choice of which treatment to receive can be substantially influenced by

comorbidity In medicine, comorbidity refers to the simultaneous presence of two or more medical conditions in a patient; often co-occurring (that is, concomitant or concurrent) with a primary condition. It originates from the Latin term (meaning "sicknes ...

assessments. ** Familial breast cancers may potentially undergo dissimilar treatment (such as

mastectomy Mastectomy is the medical term for the surgical removal of one or both breasts, partially or completely. A mastectomy is usually carried out to treat breast cancer. In some cases, women believed to be at high risk of breast cancer choose to have ...

Histopathology

Pie chart of incidence and prognosis of histopathologic breast cancer types

Histopathologic classification is based upon characteristics seen upon

light microscopy Microscopy is the technical field of using microscopes to view subjects too small to be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of microscopy: optical, el ...

of biopsy specimens. They can broadly be classified into: * Carcinoma ''

in situ is a Latin phrase meaning 'in place' or 'on site', derived from ' ('in') and ' ( ablative of ''situs'', ). The term typically refers to the examination or occurrence of a process within its original context, without relocation. The term is use ...

''. This group constitutes about 15-30% of breast biopsies, more so in countries with high coverage of

breast screening Mammography (also called mastography; DICOM modality: MG) is the process of using low-energy X-rays (usually around 30 kVp) to examine the human breast for diagnosis and screening. The goal of mammography is the early detection of breast cancer ...

programs.Page 1084
in: These have favorable prognosis, with

5-year survival The five-year survival rate is a type of survival rate for estimating the prognosis of a particular disease, normally calculated from the point of diagnosis. Lead time bias from earlier diagnosis can affect interpretation of the five-year surviva ...

rates of 97-99%. * Invasive carcinoma. This group constitutes the other 70-85%. The most common type in this group is

invasive ductal carcinoma Invasive carcinoma of no special type (invasive carcinoma NST), invasive breast carcinoma of no special type (IBC-NST), invasive ductal carcinoma (IDC), infiltrating ductal carcinoma (IDC) or invasive ductal carcinoma, not otherwise specified (NOS ...

, representing about 80% of invasive carcinomas. In the US, 55% of breast cancers are invasive ductal carcinoma.Percentage values are from United States statistics 2004. Subtype specific incidences are taken fro
Table 6
(invasive) an

(in situ) from . These are divided by total breast cancer incidence (211,300 invasive and 55,700 in situ cases) as reported from Breast Cancer Facts & Figures 2003–2004

Invasive lobular carcinoma Invasive lobular carcinoma (ILC) is breast cancer arising from the lobules of the mammary glands. It accounts for 5–10% of invasive breast cancer. Rare cases of this carcinoma have been diagnosed in men (see male breast cancer). Types The his ...

represent about 10% of invasive carcinomas, and 5% of all breast cancers in the US. The overall

rate for both invasive ductal carcinoma and invasive lobular carcinoma was approximately 85% in 2003. Ductal carcinoma in situ, on the other hand, is in itself harmless, although if untreated approximately 60% of these low-grade DCIS lesions will become invasive over the course of 40 years in follow-up.

WHO classification

The 2012

World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...

(WHO) classification of tumors of the breast which includes benign (generally harmless) tumors and malignant (cancerous) tumors, recommends the following pathological types: Invasive breast carcinomas * Invasive carcinoma ** Most are "not otherwise specified" ** The remainder are given subtypes: *** *** Pleomorphic carcinoma *** Carcinoma with

osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...

giant cells *** Carcinoma with

choriocarcinoma Choriocarcinoma is a trophoblastic cancer usually located on the placenta. It is characterized by early hematogenous spread to the lungs. It belongs to the malignant end of the spectrum in gestational trophoblastic disease (GTD). It is also cla ...

features *** Carcinoma with melanotic features *

Classic Solid Mixed Alveolar Tubulolobular Pleomorphic * Tubular carcinoma *

Invasive cribriform carcinoma of the breast Invasive cribriform carcinoma of the breast (ICCB), also termed invasive cribriform carcinoma, is a rare type of breast cancer that accounts for 0.3% to 0.6% of all carcinomas (i.e. cancers that develop from epithelial cells) in the breast. It o ...

(also termed invasive cribriform carcinoma) * Medullary carcinoma of the breast * Mucinous carcinoma and other tumours with abundant

mucin Mucins () are a family of high molecular weight, heavily glycosylated proteins ( glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in ...

Mucinous carcinoma of the breast Mucinous carcinoma of the breast is a form of mucinous carcinoma and a breast cancer type. It is a rare form of breast cancer that accounts for 2% of breast carcinomas and most commonly occurs in postmenopausal women over 70 years old. Rare case ...

Cystadenocarcinoma Cystadenocarcinoma is a malignant tumor that arises from glandular epithelial cells and forms cystic structures. It is most commonly found in the ovaries and pancreas, but it can also develop in other organs. The exact cause of cystadenocarcinoma is ...

and

columnar Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of many ...

cell mucinous carcinoma ** Signet ring cell carcinoma *

Neuroendocrine Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...

tumours ** Solid

neuroendocrine Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...

carcinoma (

carcinoid A carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) ...

of the breast) ** Atypical

tumor ** Small cell / oat cell carcinoma ** Large cell

neuroendocrine carcinoma Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lu ...

* Invasive papillary carcinoma * Invasive micropapillary carcinoma *

Pure apocrine carcinoma of the breast Pure apocrine carcinoma of the breast (PACB) is a rare carcinoma derived from the epithelium, epithelial cells in the lactiferous ducts of the mammary gland. The mammary gland is an apocrine gland. Its lactiferous ducts have two layers of epitheli ...

* Apocrine-like invasive carcinoma * Metaplastic carcinomas ** Pure

epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

metaplastic carcinomas ***

Squamous cell carcinoma Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...

***

Adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ; AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...

with spindle cell

metaplasia Metaplasia () is the transformation of a cell type to another cell type. The change from one type of cell to another may be part of a normal maturation process, or caused by some sort of abnormal stimulus. In simplistic terms, it is as if the ...

*** Adenosquamous carcinoma ***

Mucoepidermoid carcinoma Mucoepidermoid carcinoma (MEC) is the most common type of minor salivary gland malignancy in adults. Mucoepidermoid carcinoma can also be found in other organs, such as bronchi, lacrimal sac, and thyroid gland. Mucicarmine staining is one stain us ...

** Mixed

mesenchymal Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood, or bone. The interactions between mesenchyme and epithelium help to form nearly ever ...

metaplastic carcinomas (Other well-accepted subtypes of metaplastic mammary carcinoma thought to have clinical significance but not included in the decade old WHO classification: ** Matrix-producing carcinoma ** Spindle cell carcinoma ** Carcinosarcoma ** Squamous cell carcinoma of mammary origin ** Metaplastic carcinoma with osteoclastic giant cells) *

Lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

-rich carcinoma * Secretory carcinoma *

Oncocytic carcinoma An oncocytoma is a tumor made up of oncocytes, epithelial cells characterized by an excessive amount of mitochondria, resulting in an abundant acidophilic, granular cytoplasm. The cells and the tumor that they compose are often benign but someti ...

Adenoid cystic carcinoma Adenoid cystic carcinoma is a rare type of cancer that can exist in many different body sites. This tumor most often occurs in the salivary glands, but it can also be found in many anatomic sites, including the breast, lacrimal gland, human lung, ...

Acinic cell carcinoma Acinic cell carcinoma is a malignant epithelial neoplasm that shows differentiation toward serous acinar cells of salivary gland origin. First described by Godwin et al. in 1954, it represents approximately 6-15% of all salivary gland malignancies ...

Glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body. Glycogen functions as one of three regularly used forms ...

-rich clear cell carcinoma *

Sebaceous carcinoma Sebaceous carcinoma, also known as sebaceous gland carcinoma (SGc), sebaceous cell carcinoma, and meibomian gland carcinoma, is an uncommon malignant cutaneous (skin) tumor. Most are typically about 1.4 cm at presentation. SGc originates fro ...

* Inflammatory carcinoma * Bilateral breast carcinoma Mesenchymal tumors (including

sarcoma A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues. Sarcom ...

) *

Hemangioma A hemangioma or haemangioma is a usually benign vascular tumor derived from blood vessel cell types. The most common form, seen in infants, is an infantile hemangioma, known colloquially as a "strawberry mark", most commonly presenting on the sk ...

* Angiomatosis *

Hemangiopericytoma A hemangiopericytoma is a type of soft-tissue sarcoma that originates in the pericytes in the walls of capillaries. When inside the nervous system, although not strictly a meningioma tumor, it is a meningeal tumor with a special aggressive behav ...

* Pseudoangiomatous stromal hyperplasia * Myofibroblastoma *

Fibromatosis The term fibromatosis refers to a group of soft tissue tumors which have certain characteristics in common, including absence of cytologic and clinical malignant features, a histology consistent with proliferation of well-differentiated fibroblast ...

(aggressive) *

Inflammatory myofibroblastic tumor Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm of the mesodermal cells that form the connective tissues which support virtually all of the organs and tissues of the body. IMT was formerly termed inflammatory pseudotumor. Currently, h ...

Lipoma A lipoma is a benign tumor made of adipose tissue, fat tissue. They are generally soft to the touch, movable, and painless. They usually occur just under the skin, but occasionally may be deeper. Most are less than in size. Common locations inc ...

** Angiolipoma * Granular cell tumour *

Neurofibroma A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors (solitary neurofibroma, solitary nerve sheath tumor or sporadic neurofibroma), while the remainder are found in ...

Schwannoma A schwannoma (or neurilemmoma) is a usually benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves. Schwannomas are homogeneous tumors, consisting only of Schwann cells ...

Angiosarcoma Angiosarcoma is a rare and aggressive cancer that starts in the endothelial cells that line the walls of blood vessels or lymphatic vessels. Since they are made from Endothelium, vascular lining, they can appear anywhere and at any age, but older ...

Liposarcoma Liposarcomas are the most common subtype of soft tissue sarcomas, accounting for at least 20% of all sarcomas in adults. Soft tissue sarcomas are rare neoplasms with over 150 different histological subtypes or forms. Liposarcomas arise from the ...

Rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the neoplasm, tumor are identified as rhabdomyoblasts. The four ...

Osteosarcoma An osteosarcoma (OS) or osteogenic sarcoma (OGS) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchyme, mesenchymal origin (and thus a sarcoma) and that exhi ...

Leiomyoma A leiomyoma, also known as a fibroid, is a benign smooth muscle tumor that very rarely becomes cancer (0.1%). They can occur in any organ, but the most common forms occur in the uterus, small bowel, and the esophagus. Polycythemia may occur due ...

Leiomyosarcoma A leiomyosarcoma (LMS) is a rare malignant (cancerous) smooth muscle tumor. The word is . The stomach, bladder, uterus, blood vessels, and Gastrointestinal tract, intestines are examples of hollow organs made up of smooth muscles where LMS can be ...

Tumors of the male breast *

Gynecomastia Gynecomastia (also spelled gynaecomastia) is the non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (10 Novemb ...

(benign) *

Carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoder ...

(See

Male breast cancer Male breast cancer (MBC) is a cancer in males that originates in their breasts. Males account for less than 1% of new breast cancers with about 20,000 new cases being diagnosed worldwide every year. Its incidence rates in males vs. females are, ...

section on types of breast cancer) **

In situ is a Latin phrase meaning 'in place' or 'on site', derived from ' ('in') and ' ( ablative of ''situs'', ). The term typically refers to the examination or occurrence of a process within its original context, without relocation. The term is use ...

** Invasive Malignant lymphoma *

Non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...

Metastatic tumors to the breast from other places in the body Precursor lesions * Lobular neoplasia **

lobular carcinoma in situ Lobular carcinoma in situ (LCIS) is an incidental microscopic finding with characteristic cellular morphology and multifocal tissue patterns. The condition is a laboratory diagnosis and refers to unusual cells in the lobules of the breast. The lo ...

* Intraductal proliferative lesions ** Usual ductal

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of Tissue (biology), organic tissue that results from ...

** Flat epithelial hyperplasia **

Atypical ductal hyperplasia Atypical ductal hyperplasia (ADH) is the term used for a benign lesion of the breast that indicates an increased risk of breast cancer. The name of the entity is descriptive of the lesion; ADH is characterized by cellular proliferation (hyperplas ...

Ductal carcinoma in situ Ductal carcinoma ''in situ'' (DCIS), also known as intraductal carcinoma, is a pre-cancerous or non-invasive cancerous lesion of the breast. DCIS is classified as Breast cancer classification#Stage, Stage 0. It rarely produces symptoms or a ...

** Apocrine ductal carcinoma in situ * Microinvasive carcinoma * Intraductal papillary neoplasms ** Central

papilloma A papilloma (plural papillomas or papillomata) ('' papillo-'' + '' -oma'') is a benign epithelial tumor growing exophytically (outwardly projecting) in nipple-like and often finger-like fronds. In this context, papilla refers to the projection cr ...

** Peripheral papilloma ** Atypical papilloma ** Intraductal papillary carcinoma ** Intracystic papillary carcinoma Benign epithelial lesions * Adenosis, including variants ** Sclerosing adenosis **

Apocrine Apocrine () is a term used to classify the mode of secretion of exocrine glands. In apocrine secretion, secretory cells accumulate material at their apical ends, often forming blebs or "snouts", and this material then buds off from the cells ...

adenosis ** Blunt duct adenosis ** Microglandular adenosis ** Adenomyoepithelial adenosis * Radial scar / complex sclerosing lesion *

Adenoma An adenoma is a benign tumor of epithelium, epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organ (anatomy), organs, including the adrenal glands, pituitary gland, thyroid, prosta ...

s **

Tubular adenoma The colorectal adenoma is a benign adenoma, glandular tumor of the colon and the rectum. It is a precursor lesion of the colorectal adenocarcinoma (colon cancer). They often manifest as colorectal polyps. Comparison table Tubular adenoma In con ...

Lactating Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...

adenoma **

Pleomorphic adenoma Pleomorphic adenoma (or benign mixed tumor) is a common benign salivary gland neoplasm characterised by neoplastic proliferation of epithelial (ductal) cells along with myoepithelial components, having a malignant potentiality. It is the most comm ...

** Ductal adenoma Myoepithelial lesions * Myoepitheliosis * Adenomyoepithelial adenosis * Adenomyoepithelioma * Malignant myoepithelioma Fibroepithelial tumours *

Fibroadenoma Fibroadenomas are benign breast tumours characterized by an admixture of stromal and epithelial tissue. Breasts are made of lobules (milk producing glands) and ducts (tubes that carry the milk to the nipple). These are surrounded by glandular, ...

* Phyllodes tumour **

Benign Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...

** Borderline **

Malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...

* Periductal stromal

, low-grade * Mammary

hamartoma A hamartoma is a mostly benign, local malformation of cells that resembles a neoplasm of local tissue but is usually due to an overgrowth of multiple aberrant cells, with a basis in a systemic genetic condition, rather than a growth descended fr ...

Benign tumors of the nipple * Nipple adenoma *

Syringoma Syringomas are benign tumor, benign eccrine sweat gland, eccrine sweat duct tumors, typically found clustered on eyelids, although they may also be found in the armpits, abdomen, chest, neck, scalp, or groin area, including genitals, in a symmetri ...

tous adenoma * Paget's disease of the nipple Malignant tumors of the nipple * Paget's disease of the nipple

Grade

The grading of a cancer in the breast depends on the microscopic similarity of breast cancer cells to normal breast tissue, and classifies the cancer as well differentiated (low-grade), moderately differentiated (intermediate-grade), and poorly differentiated (high-grade), reflecting progressively less normal appearing cells that have a worsening prognosis. Although grading is fundamentally based on how biopsied, cultured cells behave, in practice the grading of a given cancer is derived by assessing the cellular appearance of the tumor. The closer the appearance of the cancer cells to normal cells, the slower their growth and the better the prognosis. If cells are not well differentiated, they will appear immature, will divide more rapidly, and will tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale used). The Nottingham system is recommended for breast cancer grading. The Nottingham system is also called the Bloom–Richardson–Elston system (BRE), or the Elston-Ellis modification of the Scarff-Bloom-Richardson grading system. It grades breast carcinomas by adding up scores for tubule formation, nuclear pleomorphism, and mitotic count, each of which is given 1 to 3 points. The scores for each of these three criteria are then added together to give an overall final score and corresponding grade. It is not applicable to medullary carcinomas which are histologically high-grade by definition, while being clinically low-grade if lymph nodes are negative. It is also not applicable to metaplastic carcinomas. The grading criteria are as follows:

Tubule formation

This

parameter A parameter (), generally, is any characteristic that can help in defining or classifying a particular system (meaning an event, project, object, situation, etc.). That is, a parameter is an element of a system that is useful, or critical, when ...

assesses what percent of the tumor forms normal duct structures. In cancer, there is a breakdown of the mechanisms that cells use to attach to each other and communicate with each other, to form tissues such as ducts, so the tissue structures become less orderly. Note: The overall appearance of the tumor has to be considered. * 1 point: tubular formation in more than 75% of the tumor (it may in addition be termed "majority of tumor") * 2 points: tubular formation in 10 to 75% of the tumor ("moderate") * 3 points: tubular formation in less than 10% of the tumor ("little or none")

Nuclear pleomorphism

This

assesses whether the

cell nuclei The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoc ...

are uniform like those in normal breast duct epithelial cells, or whether they are larger, darker, or irregular ( pleomorphic). In cancer, the mechanisms that control

s and

chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...

s in the nucleus break down, and irregular nuclei and pleomorphic changes are signs of abnormal cell reproduction. Note: The

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

areas having cells with the greatest cellular abnormalities should be evaluated. * 1 point: nuclei with minimal or mild variation in size and shape * 2 points: nuclei with moderate variation in size and shape * 3 points: nuclei with marked variation in size and shape File:Micrograph of ductal carcinoma with mild nuclear pleomorphism.jpg, Ductal carcinoma with mild nuclear pleomorphism. File:Micrograph of invasive ductal carcinoma of tubular type with moderate nuclear pleomorphism (crop).jpg, Invasive ductal carcinoma with moderate nuclear pleomorphism. File:Histopathology of invasive lobular carcinoma with moderate nuclear pleomorphism.jpg, Invasive lobular carcinoma with moderate nuclear pleomorphism. File:Micrograph of invasive ductal carcinoma with marked nuclear pleomorphism.jpg, Invasive ductal carcinoma with marked nuclear pleomorphism.

Mitotic count

This

assesses how many

mitotic Mitosis () is a part of the cell cycle in eukaryotic cells in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis is an equational division which gives rise to genetically identical cells in which the t ...

figures (dividing cells) the pathologist sees in 10x high power microscope field. One of the hallmarks of cancer is that cells divide uncontrollably. The more cells that are dividing, the worse the cancer. Note: Mitotic figures are counted only at the periphery of the tumor, and counting should begin in the most mitotically active areas.

Overall grade

The scores for each of these three criteria are added together to give a final overall score and a corresponding grade as follows: * 3-5 Grade 1 tumor (well-differentiated). Best

prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...

. * 6-7 Grade 2 tumor (moderately differentiated). Medium prognosis. * 8-9 Grade 3 tumor (poorly differentiated). Worst prognosis. Lower-grade tumors, with a more favorable prognosis, can be treated less aggressively, and have a better survival rate. Higher-grade tumors are treated more aggressively, and their intrinsically worse survival rate may warrant the adverse effects of more aggressive medications.

Stage

StagingWhat is Cancer Staging? American Joint Committee on Cancer 2010 May 5.http://www.cancerstaging.org/mission/whatis.html is the process of determining how much cancer there is in the body and where it is located. The underlying purpose of staging is to describe the extent or severity of an individual's cancer, and to bring together cancers that have similar

and treatment. Staging of breast cancer is one aspect of breast cancer classification that assists in making appropriate treatment choices, when considered along with other classification aspects such as

and

levels in the cancer tissue, the human epidermal growth factor receptor 2 (

) status, menopausal status, and the person's general health.National Cancer Institute. Stage Information for Breast Cancer.http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page3 Staging information that is obtained prior to surgery, for example by mammography, x-rays and CT scans, is called clinical staging and staging by surgery is known as pathological staging. Pathologic staging is more accurate than clinical staging, but clinical staging is the first and sometimes the only staging type. For example, if clinical staging reveals stage IV disease, extensive surgery may not be helpful, and (appropriately) incomplete pathological staging information will be obtained. The

American Joint Committee on Cancer The American Joint Committee on Cancer (AJCC) is an organization best known for defining and popularizing cancer staging standards, officially the AJCC staging system. The American Joint Committee on Cancer (AJCC) was established in 1959 to formul ...

(AJCC) and the International Union Against Cancer (UICC) recommend

TNM staging The TNM Classification of Malignant Tumors (TNM) is a globally recognised standard for classifying the anatomical extent of the spread of malignant tumours (cancer). It has gained wide international acceptance for many solid tumor cancers, but is ...

, which is a two step procedure. Their TNM system, which they now develop jointly, first classifies cancer by several factors, T for tumor, N for nodes, M for metastasis, and then groups these TNM factors into overall stages.

Primary Tumor (T)

Tumor – The

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

values (TX, T0, Tis, T1, T2, T3 or T4) depend on the cancer at the primary site of origin in the breast, as follows:Originally copied from Last Update: 4 June 2019
Creative Commons Attribution 4.0 International License
* TX: inability to assess that site * Tis:

(DCIS),

(LCIS) or Paget's disease * T1: Less than 2 cm :* T1a: 0.1 to 0.5 cm :* T1b: 0.5 to 1.0 cm :* T1c: 1.0 to 2.0 cm * T2: 2 to 5 cm * T3: Larger than 5 cm * T4 :* T4a: Chest wall involvement :* T4b: Skin involvement :* T4c: Both 4a and 4b :* T4d:

Inflammatory breast cancer Inflammatory breast cancer (IBC) is one of the most aggressive types of breast cancer. It can occur in women of any age (and, extremely rarely, in men, see male breast cancer). It is referred to as "inflammatory" due to its frequent presentation w ...

, a clinical circumstance where typical skin changes involve at least a third of the breast.

Regional Lymph Nodes (N)

Lymph Node – The

lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...

values (NX, N0, N1, N2 or N3) depend on the number, size and location of breast cancer cell deposits in various regional lymph nodes, such as the armpit (

axillary lymph nodes The axillary lymph nodes or armpit lymph nodes are lymph nodes in the human armpit. Between 20 and 49 in number, they drain lymph vessels from the lateral quadrants of the breast, the superficial lymph vessels from thin walls of the chest and the ...

), the collar area (

supraclavicular lymph nodes Supraclavicular lymph nodes are lymph nodes found above the clavicle, that can be felt in the supraclavicular fossa. The supraclavicular lymph nodes on the left side are called Virchow's nodes. available as full text article with multiple images at http://radiographics.rsna.org/content/10/5/857.full.pdf The armpit is designated as having three levels: level I is the low axilla, and is below or outside the lower edge of the

pectoralis minor Pectoralis minor muscle () is a thin, triangular muscle, situated at the upper part of the chest, beneath the pectoralis major in the human body. It arises from ribs III-V; it inserts onto the coracoid process of the scapula. It is innervated by ...

muscle; level II is the mid-axilla which is defined by the borders of the pectoralis minor muscle; and level III, or high ( apical) axilla which is above the pectoralis minor muscle. Each stage is as follows: * N0: There is some nuance to the official definitions for N0 disease, which includes: :* N0(i+) : Isolated Tumor Cell clusters (ITC), which are small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section, whether detected by routine histology or

immunohistochemistry Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of Antibody, antibodies binding specifically to antigens in biological tissues. Alber ...

. Updated: 8 June 2019 :* N0(mol-): regional lymph nodes have no metastases histologically, but have positive molecular findings (

RT-PCR Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase chain ...

). * N1: Metastases in 1-3 axillary lymph nodes and/or in internal mammary nodes; and/or in clinically negative internal mammary nodes with

micrometastasis A micrometastasis is a small collection of cancer cells that has been shed from the original tumor and spread to another part of the body through the lymphovascular system. Micrometastases are too few in size and quantity to be picked up in a scr ...

, or macrometastasis on sentinel lymph node biopsy. :* N1mi: Micrometastasis, that is, lymph node clusters at least 2 mm or 200 cells, but less than 2.0 mm. At least one carcinoma focus over 2.0 mm is called "Lymph node metastasis". If one node qualifies as metastasis, all other nodes even with smaller foci are counted as metastases as well. * N2: Fixed/matted ipsilateral axillary nodes. * N3 :* N3a – Ipsilateral infraclavicular nodes :* N3b – Ipsilateral internal mammary nodes :* N3c – Ipsilateral supraclavicular nodes

Distant Metastases (M)

* M0: No clinical or radiographic evidence of distant metastases * M0(i+): Molecularly or microscopically detected tumor cells in circulating blood, bone marrow or non-regional nodal tissue, no larger than 0.2 mm, and without clinical or radiographic evidence or symptoms or signs of metastases, and which, perhaps counter-intuitively, does not change the stage grouping, as staging for in M0(i+) is done according to the T and N values * M1: Distant detectable metastases as determined by classic clinical and radiographic means, and/or metastasis that are histologically larger than 0.2 mm.

Overall stage

A combination of T, N and M, as follows: * Stage 0: Tis * Stage I: T1N0 * Stage II: T2N0, T3N0 T0N1, T1N1, or T2N1 * Stage III: Invasion into skin and/or ribs, matted lymph nodes, T3N1, T0N2, T1N2, T2N2, T3N2, AnyT N3, T4 any N, locally advanced breast cancer * Stage IV: M1, advanced breast cancer

Staging and prognosis

The impact of different stages on outcome can be appreciated in the following table, taken from patient data in the 2013-2015 period, and using the AJCC 8th edition for staging. It does not show the influence of important additional factors such as

(ER) or

receptor status, and does not reflect the impact of newer treatments.

Previous editions

Although TNM classification is an internationally agreed system, it has gradually evolved through its different editions; the dates of publication and of adoption for use of AJCC editions is summarized in the table in this article; past editions are available from AJCC for web download.American Joint Committee on Cancer. Past Editions of the AJCC Cancer Staging Manual available at Several factors are important when reviewing reports for individual breast cancers or when reading the medical literature, and applying staging data. It is crucial to be aware that the TNM system criteria have varied over time, sometimes fairly substantially, according to the different editions that AJCC and UICC have released. Readers are assisted by the provision in the table of direct links to the breast cancer chapters of these various editions. As a result, a given stage may have quite a different prognosis depending on which staging edition is used, independent of any changes in diagnostic methods or treatments, an effect that can contribute to "stage migration". For example, differences in the 1998 and 2003 categories resulted in many cancers being assigned differently, with apparent improvement in survival rates. As a practical matter, reports often use the staging edition that was in place when the study began, rather than the date of acceptance or publication. However, it is worth checking whether the author updated the staging system during the study, or modified the usual classification rules for specific use in the investigation. A different effect on staging arises from evolving technologies that are used to assign patients to particular categories, such that increasingly sensitive methods tend to cause individual cancers to be reassigned to higher stages, making it improper to compare that cancer's prognosis to the historical expectations for that stage. Finally, of course, a further important consideration is the effect of improving treatments over time as well. Previous editions featured three

metastatic Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

values (MX, M0 and M1) which referred respectively to absence of adequate information, the confirmed absence, or the presence of breast cancer cells in locations other than the breast and regional lymph nodes, such as to bone, brain, lung. AJCC has provided web accessible poster versions of the current versions of these copyrighted TNM descriptors and groups,AJCC Cancer Staging Manual, 7th edition, updated Cancer Staging Posters.http://www.cancerstaging.org/staging/posters/breast8.5x11.pdf and readers should refer to that up to date, accurate information or to the

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...

(NCI) or

National Comprehensive Cancer Network The National Comprehensive Cancer Network (NCCN) is an alliance of 33 cancer centers in the United States, most of which are designated by the National Cancer Institute (one of the U.S. National Institutes of Health) as comprehensive cancer cent ...

sites which reprints these with AJCC permission. For accurate, complete, current details refer to the accessible copyrighted documentation from AJCC, or to the authorized documentation from NCI or NCCN; for past editions refer to AJCC.

Receptor status

The

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

status of

s has traditionally been identified by

(IHC), which stains the cells based on the presence of

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

(ER),

s (PR) and

HER2 Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The ...

. This remains the most common method of testing for receptor status, but DNA multi-gene expression profiles can categorize breast cancers into molecular subtypes that generally correspond to IHC receptor status; one commercial source is the BluePrint test, as discussed in the following section. Receptor status is a critical assessment for all breast cancers as it determines the suitability of using targeted treatments such as

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...

and or

trastuzumab Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together ...

. These treatments are now some of the most effective

adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Anal ...

treatments of breast cancer. Estrogen receptor positive (ER+) cancer cells depend on estrogen for their growth, so they can be treated with drugs to reduce either the effect of estrogen (e.g.

) or the actual level of estrogen (e.g.

aromatase inhibitors Aromatase inhibitors (AIs) are a class of medication, drugs used in the treatment of breast cancer in menopause, postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when suppleme ...

), and generally have a better

. Generally, prior to modern treatments, HER+ had a worse prognosis, however HER2+ cancer cells respond to drugs such as the monoclonal antibody,

, (in combination with conventional chemotherapy) and this has improved the prognosis significantly. Conversely, triple negative cancer (i.e. no positive receptors), lacking targeted treatments, now has a comparatively poor

Androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

is expressed in 80-90% of ER+ breast cancers and 40% of "triple negative" breast cancers. Activation of androgen receptors appears to suppress breast cancer growth in ER+ cancer while in ER- breast it appears to act as growth promoter. Efforts are underway to utilize this as prognostic marker and treatment.

Molecular subtype

Receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

status was traditionally considered by reviewing each individual receptor ( ER, PR,

) in turn, but newer approaches look at these together, along with the

, to categorize

into several conceptual molecular classes that have different prognoses and may have different responses to specific therapies.

DNA microarrays A DNA microarray (also commonly known as a DNA chip or biochip) is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to ...

have assisted this approach, as discussed in the following section. Proposed molecular subtypes include: * Basal-like: ER-, PR- and HER2-; also called

triple negative breast cancer Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e ...

(TNBC). Most

BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...

breast cancers are basal-like TNBC. * Luminal A: ER+ and low grade * Luminal B: ER+ but often high grade * Luminal ER-/AR+: (overlapping with apocrine and so called molecular apocrine) - recently identified androgen responsive subtype which may respond to antihormonal treatment with

bicalutamide Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...

* ERBB2/HER2-amplified: has overexpressed

* Normal breast-like *

Claudin Claudins are a family of proteins which, along with occludin, are the most important components of the tight junctions ( zonulae occludentes). Tight junctions establish the paracellular barrier that controls the flow of molecules in the inter ...

-low: a more recently described class; often triple-negative, but distinct in that there is low expression of cell-cell junction proteins including

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), is a protein that in humans is encoded by the ''CDH1'' gene (not to be confused with the APC/C activator protein CDH1). Mutations are correlated with Hereditary diffuse gastric cancer, gastric, Here ...

and frequently there is infiltration with

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...

DNA classification

Traditional DNA classification

Traditional

classification Classification is the activity of assigning objects to some pre-existing classes or categories. This is distinct from the task of establishing the classes themselves (for example through cluster analysis). Examples include diagnostic tests, identif ...

was based on the general observation that cells that are dividing more quickly have a worse

, and relied on either the presence of protein Ki67 or the percentage of cancer cell DNA in

S phase S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S ...

. These methods, and scoring systems that used DNA

ploidy Ploidy () is the number of complete sets of chromosomes in a cell, and hence the number of possible alleles for autosomal and pseudoautosomal genes. Here ''sets of chromosomes'' refers to the number of maternal and paternal chromosome copies, ...

, are used much less often now, as their

predictive A prediction (Latin ''præ-'', "before," and ''dictum'', "something said") or forecast is a statement about a future event or about future data. Predictions are often, but not always, based upon experience or knowledge of forecasters. There i ...

and

power was less substantial than other classification schemes such as the TNM stage. In contrast, modern DNA analyses are increasingly relevant in defining underlying

biology and in helping choose treatments.

HER2/neu

status can be analyzed by fluorescent in-situ hybridization (FISH) assays. Some commentators prefer this approach, claiming a higher correlation than receptor

with response to

, a targeted therapy, but guidelines permit either testing method.

DNA microarrays

Background

have compared normal cells to breast cancer cells and found differences in the expression of hundreds of

s. Although the significance of many of those genetic differences is unknown, independent analyses by different research groups has found that certain groups of genes have a tendency to co-express. These co-expressing

clusters may refer to: Science and technology Astronomy * Cluster (spacecraft), constellation of four European Space Agency spacecraft * Cluster II (spacecraft), a European Space Agency mission to study the magnetosphere * Asteroid cluster, a small ...

have included

receptor-related genes,

-related genes, a group of basal-like genes, and proliferation genes. As might therefore be anticipated, there is considerable similarity between the receptor and microarray classifications, but assignment of individual tumors is by no means identical. By way of illustration, some analyses have suggested that approximately 75% of receptor classified

triple-negative breast cancer Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e ...

s (TNBC) basal-like

s have the expected DNA expression profile, and a similar 75% of tumors with a typical basal-like DNA expression profile are receptor TNBC as well. To say this in a different way to emphasize things, this means that 25% of triple-negative breast cancer (TNBC) basal-like tumors as defined by one or other classification are excluded from the alternative classification's results. Which classification scheme (receptor

IHC IHC may refer to: Medicine * Immunohistochemistry * Intrahepatic cholestasis Science and technology * Cathode#Hot_cathode , Indirectly Heated Cathode, a type of hot cathode used in vacuum electronics tubes * Intelligent Home Control, home autom ...

or DNA expression profile) more reliably assorts particular cancers to effective therapies is under investigation. Several commercially marketed

DNA microarray A DNA microarray (also commonly known as a DNA chip or biochip) is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or t ...

tests analyze

s and may help decide which possible treatment is most effective for a particular

. The use of these assays in

s is supported by Level II evidence or Level III evidence. No tests have been verified by Level I evidence, which is rigorously defined as being derived from a prospective,

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

where patients who used the test had a better outcome than those who did not. Acquiring extensive Level I evidence would be clinically and ethically challenging. However, several validation approaches are being actively pursued. Numerous genetic profiles have been developed. The most heavily marketed are: * Oncotype DX is supported by Level II evidence, and was originally designed for use in

(ER) positive tumors, and has been endorsed by the

American Society of Clinical Oncology The American Society of Clinical Oncology (ASCO) is a professional organization representing physicians of all oncology sub-specialties who care for people with cancer. Founded in 1964 by Fred Ansfield, Harry Bisel, Herman Freckman, Arnoldus G ...

(ASCO) and the NCCN. * MammaPrint is supported only by Level III evidence, can be performed on

(ER) positive and negative tumors, and has

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approval. * Two other tests also only have Level III evidence: Theros and MapQuant Dx.Armen Hareyanon. MapQuant Dx Genomic Grade Test Identifies Breast Cancer Patients. 2 June 2008 http://www.emaxhealth.com/98/22731.html These multigene assays, some partially and some completely commercialized, have been scientifically reviewed to compare them with other standard

breast cancer classification Breast cancer classification divides breast cancer into categories according to different schemes criteria and serving a different purpose. The major categories are the histopathology, histopathological type, the #Grade, grade of the tumor, the #S ...

methods such as

and receptor status. Although these gene-expression profiles look at different individual

s, they seem to classify a given

into similar

risk In simple terms, risk is the possibility of something bad happening. Risk involves uncertainty about the effects/implications of an activity with respect to something that humans value (such as health, well-being, wealth, property or the environ ...

groups and thus provide

concordant Concordance may refer to: * Agreement (linguistics), a form of cross-reference between different parts of a sentence or phrase * Bible concordance, an alphabetical listing of terms in the Bible * Concordant coastline, in geology, where beds, or la ...

predictions of outcome. Although there is considerable evidence that these tests can refine the treatment decisions in a meaningful proportion of breast cancers they are fairly expensive; proposed selection criteria for which particular tumors may benefit by being interrogated by these assays remain

controversial Controversy (, ) is a state of prolonged public dispute or debate, usually concerning a matter of conflicting opinion or point of view. The word was coined from the Latin '' controversia'', as a composite of ''controversus'' – "turned in an opp ...

, particularly with

positive cancers. One review characterized these genetic tests collectively as adding "modest

information for patients with

-positive and triple-negative tumors, but when measures of clinical risk are equivocal (e.g., intermediate expression of ER and intermediate histologic grade), these assays could guide clinical decisions".

Oncotype DX

Oncotype DX assesses 16 cancer-related

s and 5 normal comparator reference genes, and is therefore sometimes known as the 21-gene assay. It was designed for use in

(ER) positive

s. The test is run on

formalin Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...

fixed, paraffin-embedded tissue. Oncotype results are reported as a Recurrence Score (RS), where a higher RS is associated with a worse

, referring to the likelihood of recurrence without treatment. In addition to that

role, a higher RS is also associated with a higher probability of response to

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

, which is termed a positive

factor. These results suggest that not only does Oncotype stratify estrogen-receptor positive breast cancer into different

groups, but also suggest that cancers that have a particularly favorable Oncotype DX microarray result tend to derive minimal benefit from

and so it may be appropriate to choose to avoid side effects from that additional treatment. As an additional example, a

neoadjuvant Neoadjuvant therapy is the administration of therapeutic agents before a main treatment. One example is neoadjuvant hormone therapy prior to radical radiotherapy for adenocarcinoma of the prostate. Neoadjuvant therapy aims to reduce the size o ...

clinical treatment program that included initial chemotherapy followed by surgery and subsequent additional chemotherapy,

radiotherapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a treatment using ionizing radiation, generally provided as part of cancer therapy to either kill or control the growth of malignant cells. It is normally delivered by a linear particle ...

, and

hormonal therapy Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic hor ...

found a strong correlation of the Oncotype

with the likelihood of a complete response (CR) to the presurgical chemotherapy. Since high risk features may already be evident in many high risk cancers, for example hormone-receptor negativity or HER-2 positive disease, the Oncotype test may especially improve the risk assessment that is derived from routine clinical variables in intermediate risk disease. Results from both the US and internationally suggest that Oncotype may assist in treatment decisions. Oncotype DX has been endorsed by the

(ASCO) and the

(NCCN). The NCCN Panel considers the 21-gene assay as an option when evaluating certain

s to assist in estimating likelihood of recurrence and benefit from

, emphasizing that the recurrence score should be used along with other breast cancer

elements when stratifying

. Oncotype fulfilled all California Technology Assessment Forum (CTAF) criteria in October 2006. The U.S.

(FDA) does not mandate approval of this class of tests if they are performed at a single, company-operated laboratoryNCI Cancer Bulletin FDA Update 2007 February 14, Volume 4, Number 7 as Retrieved 17 October 2010 at http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2007/021407/page5 Genomic Health, which developed Oncotype DX, offers the test under these so-called home brew rules and, accordingly, to that extent the Oncotype DX assay is not specifically FDA approved.

MammaPrint and BluePrint

The MammaPrint gene pattern is a commercial-stage 70-

panel marketed by Agendia,The mission of Agendia. Agendia web isite.http://www.agendia.com/pages/mission/86.php that was developed in patients under age 55 years who had

negative

s (N0).Tice JA. The 70-Gene Signature (MammaPrint) as a Guide for the Management of Early Stage Breast Cancer. California Technology Assessment Forum. 2010 June 2nd. Full text accessioned 2010 Dec 19 at http://www.ctaf.org/content/assessments/detail/?id=1178 The commercial test is marketed for use in breast cancer irrespective of

(ER) status. The test is run on formalin fixed, paraffin-embedded tissue. MammaPrint traditionally used rapidly frozen tissue but a room temperature, molecular fixative is available for use within 60 minutes of obtaining fresh tissue samples.Ordering Symphony is a simple process. Agendia web site.http://www.agendia.com/pages/ordering_symphony/38.php A summary of

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s using MammaPrint is included in the MammaPrint main article. The available evidence for Mammaprint was reviewed by California Technology Assessment Forum (CTAF) in June 2010; the written report indicated that MammaPrint had not yet fulfilled all CTAF criteria. MammaPrint has 5

clearances and is the only FDA cleared microarray assay available. To be eligible for the MammaPrint gene expression profile, a breast cancer should have the following characteristics:

1 or 2, tumor size less than 5.0 cm,

positive (ER+) or estrogen receptor negative (ER-). In the US, the tumor should also be

negative (N0), but internationally the test may be performed if the lymph node status is negative or positive with up to 3 nodes.MammaPrint Patient Eligibility Internationally (Outside of the USA) http://www.agendia.com/pages/patient_eligibility_internationally/317.php One method of assessing the molecular subtype of a

is by BluePrint,Introducing BluePrint: A Molecular Subtyping Profile for Breast Cancer. Agendia web site.http://www.agendia.com/pages/blueprint/324.php a commercial-stage 80-gene panel marketed by Agendia, either as a standalone test, or combined with the MammaPrint gene profile.

Other DNA assays and choice of treatment

The choice of established chemotherapy medications, if chemotherapy is needed, may also be affected by DNA assays that predict relative resistance or sensitivity.

Topoisomerase II Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of Adenosine triphosphate, ATP, unlike Type I topoisomerase. In this process, t ...

(TOP2A) expression predicts whether

doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...

is relatively useful. Expression of genes that regulate

tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytosk ...

may help predict the activity of

taxane Taxanes are a class of diterpenes. They were originally identified from plants of the genus ''Taxus'' (yews), and feature a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents. Cabazitaxel was FDA app ...

s. Various molecular pathway targets and DNA results are being incorporated in the design of clinical trials of new medicines. Specific genes such as p53, NME1, BRCA and PIK3CA/Akt may be associated with responsiveness of the cancer cells to innovative research pharmaceuticals.

and

BRCA2 ''BRCA2'' and BRCA2 () are human genes and their protein products, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associate ...

polymorphic variants can increase the risk of breast cancer, and these cancers tend to express a pr ofile of genes, such as p53, in a pattern that has been called "BRCA-ness." Cancers arising from BRCA1 and BRCA2 mutations, as well as other cancers that share a similar "BRCA-ness" profile, including some basal-like receptor triple negative breast cancers, may respond to treatment with

PARP inhibitors PARP inhibitors are a class of drugs that are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP), which plays a role in repairing DNA in damaged cells. Medical uses of these drugs include the treatment of heri ...

such as olaparib. Combining these newer medicines with older agents such as 6-Thioguanine (6TG) may overcome the resistance that can arise in BRCA cancers to PARP inhibitors or platinum-based chemotherapy. Correction published at Correction: 6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance Cancer Res 2010 October 1;70:7734

mTOR The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...

inhibitors such as

everolimus Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours. This compoun ...

may show more effect in PIK3CA/Akt e9 mutants than in e20 mutants or wild types.

DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter (genetics), promoter, DNA methylati ...

patterns can

epigenetically In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...

affect gene expression in breast cancer and may contribute to some of the observed differences between genetic subtypes. Tumors overexpressing the

Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...

co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) may represent a distinct subtype of breast cancer and a potential treatment target. Numerous clinical investigations looked at whether testing for variant genotype polymorphic

alleles An allele is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule. Alleles can differ at a single position through single nucleotide polymorphisms (SNP), but they can also have insertions and deletions ...

of several genes could predict whether or not to prescribe

; this was based on possible differences in the rate of conversion of tamoxifen to the active metabolite, endoxifen. Although some studies had suggested a potential advantage from

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

testing, data from two large clinical trials found no benefit. Testing for the CYP2C19*2 polymorphism gave counterintuitive results. The medical utility of potential

biomarkers In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

of tamoxifen responsiveness such as HOXB13, PAX2, and estrogen receptor (ER) alpha and beta

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

interaction with SRC3 have all yet to be fully defined.

Other classification approaches

Computer models

Computer models consider several traditional factors concurrently to derive individual survival predictions and calculations of potential treatment benefits. The validated

s can present visually appealing graphics that assist in treatment decisions. In addition, other classifications of breast cancers do exist and no uniform system has been consistently adopted worldwide. Adjuvant! is based on US cohorts and presents colored bar charts that display information that may assist in decisions regarding systemic

therapies. Successful validation was seen with Canadian and Dutch cohorts. Adjuvant! seemed less applicable to a British cohort and accordingly PREDICT is being developed in the United Kingdom.

Other immunohistochemical tests

Among the

immunohistochemical Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of antibodies binding specifically to antigens in biological tissues. Albert Hewett ...

tests that may further stratify

BCL2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the apoptosis regulator proteins, Bcl-2 family, Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can eithe ...

has shown promise in preliminary studies.

Van Nuys prognostic index

The USC/Van Nuys prognostic index (VNPI) classifies

(DCIS) into dissimilar risk categories that may be treated accordingly.

Notes

References

{{Authority control Breast neoplasia Breast cancer Cancer staging Medical classification Classification systems