Breast cancer classification
Encyclopedia
Breast cancer classification divides breast cancer
into several categories according to multiple different schemes, each based on different criteria and serving a different purpose. A typical description usually considers each of these aspects in turn: the histolopathological
type, the grade of the tumor, the stage of the tumor, and the expression of protein
s and gene
s. As knowledge of cancer cell biology develops these classifications are updated.
The practical purpose of classification is to describe each individual instance of breast cancer in a way that helps select which treatment approach is anticipated to have the best chance for a good outcome, with increased efficacy
and low toxicity
. Treatment algorithms 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
factors, which estimate disease outcomes such as disease-free or overall survival in the absence of therapy, or true predictive factors, which estimate the liklihood of response or lack of response to a specific treatment.
Classification of breast cancer is usually, but not always, primarily based on the histological appearance of tissue in the tumor. A variant from this approach, defined on the basis of physical exam findings, is that inflammatory breast cancer
(IBC), a form of ductal carcinoma or malignant cancer in the ducts, is distinguished from other carcinoma
s by the inflamed
appearance of the affected breast, which correlates with increased cancer aggressivity.
The main stages are:
of biopsy specimens. The three most common histopathological types collectively represent approximately three-quarters of breast cancers:
The overall 5-year survival 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 of tumors of the breast which includes benign (harmless) tumors and malignant (cancerous) tumors, recommends the following pathological types:
Invasive breast carcinomas
Mesenchymal tumors (including sarcoma
)
Tumors of the male breast
Malignant lymphoma
Metastatic tumors to the breast from other places in the body
Precursor lesions
Benign epithelial lesions
Myoepithelial lesions
Fibroepithelial tumours
Benign tumors of the nipple
Malignant tumors of the nipple
The Nottingham (also called Elston-Ellis) modification of the Scarff-Bloom-Richardson grading system
, is recommended, which 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 and then added together to give an overall final score and corresponding grade as follows.
The grading criteria are as follows:
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.
assesses whether the cell nuclei
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 gene
s and chromosome
s in the nucleus break down, and irregular nuclei and pleomorphic changes are signs of abnormal cell reproduction.
Note: The cancer
areas having cells with the greatest cellular abnormalities
should be evaluated.
assesses how many mitotic figures (dividing cells) the pathologist sees in a 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.
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.
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 prognosis
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 estrogen receptor
and progesterone receptor
levels in the cancer tissue, the human epidermal growth factor receptor 2 (HER2/neu
) status, menopausal status, and the person's general health.
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 not helpful, and (appropriately) incomplete pathological staging information will be obtained.
(AJCC) and the International Union Against Cancer
(UICC) recommend TNM staging, 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.
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.
AJCC has provided web accessible poster versions of the current versions of these copyrighted TNM descriptors and groups, and readers should refer to that up to date, accurate information or to the National Cancer Institute
(NCI) or NCCN sites which reprints these with AJCC permission.
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.
; for past editions refer to AJCC. The comments here highlight selected features of the 2010 scheme:
Tumor - The tumor
values (TX, T0, Tis, T1, T2, T3 or T4) depend on the cancer at the primary site of origin in the breast. TX refers to an inability to assess that site; Tis refers to DCIS
, LCIS, or Paget's disease
; T4d refers to inflammatory breast cancer
, a clinical circumstance where typical skin changes involve at least a third of the breast.
Lymph Node - The lymph node
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 collar area (supraclavicular lymph nodes
), and inside the chest (internal mammary lymph nodes.) 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 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. There is some nuance to the official definitions for N0 disease, which includes N0(i+) which refers to 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
(IHC); N0 also includes N0(mol-), in which regional lymph nodes have no metastases histologically, but have positive molecular findings (RT-PCR).
Metastases - Previous editions featured three metastatic 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. The present TNM edition no longer uses the MX option, and allocates tumors to one of three clinical categories: M0 refers to no clinical or radiographic evidence of distant metastases; cM0(i+) refers to 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; and M1, which refers to distant detectable metastases as determined by classic clinical and radiographic means, and/or metastasis that are histologically larger than 0.2 mm.
(ER) or HER2/neu
receptor status, and does not reflect the impact of newer treatments.
status of breast cancer
s has traditionally been identified by immunohistochemistry
(IHC), which stains the cells based on the presence of estrogen
receptors
(ER), progestin
receptors (PR) and HER2 receptors. This remains the commonest 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
and or trastuzumab
. These treatments are now some of the most effective adjuvant
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. tamoxifen
) or the actual level of estrogen (e.g. aromatase inhibitors), and generally have a better prognosis
. Generally, prior to modern treatments, HER+ had a worse prognosis, however HER2+ cancer cells respond to drugs such as the monoclonal antibody, trastuzumab
, (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 prognosis
.
status was traditionally considered by reviewing each individual receptor (ER, PR, her2) in turn, but newer approaches look at these together, along with the tumor
grade, to categorize breast cancer
into several conceptual molecular classes that have different prognoses
and may have different responses to specific therapies. DNA microarrays have assisted this approach, as discussed in the following section. Proposed molecular subtypes include:
classification
was based on the general observation that cells that are dividing
more quickly have a worse prognosis
, and relied on either the presence of protein Ki67 or the percentage of cancer cell DNA in S phase
. These methods, and scoring systems that used DNA ploidy
, are used much less often now, as their predictive and prognostic power was less substantial than other classification schemes such as the TNM stage. In contrast, modern DNA analyses are increasingly relevant in defining underlying cancer
biology and in helping choose treatments.
status can be analyzed by fluorescent in-situ hybridization (FISH) assays. Some commentators prefer this approach, claiming a higher correlation than receptor immunohistochemistry
with response to trastuzumab
, a targeted therapy, but guidelines permit either testing method.
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 cluster
s have included hormone
receptor-related
genes, HER2-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 cancers (TNBC) basal-like tumor
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 differently 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
or DNA expression profile) more reliably assorts particular cancers to effective therapies is under investigation.
Several commercially marketed DNA microarray
tests analyze cluster
s of gene
s and may help decide which possible treatment is most effective for a particular cancer
. The use of these assays in breast cancer
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
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 prominent are:
These multigene assays, some partially and some completely commercialized, have been scientifically reviewed to compare them with other standard breast cancer classification methods such as grade and receptor status. Although these gene-expression profile
s look at different individual gene
s, they seem to classify a given tumor
into similar risk
groups and thus provide concordant
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
, particularly with lymph node
positive cancers. One review characterized these genetic tests collectively as adding "modest prognostic information for patients with HER2-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".
s and 5 normal comparator reference genes, and is therefore sometimes known as the 21-gene assay. It was designed for use in estrogen
receptor
(ER) positive tumor
s. The test is run on formalin fixed, paraffin-embedded tissue. Oncotype results are reported as a Recurrence Score (RS), where a higher RS is associated with a worse prognosis
, referring to the likelihood of recurrence without treatment. In addition to that prognostic role, a higher RS is also associated with a higher probability of response to chemotherapy
, which is termed a positive predictive factor.
A summary of clinical trial
s using Oncotype is included in the Oncotype DX main article
. These results suggest that not only does Oncotype stratify estrogen-receptor positive breast cancer into different prognostic groups, but also suggest that cancers that have a particularly favorable Oncotype DX microarray result tend to derive minimal benefit from adjuvant
chemotherapy
and so it may be appropriate to choose to avoid side effects from that additional treatment. As an additional example, a neoadjuvant clinical treatment program that included initial chemotherapy followed by surgery and subsequent additional chemotherapy, radiotherapy, and hormonal therapy found a strong correlation of the Oncotype classification
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 American Society of Clinical Oncology
(ASCO) and the NCCN
. The NCCN Panel considers the 21-gene assay as an option when evaluating certain tumor
s to assist in estimating likelihood of recurrence and benefit from chemotherapy
, emphasizing that the recurrence score should be used along with other breast cancer classification elements when stratifying
risk
. Oncotype fulfilled all California Technology Assessment Forum (CTAF) criteria in October 2006. The U.S. Food and Drug Administration
(FDA) does not mandate approval of this class of tests if they are performed at a single, company-operated laboratory 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.
panel marketed by Agendia, that was developed in patients under age 55 years who had lymph node
negative breast cancer
s (N0). The commercial test is marketed for use in breast cancer irrespective of estrogen
receptor
(ER) status. MammaPrint traditionally used rapidly frozen tissue but a room temperature, molecular fixative
is available for use within 60 minutes of obtaining fresh tissue samples. MammaPrint categorizes tumor
s as either high or low risk
.
A summary of clinical trial
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 FDA
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: stage 1 or 2, tumor size less than 5.0 cm, estrogen
receptor
positive (ER+) or estrogen receptor negative (ER-). In the US, the tumor should also be lymph node
negative (N0), but internationally the test may be performed if the lymph node status is negative or positive with up to 3 nodes.
One method of assessing the molecular subtype of a breast cancer
is by BluePrint, a commercial-stage 80-gene panel marketed by Agendia, either as a standalone
test, or combined with the MammaPrint
gene profile.
is relatively useful. Expression of genes that regulate tubulin
may help predict the activity of taxane
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. BRCA1
and BRCA2
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 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. mTOR inhibitors such as everolimus
may show more effect in PIK3CA/Akt e9 mutants than in e20 mutants or wild types.
DNA methylation
patterns can epigenetically
affect gene expression in breast cancer and may contribute to some of the observed differences between genetic subtypes.
Tumors overexpressing the Wnt signaling pathway
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 of several genes could predict whether or not to prescribe tamoxifen
; 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
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
of tamoxifen responsiveness such as HOXB13
, PAX2
, and estrogen receptor (ER) alpha and beta isoforms interaction with SRC3
have all yet to be fully defined.
s can present visually appealing graphics that assist in treatment decisions.
Adjuvant! is based on US cohorts
and presents colored bar charts that display information that may assist in decisions regarding systemic
adjuvant
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.
tests that may further stratify prognosis
, BCL2 has shown promise in preliminary studies.
assessments.
s, such as
Hereditary breast—ovarian cancer syndrome, may have a dissimilar prognosis. Also potentially dissimilar treatment.
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
into several categories according to multiple different schemes, each based on different criteria and serving a different purpose. A typical description usually considers each of these aspects in turn: the histolopathological
Histopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
type, the grade of the tumor, the stage of the tumor, and the expression of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s and gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s. As knowledge of cancer cell biology develops these classifications are updated.
The practical purpose of classification is to describe each individual instance of breast cancer in a way that helps select which treatment approach is anticipated to have the best chance for a good outcome, with increased efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
and low toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
. Treatment algorithms rely on breast cancer classification to define specific subgroups that are each treated according to the best evidence available
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...
. Classification aspects must be carefully tested and validated, such that confounding effects
Confounding
In statistics, a confounding variable is an extraneous variable in a statistical model that correlates with both the dependent variable and the independent variable...
are minimized, making them either true prognostic
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
factors, which estimate disease outcomes such as disease-free or overall survival in the absence of therapy, or true predictive factors, which estimate the liklihood of response or lack of response to a specific treatment.
Classification of breast cancer is usually, but not always, primarily based on the histological appearance of tissue in the tumor. A variant from this approach, defined on the basis of physical exam findings, is that inflammatory breast cancer
Inflammatory breast cancer
Inflammatory breast cancer is an especially aggressive type of breast cancer that can occur in women of any age .It is called inflammatory because it frequently presents with symptoms resembling an inflammation...
(IBC), a form of ductal carcinoma or malignant cancer in the ducts, is distinguished from other carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
s by the inflamed
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
appearance of the affected breast, which correlates with increased cancer aggressivity.
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 physical exam. A full classification includes histopathological type, grade, stage (TNM), receptor status, and the presence or absence of genes as determined by DNA testing:- Histopathology. Although breast cancer has many different histologiesHistopathologyHistopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
, the considerable majority of breast cancers are derived from the epithelium lining the ducts or lobules, and are classified as mammary ductal carcinoma. Carcinoma in situ 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 stagingCancer stagingThe stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...
breast cancer 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 (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 (DCIS) or lobular carcinoma in situLobular carcinoma in situLobular carcinoma in situ is a condition caused by unusual cells in the lobules of the breast.It is usually not considered cancer, but it can indicate an increased risk of future cancer...
(LCIS). - Stages 1–3 are within the breast or regional lymph nodes.
- Stage 4 is metastatic cancer that has a less favorable prognosis.
- Receptor status. Cells have receptorsReceptor (biochemistry)In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
on their surface and in their cytoplasmCytoplasmThe cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
and nucleusCell nucleusIn cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
. Chemical messengers such as hormoneHormoneA hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
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 receptorEstrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER), progesterone receptorProgesterone receptorThe progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
(PR), and HER2/neuHER2/neuHER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
. 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 negativeTriple Negative Breast CancerTriple-negative breast cancer refers to any breast cancer that does not express the genes for estrogen receptor , progesterone receptor or Her2/neu. Triple negative is sometimes used as a surrogate term for basal-like, however more detailed classification is possible providing better guidance for...
.
- DNA-based classification. Understanding the specific details of a particular breast cancer may include looking at the cancer cell DNADNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
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 the DNA profile which non-targeted therapies are most effective.
- Other classification approaches.
- Computer models such as Adjuvant! can combine the various classification aspects according to validated algorithmAlgorithmIn mathematics and computer science, an algorithm is an effective method expressed as a finite list of well-defined instructions for calculating a function. Algorithms are used for calculation, data processing, and automated reasoning...
s and present visually appealing graphics that assist in treatment decisions. - The USC/Van Nuys prognostic index (VNPI) classifies ductal carcinoma in situ (DCIS) into dissimilar risk categories that may be treated accordingly.
- The choice of which treatment to receive can be substantially influenced by comorbidityComorbidityIn medicine, comorbidity is either the presence of one or more disorders in addition to a primary disease or disorder, or the effect of such additional disorders or diseases.- In medicine :...
assessments. - Familial breast cancers may potentially undergo dissimilar treatment (such as mastectomy).
- Computer models such as Adjuvant! can combine the various classification aspects according to validated algorithm
Histopathology
Histopathologic classification is based upon characteristics seen upon light microscopyOptical microscope
The optical microscope, often referred to as the "light microscope", is a type of microscope which uses visible light and a system of lenses to magnify images of small samples. Optical microscopes are the oldest design of microscope and were possibly designed in their present compound form in the...
of biopsy specimens. The three most common histopathological types collectively represent approximately three-quarters of breast cancers:
- Invasive ductal carcinoma - 55% of breast cancers
- Ductal carcinoma in situ - 13%
- Invasive lobular carcinomaInvasive lobular carcinomaInvasive lobular carcinoma accounts for 5-10% of invasive breast cancer.The histologic patterns include: Overall, the 5-year survival rate of invasive lobular carcinoma was approximately 85% in 2003....
- 5%
The overall 5-year survival 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 2003 World Health OrganizationWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(WHO) classification of tumors of the breast which includes benign (harmless) tumors and malignant (cancerous) tumors, recommends the following pathological types:
Invasive breast carcinomas
- Invasive ductal carcinoma
- Most are "not otherwise specified"
- The remainder are given subtypes:
- Mixed type carcinoma
- PleomorphicPleomorphism (cytology)Pleomorphism is a term used in histology and cytopathology to describe variability in the size and shape of cells and/or their nuclei. It is a feature characteristic of malignant neoplasms....
carcinoma - Carcinoma with osteoclastOsteoclastAn osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
giant cells - Carcinoma with choriocarcinomaChoriocarcinomaChoriocarcinoma is a malignant, trophoblastic and aggressive cancer, usually of the placenta. It is characterized by early hematogenous spread to the lungs...
features - Carcinoma with melanotic features
- Invasive lobular carcinomaInvasive lobular carcinomaInvasive lobular carcinoma accounts for 5-10% of invasive breast cancer.The histologic patterns include: Overall, the 5-year survival rate of invasive lobular carcinoma was approximately 85% in 2003....
- Tubular carcinoma
- Invasive cribriform carcinoma
- Medullary carcinomaMedullary carcinomaMedullary carcinoma refers to one of several tumors.The most common types are:* Medullary thyroid cancer* Medullary carcinoma of the breastMedullary carcinoma is also described in the following organs* Pancreas* Ampulla of Vater* Gallbladder* Stomach...
- Mucinous carcinoma and other tumours with abundant mucinMucinMucins are a family of high molecular weight, heavily glycosylated proteins produced by epithelial tissues in most metazoans. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell...
- Mucinous carcinomaMucinous carcinomaMucinous carcinoma is a type of cancer that begins in cells that line certain internal organs and skin, and produce mucin ....
- CystadenocarcinomaCystadenocarcinomaCystadenocarcinoma is a malignant form of a cystadenoma and is a malignant neoplasm derived from glandular epithelium, in which cystic accumulations of retained secretions are formed. The neoplastic cells manifest varying degrees of anaplasia and invasiveness, and local extension and metastases occur...
and columnarColumnarIn biology, columnar refers to the shape of epithelial cells that are taller than they are wide. Form follows function in biology, and columnar morphorphology hints at the functions of the cell. Columnar cells are important in absorption and movement of mucus...
cell mucinous carcinomaMucinous carcinomaMucinous carcinoma is a type of cancer that begins in cells that line certain internal organs and skin, and produce mucin .... - Signet ring cell carcinomaSignet ring cell carcinomaSignet ring cell carcinoma is an epithelial malignancy characterized by the histologic appearance of signet ring cells.It is a form of adenocarcinoma.-Histologic appearance:...
- Mucinous carcinoma
- Neuroendocrine tumours
- Solid neuroendocrine carcinoma (carcinoidCarcinoidCarcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
of the breast) - Atypical carcinoidCarcinoidCarcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
tumor - Small cell / oat cell carcinoma
- Large cell neuroendocrine carcinoma
- Solid neuroendocrine carcinoma (carcinoid
- Invasive papillary carcinoma
- Invasive micropapillary carcinoma
- ApocrineApocrineApocrine is a term used to classify exocrine glands in the study of histology. Cells which are classified as apocrine bud their secretions off through the plasma membrane producing membrane-bound vesicles in the lumen. This method is also called decapitation secretion...
carcinoma - MetaplasticMetaplasiaMetaplasia is the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another may generally be a part of normal maturation process or caused by some sort of abnormal stimulus...
carcinomas- Pure epithelial metaplasticMetaplasiaMetaplasia is the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another may generally be a part of normal maturation process or caused by some sort of abnormal stimulus...
carcinomas- Squamous cell carcinomaSquamous cell carcinomaSquamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
- AdenocarcinomaAdenocarcinomaAdenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
with spindle cell metaplasiaMetaplasiaMetaplasia is the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another may generally be a part of normal maturation process or caused by some sort of abnormal stimulus... - Adenosquamous carcinomaAdenosquamous carcinomaAdenosquamous carcinoma is a type of cancer that contains two types of cells: squamous cells and gland-like cells.- External links :* entry in the public domain NCI Dictionary of Cancer Terms...
sukers - Mucoepidermoid carcinomaMucoepidermoid carcinomaMucoepidermoid carcinoma is the most common type of salivary gland malignancy in children. Mucoepidermoid carcinoma can also be found in other organs, as bronchi, lacrimal sac and thyroid.Mucicarmine staining is one stain used by pathologist for detection....
- Squamous cell carcinoma
- Mixed epithelial/mesenchymal metaplasticMetaplasiaMetaplasia is the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another may generally be a part of normal maturation process or caused by some sort of abnormal stimulus...
carcinomas
- Pure epithelial metaplastic
- LipidLipidLipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
-rich carcinoma - Secretory carcinoma
- Oncocytic carcinoma
- Adenoid cystic carcinomaAdenoid cystic carcinomaAdenoid cystic cancer is a rare type of cancer that can exist in many different body sites. It most often occurs in the areas of the head and neck, in particular the salivary glands; but has also been reported in the breast, lacrimal gland of the eye, lung, brain, bartholin gland, trachea, and...
- Acinic cell carcinomaAcinic cell carcinomaAcinic cell carcinoma is a tumor most commonly found in the parotid gland. The disease presents as a slow growing mass, sometimes associated with pain or tenderness....
- GlycogenGlycogenGlycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
-rich clear cell carcinoma - Sebaceous carcinomaSebaceous carcinomaSebaceous carcinoma is an uncommon and aggressive malignant cutaneous tumor. Most are typically about 10 mm in size at presentation. This neoplasm is thought to arise from sebaceous glands in the skin and, therefore, may originate anywhere in the body where these glands are found. Because the...
- Inflammatory carcinomaInflammatory breast cancerInflammatory breast cancer is an especially aggressive type of breast cancer that can occur in women of any age .It is called inflammatory because it frequently presents with symptoms resembling an inflammation...
- Bilateral breast carcinoma
Mesenchymal tumors (including sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
)
- HemangiomaHemangiomaA hemangioma of infancy is a benign self-involuting tumor of endothelial cells, the cells that line blood vessels. It usually appears during the first weeks of life and sometimes resolves by age 10. In more severe case hemangioma may have permanency, if not treated by a physician...
- AngiomatosisAngiomatosisAngiomatosis is a non-neoplastic condition presenting with little knots of capillaries in various organs. It consists of many angiomas. It is also known as Von Hippel-Lindau Disease and is a rare genetic multi system disorder characterized by the abnormal growth of tumours in the body...
- HemangiopericytomaHemangiopericytomaA hemangeopericytoma 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 an especially aggressive behavior.It was characterized in...
- Pseudoangiomatous stromal hyperplasiaPseudoangiomatous stromal hyperplasiaIn breast pathology, pseudoangiomatous stromal hyperplasia, commonly abbreviated PASH, is an overgrowth of myofibroblastic cells and has an appearance similar to fibroadenomatoid changes....
- MyofibroblastomaMammary myofibroblastomaMammary myofibroblastoma, abbreviated MMFB, is a rare, benign tumour of the breast.-Diagnosis:The diagnosis is based on examination under a microscope, by a pathologist...
- FibromatosisFibromatosisThe term fibromatosis refers to a group of benign 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 fibroblasts, an infiltrative growth pattern, and...
(aggressive) - Inflammatory myofibroblastic tumor
- LipomaLipomaA lipoma is a benign tumor composed of adipose tissue. It is the most common form of soft tissue tumor. Lipomas are soft to the touch, usually movable, and are generally painless. Many lipomas are small but can enlarge to sizes greater than six centimeters. Lipomas are commonly found in adults...
- AngiolipomaAngiolipomaAngiolipoma is a subcutaneous nodule with vascular structure, having all other features of a typical lipoma. They are commonly painful....
- Angiolipoma
- Granular cell tumour
- NeurofibromaNeurofibromaA neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I , an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability...
- SchwannomaSchwannomaA schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....
- AngiosarcomaAngiosarcomaAngiosarcoma is a malignant neoplasm of endothelial-type cells that line vessel walls. This may be in reference to blood or lymphatic vessels ....
- LiposarcomaLiposarcomaLiposarcoma is a malignant tumor that arises in fat cells in deep soft tissue, such as that inside the thigh or in the retroperitoneum.They are typically large bulky tumors which tend to have multiple smaller satellites extending beyond the main confines of the tumor.Liposarcomas, like all...
- RhabdomyosarcomaRhabdomyosarcomaA rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
- OsteosarcomaOsteosarcomaOsteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
- LeiomyomaLeiomyomaA leiomyoma is a benign smooth muscle neoplasm that is not premalignant. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus.- Etymology:* Greek:** λεῖος leios "smooth"...
- LeiomyosarcomaLeiomyosarcomaLeiomyosarcoma , aka LMS, is a malignant cancer of smooth muscle....
Tumors of the male breast
- GynecomastiaGynecomastiaGynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
(benign) - CarcinomaCarcinomaCarcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
- In situIn situIn situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...
- InvasiveInvasiveInvasive may refer to:*A military invasion*An invasive species*An invasive medical procedure*The invasively progressive spread of disease from one organ in the body to another, especially in reference to cancer...
- In situ
Malignant lymphoma
- Non-Hodgkin lymphomaNon-Hodgkin lymphomaThe non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
Metastatic tumors to the breast from other places in the body
Precursor lesions
- Lobular neoplasiaLobular neoplasiaLobular neoplasia can refer to:* Lobular carcinoma in situ* Invasive lobular carcinoma...
- lobular carcinoma in situLobular carcinoma in situLobular carcinoma in situ is a condition caused by unusual cells in the lobules of the breast.It is usually not considered cancer, but it can indicate an increased risk of future cancer...
- lobular carcinoma in situ
- Intraductal proliferative lesions
- Usual ductal hyperplasiaHyperplasiaHyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
- Flat epithelial hyperplasia
- Atypical ductal hyperplasiaAtypical ductal hyperplasiaAtypical ductal hyperplasia, abbreviated ADH, is the term used for a benign lesion of the breast that indicates an increased risk of breast cancer....
- Ductal carcinoma in situ
- Usual ductal hyperplasia
- Microinvasive carcinoma
- Intraductal papillary neoplasms
- Central papillomaPapillomaPapilloma refers to a benign epithelial tumor growing exophytically in finger-like fronds. In this context papilla refers to the projection created by the tumor, not a tumor on an already existing papilla . When used without context, it frequently refers to infections caused by human...
- Peripheral papilloma
- Atypical papilloma
- Intraductal papillary carcinoma
- Intracystic papillary carcinoma
- Central papilloma
Benign epithelial lesions
- AdenosisAdenosisAdenosis is a disease of a gland. The diseased gland has abnormal formation of glandular tissue or abnormal enlargement of glandular tissue....
, including variants- SclerosingSclerosis (medicine)In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...
adenosis - ApocrineApocrineApocrine is a term used to classify exocrine glands in the study of histology. Cells which are classified as apocrine bud their secretions off through the plasma membrane producing membrane-bound vesicles in the lumen. This method is also called decapitation secretion...
adenosisAdenosisAdenosis is a disease of a gland. The diseased gland has abnormal formation of glandular tissue or abnormal enlargement of glandular tissue.... - Blunt duct adenosisAdenosisAdenosis is a disease of a gland. The diseased gland has abnormal formation of glandular tissue or abnormal enlargement of glandular tissue....
- Microglandular adenosisAdenosisAdenosis is a disease of a gland. The diseased gland has abnormal formation of glandular tissue or abnormal enlargement of glandular tissue....
- Adenomyoepithelial adenosisAdenosisAdenosis is a disease of a gland. The diseased gland has abnormal formation of glandular tissue or abnormal enlargement of glandular tissue....
- Sclerosing
- Radial scar / complex sclerosingSclerosis (medicine)In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...
lesion - AdenomaAdenomaAn adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
s- Tubular adenoma
- Lactating adenoma
- ApocrineApocrineApocrine is a term used to classify exocrine glands in the study of histology. Cells which are classified as apocrine bud their secretions off through the plasma membrane producing membrane-bound vesicles in the lumen. This method is also called decapitation secretion...
adenoma - Pleomorphic adenomaPleomorphic adenomaPleomorphic adenoma is a common benign salivary gland neoplasm characterised by neoplastic proliferation of parenchymatous glandular cells along with myoepithelial components, having a malignant potentiality. It is the most common type of salivary gland tumor and the most common tumor of the...
- Ductal adenoma
Myoepithelial lesions
- Myoepitheliosis
- Adenomyoepithelial adenosis
- AdenomyoepitheliomaAdenomyoepithelioma of the breastAn adenomyoepithelioma of the breast, also adenomyoepithelioma, is a rare tumour in the breast composed of glandular elements and myoepithelial cells. It is usually benign; however, there are reports of malignant behaviour....
- Malignant myoepithelioma
Fibroepithelial tumours
- FibroadenomaFibroadenomaFibroadenomas of the breast, are lumps composed of fibrous and glandular tissue. Because breast cancer can also appear as a lump, doctors may recommend a tissue sample to rule out cancer in older patients...
- Phyllodes tumour
- BenignBenignA benign tumor is a tumor that lacks the ability to metastasize. Common examples of benign tumors include moles and uterine fibroids.The term "benign" implies a mild and nonprogressive disease. Indeed, many kinds of benign tumors are harmless to human health...
- BorderlineBorderlineBorderline or border line may refer to:*Border-In film:*Borderline , a film starring Paul Robeson*Borderline , a film noir starring Fred MacMurray*Borderline , a film starring Charles Bronson...
- MalignantMalignantMalignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
- Benign
- Periductal stromal sarcomaSarcomaA sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
, low grade - Mammary hamartomaHamartomaA hamartoma is a benign, focal malformation that resembles a neoplasm in the tissue of its origin. This is not a malignant tumor, and it grows at the same rate as the surrounding tissues. It is composed of tissue elements normally found at that site, but which are growing in a disorganized mass...
Benign tumors of the nipple
- Nipple adenomaNipple adenomaA nipple adenoma is a rare benign tumour of the breast.The condition may also be known as :*Florid papillomatosis of the nipple*Florid adenomatosis*Subareolar duct papillomatosis*Erosive adenomatosis-Definition:...
- Syringomatous adenoma
- Paget's diseasePaget's disease of the breastPaget's disease of the breast is a malignant condition that outwardly may have the appearance of eczema, with skin changes involving the nipple of the breast....
of the nipple
Malignant tumors of the nipple
- Paget's diseasePaget's disease of the breastPaget's disease of the breast is a malignant condition that outwardly may have the appearance of eczema, with skin changes involving the nipple of the breast....
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 (also called Elston-Ellis) modification of the Scarff-Bloom-Richardson grading system
Bloom-Richardson grade
The Bloom–Richardson grading system from 1957 refers to a breast cancer classification system to grade breast cancers, and was the precursor of the present criteria, the modified Bloom–Richardson–Elston grading system The cells and tissue structure of the breast cancer are examined...
, is recommended, which 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 and then added together to give an overall final score and corresponding grade as follows.
The grading criteria are as follows:
Tubule formation
This parameterParameter
Parameter from Ancient Greek παρά also “para” meaning “beside, subsidiary” and μέτρον also “metron” meaning “measure”, can be interpreted in mathematics, logic, linguistics, environmental science and other disciplines....
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
- 2 points: tubular formation in 10 to 75% of the tumor
- 3 points: tubular formation in less than 10% of the tumor
Nuclear pleomorphism
This parameterParameter
Parameter from Ancient Greek παρά also “para” meaning “beside, subsidiary” and μέτρον also “metron” meaning “measure”, can be interpreted in mathematics, logic, linguistics, environmental science and other disciplines....
assesses whether the cell nuclei
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
are uniform like those in normal breast duct epithelial cells, or whether they are larger, darker, or irregular (pleomorphic
Pleomorphism (cytology)
Pleomorphism is a term used in histology and cytopathology to describe variability in the size and shape of cells and/or their nuclei. It is a feature characteristic of malignant neoplasms....
). In cancer, the mechanisms that control gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s and chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s in the nucleus break down, and irregular nuclei and pleomorphic changes are signs of abnormal cell reproduction.
Note: The cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
areas having cells with the greatest cellular abnormalities
Atypia
Atypia is a clinical term for abnormality in a cell. The term is medical jargon for an atypical cell. Atypia: Etymology: Gk, a + typos, without type; a condition of being irregular or nonstandard....
should be evaluated.
- 1 point: nuclei with mimimal 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
Mitotic count
This parameterParameter
Parameter from Ancient Greek παρά also “para” meaning “beside, subsidiary” and μέτρον also “metron” meaning “measure”, can be interpreted in mathematics, logic, linguistics, environmental science and other disciplines....
assesses how many mitotic figures (dividing cells) the pathologist sees in a 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.
- 1 point: 0-9 mitotic counts per field under X25 objective using the Leitz Ortholux microscope, 0-5 mitotic counts per field under X40 objective using the Nikon Labophot microscope, or 0-11 mitotic counts per field under X40 objective using the Leitz Daiplan microscope
- 2 points: 10-19 mitotic counts per field under X25 objective using the Leitz Ortholux microscope, 6-10 mitotic counts per field under X40 objective using the Nikon Labophot microscope, or 12-22 mitotic counts per field under X40 objective using the Leitz Daiplan microscope
- 3 points: Over 19 mitotic counts per field under X25 objective using the Leitz Ortholux microscope, over 10 mitotic counts per field under X40 objective using the Nikon Labophot microscope, or over 22 mitotic counts per field under X40 objective using the Leitz Daiplan microscope
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 prognosisPrognosisPrognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
. - 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
StagingCancer staging
The stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...
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 prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
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 estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
and progesterone receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
levels in the cancer tissue, the human epidermal growth factor receptor 2 (HER2/neu
HER2/neu
HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
) status, menopausal status, and the person's general health.
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 not helpful, and (appropriately) incomplete pathological staging information will be obtained.
TNM system
The American Joint Committee on CancerAmerican Joint Committee on Cancer
The American Joint Committee on Cancer is an organization best known for defining and popularizing cancer staging standards, officially the AJCC staging system....
(AJCC) and the International Union Against Cancer
International Union Against Cancer
The International Union Against Cancer, or UICC is the only non-governmental organization dedicated exclusively to the global control of cancer. Its vision is of a world where cancer is eliminated as a major life-threatening disease for future generations...
(UICC) recommend TNM staging, 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.
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.
AJCC has provided web accessible poster versions of the current versions of these copyrighted TNM descriptors and groups, and readers should refer to that up to date, accurate information or to the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
(NCI) or NCCN sites which reprints these with AJCC permission.
Stage migration
Several factors are important when reviewing reports for individual breast cancers or when reading the medical literature, and applying staging data.| AJCC edition | published | went into effect | Breast cancer link(s) and page numbers in the original |
|---|---|---|---|
| 7 | 2009 | 2010 | AJCC or NCI |
| 6 | 2002 | 2003 | AJCC; original pages 223-240 |
| 5 | 1997 | 1998 | AJCC; original pages 171-180 |
| 4 | 1992 | 1993 | AJCC; original pages 149-154 |
| 3 | 1988 | 1989 | AJCC; original pages 145-150 |
| 2 | 1983 | 1984 | AJCC; original pages 127-134 |
| 1 | 1977 | 1978 | AJCC; original pages 101-108 |
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
UICC
The UICC is the smart card used in mobile terminals in GSM and UMTS networks. The UICC ensures the integrity and security of all kinds of personal data, and it typically holds a few hundred kilobytes...
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"
Cancer staging
The stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...
. 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.
TNM highlights
For accurate, complete, current details refer to the accessible copyrighted documentation from AJCC, or to the authorized documentation from NCI or NCCNNational Comprehensive Cancer Network
National Comprehensive Cancer Network is an alliance of twenty-one cancer centers in the United States, most of which are designated by the National Cancer Institute as comprehensive cancer centers...
; for past editions refer to AJCC. The comments here highlight selected features of the 2010 scheme:
Tumor - The tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
values (TX, T0, Tis, T1, T2, T3 or T4) depend on the cancer at the primary site of origin in the breast. TX refers to an inability to assess that site; Tis refers to DCIS
Ductal carcinoma
Mammary ductal carcinoma is the most common type of breast cancer in women. It comes in two forms: invasive ductal carcinoma , an infiltrating, malignant and abnormal proliferation of neoplastic cells in the breast tissue, or ductal carcinoma in situ , a noninvasive, possibly malignant, neoplasm...
, LCIS, or Paget's disease
Paget's disease of the breast
Paget's disease of the breast is a malignant condition that outwardly may have the appearance of eczema, with skin changes involving the nipple of the breast....
; T4d refers to inflammatory breast cancer
Inflammatory breast cancer
Inflammatory breast cancer is an especially aggressive type of breast cancer that can occur in women of any age .It is called inflammatory because it frequently presents with symptoms resembling an inflammation...
, a clinical circumstance where typical skin changes involve at least a third of the breast.
Lymph Node - The lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
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 collar area (supraclavicular lymph nodes
Supraclavicular fossa
The Supraclavicular fossa is an indentation immediately above the clavicle.In terminologia anatomica, it is divided into fossa supraclavicularis major and fossa supraclavicularis minor-External links:*...
), and inside the chest (internal mammary lymph nodes.) 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 muscle; level II is the mid-axilla which is defined by the borders of the pectoralis minor muscle; and level III, or high (apical
Apex
Apex may refer to:- Biology :* Apex , the tip of the spire of the shell of a gastropod* Apex is the Apical meristem or its remnant on a flower...
) axilla which is above the pectoralis minor muscle. There is some nuance to the official definitions for N0 disease, which includes N0(i+) which refers to 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
H&E stain
H&E stain, HE stain or hematoxylin and eosin stain is a popular staining method in histology. It is the most widely used stain in medical diagnosis; for example when a pathologist looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E and termed H&E...
or immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
(IHC); N0 also includes N0(mol-), in which regional lymph nodes have no metastases histologically, but have positive molecular findings (RT-PCR).
Metastases - Previous editions featured three metastatic 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. The present TNM edition no longer uses the MX option, and allocates tumors to one of three clinical categories: M0 refers to no clinical or radiographic evidence of distant metastases; cM0(i+) refers to 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; and M1, which refers to distant detectable metastases as determined by classic clinical and radiographic means, and/or metastasis that are histologically larger than 0.2 mm.
| Breast cancer stage (AJCC 5th edition) | 5-year overall survival of over 50,000 patients from 1989 |
|---|---|
| Stage 0 | 92% |
| Stage I | 87% |
| Stage II | 75% |
| Stage III | 46% |
| Stage IV | 13% |
Staging and prognosis
The impact of different stages on outcome can be appreciated in the following table, published in a 2007 textbook, which shows the observed 5-year overall survival of over 50,000 patients from 1989 who were reclassified using the AJCC 5th edition criteria; the data is also available in the AJCC source, which also gives the relative survival rate in comparison to an age-matched (actually, age- sex- and race-matched) population. This data is historical, does not show the influence of important additional factors such as estrogen receptorEstrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER) or HER2/neu
HER2/neu
HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
receptor status, and does not reflect the impact of newer treatments.
Receptor status
The receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
status of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
s has traditionally been identified by immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
(IHC), which stains the cells based on the presence of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
receptors
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER), progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
receptors (PR) and HER2 receptors. This remains the commonest method of testing for receptor status, but DNA multi-gene expression profiles
DNA microarray
A DNA microarray 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 genotype multiple regions of a genome...
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
Targeted therapy
Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells...
such as tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
and or trastuzumab
Trastuzumab
Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
. These treatments are now some of the most effective adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
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. tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
) or the actual level of estrogen (e.g. aromatase inhibitors), and generally have a better prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
. Generally, prior to modern treatments, HER+ had a worse prognosis, however HER2+ cancer cells respond to drugs such as the monoclonal antibody, trastuzumab
Trastuzumab
Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
, (in combination with conventional chemotherapy) and this has improved the prognosis significantly. Conversely, triple negative cancer
Triple Negative Breast Cancer
Triple-negative breast cancer refers to any breast cancer that does not express the genes for estrogen receptor , progesterone receptor or Her2/neu. Triple negative is sometimes used as a surrogate term for basal-like, however more detailed classification is possible providing better guidance for...
(i.e. no positive receptors), lacking targeted treatments now has a comparatively poor prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
.
Molecular subtype
ReceptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
status was traditionally considered by reviewing each individual receptor (ER, PR, her2) in turn, but newer approaches look at these together, along with the tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
grade, to categorize breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
into several conceptual molecular classes that have different prognoses
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
and may have different responses to specific therapies. DNA microarrays 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 cancerTriple Negative Breast CancerTriple-negative breast cancer refers to any breast cancer that does not express the genes for estrogen receptor , progesterone receptor or Her2/neu. Triple negative is sometimes used as a surrogate term for basal-like, however more detailed classification is possible providing better guidance for...
(TNBC) Most BRCA1BRCA1BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
breast cancers are basal-like TNBC. - Luminal A: ER+ and low grade
- Luminal B: ER+ but often high grade
- ERBB2/HER2+: has amplified HER2/neuHER2/neuHER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
- Normal breast-like
- ClaudinClaudinClaudins are a family of proteins that are the most important components of the tight junctions, where they establish the paracellular barrier that controls the flow of molecules in the intercellular space between the cells of an epithelium...
-low: a more recently described class; often triple-negative, but distinct in that there is low expression of cell-cell junction proteinsTight junction proteinTight junction protein may refer to:*Tight junction protein 1*Tight junction protein 2...
including E-cadherin and frequently there is infiltration with lymphocyteLymphocyteA lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s.
Traditional DNA classification
Traditional DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
classification
Categorization
Categorization is the process in which ideas and objects are recognized, differentiated and understood. Categorization implies that objects are grouped into categories, usually for some specific purpose. Ideally, a category illuminates a relationship between the subjects and objects of knowledge...
was based on the general observation that cells that are dividing
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
more quickly have a worse prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
, and relied on either the presence of protein Ki67 or the percentage of cancer cell DNA in S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
. These methods, and scoring systems that used DNA ploidy
Ploidy
Ploidy is the number of sets of chromosomes in a biological cell.Human sex cells have one complete set of chromosomes from the male or female parent. Sex cells, also called gametes, combine to produce somatic cells. Somatic cells, therefore, have twice as many chromosomes. The haploid number is...
, are used much less often now, as their predictive and prognostic power was less substantial than other classification schemes such as the TNM stage. In contrast, modern DNA analyses are increasingly relevant in defining underlying cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
biology and in helping choose treatments.
HER2/neu
HER2/neuHER2/neu
HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
status can be analyzed by fluorescent in-situ hybridization (FISH) assays. Some commentators prefer this approach, claiming a higher correlation than receptor immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
with response to trastuzumab
Trastuzumab
Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
, a targeted therapy, but guidelines permit either testing method.
Background
DNA microarrays have compared normal cells to breast cancer cells and found differences in the expression of hundreds of geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
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 cluster
Cluster
-In science:* Cluster , a small group of atoms or molecules* Cluster chemistry, an array of bound atoms intermediate in character between a molecule and a solid...
s have included hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
receptor-related
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
genes, HER2-related genes, a group of basal-like genes, and proliferation
Proliferation
Proliferation may refer to:*Nuclear proliferation*Chemical weapon proliferation*Cell proliferation* The proliferative phase of wound healing...
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 cancers (TNBC) basal-like tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
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 differently 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
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
or DNA expression profile) more reliably assorts particular cancers to effective therapies is under investigation.
Several commercially marketed DNA microarray
DNA microarray
A DNA microarray 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 genotype multiple regions of a genome...
tests analyze cluster
Cluster
-In science:* Cluster , a small group of atoms or molecules* Cluster chemistry, an array of bound atoms intermediate in character between a molecule and a solid...
s of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s and may help decide which possible treatment is most effective for a particular cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. The use of these assays in breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
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
Prospective
Prospective literally means "looking forward". It can also refer to an event that is likely or expected to happen in the future. For example, a prospective student is someone who is considering attending a school — typically a high school student who is seriously considering applying to a...
, randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
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 prominent are:
- Oncotype DXOncotype DXOncotype DX, developed by Genomic Health, is a diagnostic test that quantifies the likelihood of disease recurrence in women with early-stage hormone estrogen receptor positive only breast cancer and assesses the likely benefit from certain types of chemotherapy .Oncotype DX analyzes a panel of...
is supported by Level II evidence, and was originally designed for use in estrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
receptorEstrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER) positive tumors, and has been endorsed by the American Society of Clinical OncologyAmerican Society of Clinical OncologyThe American Society of Clinical Oncology is the world's leading professional organization representing physicians of all oncology subspecialties who care for people with cancer. Founded in 1964 by Drs...
(ASCO) and the NCCNNational Comprehensive Cancer NetworkNational Comprehensive Cancer Network is an alliance of twenty-one cancer centers in the United States, most of which are designated by the National Cancer Institute as comprehensive cancer centers...
. - MammaPrintMammaPrintMammaPrint is a diagnostic test used by physicians to assess the risk that a breast tumor will metastasize to other parts of the body. This helps physicians determine whether or not each patient will benefit from chemotherapy...
is supported by Level III evidence, can be performed on estrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
receptorEstrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER) positive and negative tumors, and has FDAFood and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approval. - Two other tests also have Level III evidence: Theros and MapQuant Dx.
These multigene assays, some partially and some completely commercialized, have been scientifically reviewed to compare them with other standard breast cancer classification methods such as grade and receptor status. Although these gene-expression profile
DNA microarray
A DNA microarray 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 genotype multiple regions of a genome...
s look at different individual gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, they seem to classify a given tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
into similar risk
Risk
Risk is the potential that a chosen action or activity will lead to a loss . The notion implies that a choice having an influence on the outcome exists . Potential losses themselves may also be called "risks"...
groups and thus provide concordant
Inter-rater reliability
In statistics, inter-rater reliability, inter-rater agreement, or concordance is the degree of agreement among raters. It gives a score of how much homogeneity, or consensus, there is in the ratings given by judges. It is useful in refining the tools given to human judges, for example by...
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
Controversy is a state of prolonged public dispute or debate, usually concerning a matter of opinion. The word was coined from the Latin controversia, as a composite of controversus – "turned in an opposite direction," from contra – "against" – and vertere – to turn, or versus , hence, "to turn...
, particularly with lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
positive cancers. One review characterized these genetic tests collectively as adding "modest prognostic information for patients with HER2-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 geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s and 5 normal comparator reference genes, and is therefore sometimes known as the 21-gene assay. It was designed for use in estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER) positive tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s. The test is run on formalin fixed, paraffin-embedded tissue. Oncotype results are reported as a Recurrence Score (RS), where a higher RS is associated with a worse prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
, referring to the likelihood of recurrence without treatment. In addition to that prognostic role, a higher RS is also associated with a higher probability of response to chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, which is termed a positive predictive factor.
A summary of clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s using Oncotype is included in the Oncotype DX main article
Oncotype DX
Oncotype DX, developed by Genomic Health, is a diagnostic test that quantifies the likelihood of disease recurrence in women with early-stage hormone estrogen receptor positive only breast cancer and assesses the likely benefit from certain types of chemotherapy .Oncotype DX analyzes a panel of...
. These results suggest that not only does Oncotype stratify estrogen-receptor positive breast cancer into different prognostic groups, but also suggest that cancers that have a particularly favorable Oncotype DX microarray result tend to derive minimal benefit from adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and so it may be appropriate to choose to avoid side effects from that additional treatment. As an additional example, a neoadjuvant clinical treatment program that included initial chemotherapy followed by surgery and subsequent additional chemotherapy, radiotherapy, and hormonal therapy found a strong correlation of the Oncotype classification
Classification
Classification may refer to:* Library classification and classification in general* Taxonomic classification * Biological classification of organisms* Medical classification* Scientific classification...
with the likelihood of a complete response
Response Evaluation Criteria in Solid Tumors
Response Evaluation Criteria In Solid Tumors is a set of published rules that define when cancer patients improve , stay the same , or worsen during treatments...
(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 American Society of Clinical Oncology
American Society of Clinical Oncology
The American Society of Clinical Oncology is the world's leading professional organization representing physicians of all oncology subspecialties who care for people with cancer. Founded in 1964 by Drs...
(ASCO) and the NCCN
National Comprehensive Cancer Network
National Comprehensive Cancer Network is an alliance of twenty-one cancer centers in the United States, most of which are designated by the National Cancer Institute as comprehensive cancer centers...
. The NCCN Panel considers the 21-gene assay as an option when evaluating certain tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s to assist in estimating likelihood of recurrence and benefit from chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, emphasizing that the recurrence score should be used along with other breast cancer classification elements when stratifying
Stratified medicine
Stratified medicine is the management of a group of patients with shared biological characteristics by using molecular diagnostic testing to select the best therapy in order to achieve the best possible medicinal outcome for that group....
risk
Risk
Risk is the potential that a chosen action or activity will lead to a loss . The notion implies that a choice having an influence on the outcome exists . Potential losses themselves may also be called "risks"...
. Oncotype fulfilled all California Technology Assessment Forum (CTAF) criteria in October 2006. The U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) does not mandate approval of this class of tests if they are performed at a single, company-operated laboratory 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-geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
panel marketed by Agendia, that was developed in patients under age 55 years who had lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
negative breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
s (N0). The commercial test is marketed for use in breast cancer irrespective of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER) status. MammaPrint traditionally used rapidly frozen tissue but a room temperature, molecular fixative
Fixation (histology)
In the fields of histology, pathology, and cell biology, fixation is a chemical process by which biological tissues are preserved from decay, thereby preventing autolysis or putrefaction...
is available for use within 60 minutes of obtaining fresh tissue samples. MammaPrint categorizes tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s as either high or low risk
Risk
Risk is the potential that a chosen action or activity will lead to a loss . The notion implies that a choice having an influence on the outcome exists . Potential losses themselves may also be called "risks"...
.
A summary of clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s using MammaPrint is included in the MammaPrint main article
MammaPrint
MammaPrint is a diagnostic test used by physicians to assess the risk that a breast tumor will metastasize to other parts of the body. This helps physicians determine whether or not each patient will benefit from chemotherapy...
. 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 FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
clearances and is the only FDA cleared microarray assay available. To be eligible for the MammaPrint gene expression profile
DNA microarray
A DNA microarray 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 genotype multiple regions of a genome...
, a breast cancer should have the following characteristics: stage 1 or 2, tumor size less than 5.0 cm, estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
positive (ER+) or estrogen receptor negative (ER-). In the US, the tumor should also be lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
negative (N0), but internationally the test may be performed if the lymph node status is negative or positive with up to 3 nodes.
One method of assessing the molecular subtype of a breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
is by BluePrint, a commercial-stage 80-gene panel marketed by Agendia, either as a standalone
Standalone
A standalone entity is something that has no dependencies; it can "stand alone". Standalone may also refer to the following topics:*Standalone software*the standalone attribute in XML*a standalone expansion pack for games...
test, or combined with the MammaPrint
MammaPrint
MammaPrint is a diagnostic test used by physicians to assess the risk that a breast tumor will metastasize to other parts of the body. This helps physicians determine whether or not each patient will benefit from chemotherapy...
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 (TOP2A) expression predicts whether doxorubicinDoxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
is relatively useful. Expression of genes that regulate tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
may help predict the activity of taxane
Taxane
The taxanes are diterpenes produced by the plants of the genus Taxus . As their name suggests, they were first derived from natural sources, but some have been synthesized artificially. Taxanes include paclitaxel and docetaxel . Paclitaxel was originally derived from the Pacific yew tree.Taxanes...
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. BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
and BRCA2
BRCA2
BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
polymorphic variants
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
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 such as olaparib
Olaparib
Olaparib is a chemotherapeutic agent developed by KuDOS Pharmaceuticals and later by Astra Zeneca. It is an inhibitor of PARP, an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate cancers...
. 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. mTOR inhibitors such as everolimus
Everolimus
Everolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
may show more effect in PIK3CA/Akt e9 mutants than in e20 mutants or wild types.
DNA methylation
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
patterns can epigenetically
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
affect gene expression in breast cancer and may contribute to some of the observed differences between genetic subtypes.
Tumors overexpressing the Wnt signaling pathway
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
co-receptor low-density lipoprotein receptor-related protein 6
LRP6
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene....
(LRP6) may represent a distinct subtype of breast cancer and a potential treatment target.
Numerous clinical investigations looked at whether testing for variant genotype
SNP genotyping
SNP genotyping is the measurement of genetic variations of single nucleotide polymorphisms between members of a species. It is a form of genotyping, which is the measurement of more general genetic variation. SNPs are one of the most common types of genetic variation...
polymorphic
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
alleles of several genes could predict whether or not to prescribe tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
; 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
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
testing, data from two large clinical trials found no benefit. Testing for the CYP2C19*2
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
polymorphism gave counterintuitive results. The medical utility of potential biomarkers
Biomarker (medicine)
In medicine, a biomarker is a term often used to refer to a protein measured in blood whose concentration reflects the severity or presence of some disease state...
of tamoxifen responsiveness such as HOXB13
HOXB13
Homeobox protein Hox-B13 is a protein that in humans is encoded by the HOXB13 gene.-Further reading:...
, PAX2
PAX2
Paired box gene 2, also known as PAX2 is a protein which in humans is encoded by the PAX2 gene.-Function:PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding...
, and estrogen receptor (ER) alpha and beta isoforms interaction with SRC3
Nuclear receptor coactivator 3
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' , steroid receptor coactivator-3 , or thyroid hormone receptor activator molecule 1 .-Function:NCOA3 is a transcriptional...
have all yet to be fully defined.
Computer models
Computer models consider several traditional factors concurrently to derive individual survival predictions and calculations of potential treatment benefits. The validated algorithmAlgorithm
In mathematics and computer science, an algorithm is an effective method expressed as a finite list of well-defined instructions for calculating a function. Algorithms are used for calculation, data processing, and automated reasoning...
s can present visually appealing graphics that assist in treatment decisions.
Adjuvant! is based on US cohorts
Cohort study
A cohort study or panel study is a form of longitudinal study used in medicine, social science, actuarial science, and ecology. It is an analysis of risk factors and follows a group of people who do not have the disease, and uses correlations to determine the absolute risk of subject contraction...
and presents colored bar charts that display information that may assist in decisions regarding systemic
Systemic
Systemic refers to something that is spread throughout, system-wide, affecting a group or system such as a body, economy, market or society as a whole. Systemic may also refer to:-In medicine:...
adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
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 many immunohistochemicalImmunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
tests that may further stratify prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
, BCL2 has shown promise in preliminary studies.
Van Nuys prognostic index
The USC/Van Nuys prognostic index (VNPI) is widely used to classify ductal carcinoma in situ (DCIS) into dissimilar risk categories that may be treated accordingly.Comorbidity assessments
The choice of which treatment to receive can be substantially influenced by comorbidityComorbidity
In medicine, comorbidity is either the presence of one or more disorders in addition to a primary disease or disorder, or the effect of such additional disorders or diseases.- In medicine :...
assessments.
Familial breast cancers
There is some evidence that breast cancers that arise in familial clusterCluster
-In science:* Cluster , a small group of atoms or molecules* Cluster chemistry, an array of bound atoms intermediate in character between a molecule and a solid...
s, such as
Hereditary breast—ovarian cancer syndrome, may have a dissimilar prognosis. Also potentially dissimilar treatment.