View source for Breast cancer classification

{{Short description|Medical classification system}}
{{Use dmy dates|date=August 2022}}
Breast cancer classification divides [[breast cancer]] into categories according to different schemes criteria and serving a different purpose. The major categories are the [[histopathology|histopathological]] type, the [[#Grade|grade]] of the tumor, the [[#Stage|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 purpose of classification is to select the best treatment. The effectiveness of a specific treatment is demonstrated for a specific breast cancer (usually by randomized, controlled trials). That treatment may not be effective in a different breast cancer. Some breast cancers are aggressive and life-threatening, and must be treated with aggressive treatments that have major adverse effects. Other breast cancers are less aggressive and can be treated with less aggressive treatments, such as lumpectomy.

Treatment [[algorithm]]s rely on breast cancer classification to define specific subgroups that are each treated according to [[Evidence-based medicine|the best evidence available]]. Classification aspects must be carefully tested and validated, such that [[confounding|confounding effects]] are minimized, making them either true [[prognosis|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 likelihood of response or lack of response to a specific treatment.<ref name="pmid17993229">{{cite book |vauthors=Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN |chapter=Overview of Resistance to Systemic Therapy in Patients with Breast Cancer |title=Breast Cancer Chemosensitivity |editor1-link=Dihua Yu |editor2-link=Mien-Chie Hung |veditors=Yu D, Hung MC |year=2007 |pmid=17993229 |doi=10.1007/978-0-387-74039-3_1 |chapter-url=https://archive.org/details/breastcancerchem00dihu/page/n18 |series=Advances in Experimental Medicine and Biology |volume=608 |pages=1–22 |isbn=978-0-387-74037-9 |chapter-url-access=registration }}</ref>

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 [[inflammation|inflamed]] appearance of the affected breast, which correlates with increased cancer aggressivity.<ref>{{cite journal |vauthors=Giordano SH, Hortobagyi GN |title=Inflammatory breast cancer: Clinical progress and the main problems that must be addressed |journal=Breast Cancer Res. |volume=5 |issue=6 |pages=284–8 |year=2003 |pmid=14580242 |pmc=314400 |doi=10.1186/bcr608 |doi-access=free }}</ref>

== Schemes or aspects ==

=== Overview ===
Breast cancers can be classified by different schemata. Each of these aspects influences treatment response and prognosis. Description of a breast cancer would optimally include all of these classification aspects, as well as other findings, such as signs found on [[physical exam]]. A full classification includes [[#Histopathology|histopathological type]], [[#Grade|grade]], [[#Stage|stage]] [[#TNM system|(TNM)]], [[#Receptor status|receptor status]], and the presence or absence of genes as determined by [[#DNA classification|DNA testing]]:
* Histopathology. Although breast cancer has many different [[Histopathology|histologies]], 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.<ref>[http://www.merck.com/mmpe/sec18/ch253/ch253e.html Merck Manual, Professional Edition] {{Webarchive|url=https://web.archive.org/web/20100701133007/http://www.merck.com/mmpe/sec18/ch253/ch253e.html |date=1 July 2010 }}, Ch. 253, Breast Cancer.</ref> 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. [[#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 [[Cancer staging|staging]] [[#Staging|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 situ (LCIS).
** Stages 1–3 are within the breast or regional lymph nodes.
** Stage 4 is a [[metastasis|metastatic cancer]]. [[Metastatic breast cancer]] has a less favorable prognosis.
* Receptor status. Cells have [[receptor (biochemistry)|receptors]] on their surface and in their [[cytoplasm]] and [[Cell nucleus|nucleus]]. Chemical messengers such as [[hormone]]s bind to receptors, and this causes changes in the cell. Breast cancer cells may or may not have many different types of receptors, the three most important in the present classification being: [[estrogen receptor]] (ER), [[progesterone receptor]] (PR), and [[HER2/neu]]. Cells with or without these receptors are called ER positive (ER+), ER negative (ER-), PR positive (PR+), PR negative (PR-), HER2 positive (HER2+), and HER2 negative (HER2-). Cells with none of these receptors are called basal-like or [[triple negative breast cancer|triple negative]]. HER2-low has some HER2 proteins on the cell surface, but not enough to be classified as HER2-positive.<ref name="FDA 20220805" /> [[Trastuzumab deruxtecan]] is the first approved therapy by the US [[Food and Drug Administration]] (FDA) targeted to people with the HER2-low breast cancer subtype.<ref name="FDA 20220805">{{cite press release | title=FDA Approves First Targeted Therapy for HER2-Low Breast Cancer | website=U.S. [[Food and Drug Administration]] (FDA) | date=5 August 2022 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-her2-low-breast-cancer | access-date=5 August 2022 | archive-date=6 August 2022 | archive-url=https://web.archive.org/web/20220806001339/https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-her2-low-breast-cancer | url-status=dead }} {{PD-notice}}</ref>
* DNA-based classification. Understanding the specific details of a particular breast cancer may include looking at the cancer cell [[DNA]] or [[RNA]] by several different laboratory approaches. When specific DNA mutations or gene expression profiles are identified in the cancer cells this may guide the selection of treatments, either by targeting these changes, or by predicting from these alterations which non-targeted therapies are most effective.
* Other classification approaches.
** Computer models such as Adjuvant can combine the various classification aspects according to validated [[algorithm]]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 [[comorbidity]] assessments.
** Familial breast cancers may potentially undergo dissimilar treatment (such as [[mastectomy]]).

== Histopathology ==
[[File:Pie chart of incidence and prognosis of histopathologic breast cancer types.png|thumb|310px|Histopathologic types of breast cancer, with relative incidences and prognoses.<ref name=IncidenceMalignancy> References for pie chart is located at [[Commons:File:Pie_chart_of_incidence_and_prognosis_of_histopathologic_breast_cancer_types.png#References|Image description page in commons]]</ref>]]
[[File:Lobules and ducts of the breast.jpg|thumb|140px|[[Lactiferous duct|Ducts]] and lobules, the locations of ductal and lobular carcinoma, respectively.]]
Histopathologic classification is based upon characteristics seen upon [[Optical microscope|light microscopy]] of biopsy specimens. They can broadly be classified into:
* Carcinoma ''[[in situ]]''. This group constitutes about 15-30% of [[breast biopsy|breast biopsies]], more so in countries with high coverage of [[breast screening]] programs.<ref name=robbins2010>[https://books.google.com/books?id=mwD5Y0jMUZAC&pg=PA1084 Page 1084] {{Webarchive|url=https://web.archive.org/web/20220806001338/https://books.google.se/books?id=mwD5Y0jMUZAC&pg=PA1084 |date=6 August 2022 }} in: {{cite book | last=Robbins | first=Stanley | title=Robbins and Cotran pathologic basis of disease | publisher=Saunders/Elsevier | location=Philadelphia, PA | year=2010 | isbn=978-1-4377-2182-9 | oclc=489074868 }}</ref> These have favorable prognosis, with [[5-year survival]] rates of 97-99%.<ref>Ductal carcinoma in situ: 99% - {{cite journal|last1=Kerlikowske|first1=K|title=Epidemiology of ductal carcinoma in situ.|journal=Journal of the National Cancer Institute. Monographs|date=2010|volume=2010|issue=41|pages=139–41|pmid=20956818|doi=10.1093/jncimonographs/lgq027|pmc=5161058}}<br />Lobular carcinoma in situ: 97% - {{cite journal|last1=Xie|first1=Ze-Ming|last2=Sun|first2=Jian|last3=Hu|first3=Zhe-Yu|last4=Wu|first4=Yao-Pan|last5=Liu|first5=Peng|last6=Tang|first6=Jun|last7=Xiao|first7=Xiang-Sheng|last8=Wei|first8=Wei-Dong|last9=Wang|first9=Xi|last10=Xie|first10=Xiao-Ming|last11=Yang|first11=Ming-Tian|title=Survival outcomes of patients with lobular carcinoma in situ who underwent bilateral mastectomy or partial mastectomy|journal=European Journal of Cancer|volume=82|year=2017|pages=6–15|issn=0959-8049|doi=10.1016/j.ejca.2017.05.030|pmid=28646773}}</ref>
* Invasive carcinoma. This group constitutes the other 70-85%.<ref name=robbins2010/> The most common type in this group is [[invasive ductal carcinoma]], representing about 80% of invasive carcinomas.<ref name=robbins2010/> In the US, 55% of breast cancers are invasive ductal carcinoma.<ref name=USA-2004>Percentage values are from United States statistics 2004. Subtype specific incidences are taken from [http://cebp.aacrjournals.org/content/18/6/1763/T6.expansion.html Table 6] {{webarchive|url=https://archive.today/20130223233954/http://cebp.aacrjournals.org/content/18/6/1763/T6.expansion.html |date=23 February 2013 }} (invasive) and [http://cebp.aacrjournals.org/content/18/6/1763/T3.expansion.html Table 3] {{webarchive|url=https://archive.today/20130223054758/http://cebp.aacrjournals.org/content/18/6/1763/T3.expansion.html |date=23 February 2013 }} (in situ) from {{cite journal |vauthors=Eheman CR, Shaw KM, Ryerson AB, Miller JW, Ajani UA, White MC |title=The changing incidence of in situ and invasive ductal and lobular breast carcinomas: United States, 1999–2004 |journal=Cancer Epidemiol. Biomarkers Prev. |volume=18 |issue=6 |pages=1763–9 |date=June 2009 |pmid=19454615 |doi=10.1158/1055-9965.EPI-08-1082 |doi-access=free }}. These are divided by total breast cancer incidence (211,300 invasive and 55,700 in situ cases) as reported from Breast Cancer Facts & Figures 2003–2004 {{cite web |url=http://www.cancer.org/docroot/stt/content/stt_1x_breast_cancer_facts__figures_2003-2004.asp |title=ACS :: Breast Cancer Facts & Figures 2003-2004 |access-date=15 June 2010 |url-status=dead |archive-url=https://web.archive.org/web/20090415173047/http://www.cancer.org/docroot/STT/content/STT_1x_Breast_Cancer_Facts__Figures_2003-2004.asp |archive-date=15 April 2009 }}</ref> [[Invasive lobular carcinoma]] represent about 10% of invasive carcinomas,<ref name=robbins2010/> and 5% of all breast cancers in the US.<ref name=USA-2004/> The overall [[5-year survival]] rate for both invasive ductal carcinoma and invasive lobular carcinoma was approximately 85% in 2003.<ref>''NOTE: Number really refers to invasive ductal carcinoma, despite title.'' {{cite journal |vauthors=Arpino G, Bardou VJ, Clark GM, Elledge RM |title=Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome |journal=Breast Cancer Res. |volume=6 |issue=3 |pages=R149–56 |year=2004 |pmid=15084238 |pmc=400666 |doi=10.1186/bcr767 |doi-access=free }}</ref> 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.<ref>{{Cite journal |last1=Evans |first1=A. |year=2004 |title=Ductal carcinoma in situ (DCIS): are we overdetecting it? |journal=Breast Cancer Research |volume=6 |issue=Suppl 1 |pages=23 |doi=10.1186/bcr842 |pmc=3300383 |doi-access=free}} [http://breast-cancer-research.com/content/6/S1/P23] {{Webarchive|url=https://web.archive.org/web/20110708092828/http://breast-cancer-research.com/content/6/S1/P23|date=8 July 2011}}</ref>

=== WHO classification ===
The 2012 [[World Health Organization]] (WHO) classification of tumors of the breast<ref>{{cite book|title=World Health Organization: Tumours of the Breast and Female Genital Organs |publisher=Oxford University Press |location=Oxford [Oxfordshire] |year=2003 |isbn=978-92-832-2412-9 }}</ref> which includes benign (generally harmless) tumors and malignant (cancerous) tumors, recommends the following pathological types:

{{col-begin}}
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Invasive breast carcinomas
* [[Invasive carcinoma]]
** Most are "not otherwise specified"
** The remainder are given subtypes:
***
*** [[Pleomorphism (cytology)|Pleomorphic]] carcinoma
*** Carcinoma with [[osteoclast]] giant cells
*** Carcinoma with [[choriocarcinoma]] features
*** Carcinoma with melanotic features
* [[Invasive lobular carcinoma]]
Classic
Solid
Mixed
Alveolar
Tubulolobular
Pleomorphic

* [[Tubular carcinoma]]
* [[Invasive cribriform carcinoma of the breast]] (also termed invasive cribriform carcinoma)
* [[Medullary carcinoma of the breast]]
* Mucinous carcinoma and other tumours with abundant [[mucin]]
** [[Mucinous carcinoma of the breast]]
** [[Cystadenocarcinoma]] and [[columnar]] cell [[mucinous carcinoma]]
** [[Signet ring cell carcinoma]]
* [[Neuroendocrine]] tumours
** Solid [[neuroendocrine tumor|neuroendocrine]] carcinoma ([[carcinoid]] of the breast)
** Atypical [[carcinoid]] tumor
** Small cell / [[oat cell carcinoma]]
** Large cell [[neuroendocrine tumor|neuroendocrine carcinoma]]
* [[Papillary carcinomas of the breast#Invasive papillary carcinoma|Invasive papillary carcinoma]]
* Invasive micropapillary carcinoma
* [[Pure apocrine carcinoma of the breast]]
* Apocrine-like invasive carcinoma 
* [[Metaplasia|Metaplastic]] carcinomas
** Pure [[epithelial]] [[metaplasia|metaplastic]] carcinomas
*** [[Squamous cell carcinoma]]
*** [[Adenocarcinoma]] with spindle cell [[metaplasia]]
*** [[Adenosquamous carcinoma]]
*** [[Mucoepidermoid carcinoma]]
** Mixed [[epithelial]]/[[mesenchymal]] [[metaplasia|metaplastic]] carcinomas
(Other well-accepted subtypes of metaplastic mammary carcinoma thought to have clinical significance but not included in the decade old WHO classification:
** Matrix-producing carcinoma
** Spindle cell carcinoma
** Carcinosarcoma
** Squamous cell carcinoma of mammary origin
** Metaplastic carcinoma with osteoclastic giant cells)
* [[Lipid]]-rich carcinoma
* [[Secretory carcinoma]]
* [[Oncocytic carcinoma]]
* [[Adenoid cystic carcinoma]]
* [[Acinic cell carcinoma]]
* [[Glycogen]]-rich clear cell carcinoma
* [[Sebaceous carcinoma]]
* [[Inflammatory breast cancer|Inflammatory carcinoma]]
* Bilateral breast carcinoma

Mesenchymal tumors (including [[sarcoma]])
* [[Hemangioma]]
* [[Angiomatosis]]
* [[Hemangiopericytoma]]
* [[Pseudoangiomatous stromal hyperplasia]]
* [[Mammary myofibroblastoma|Myofibroblastoma]]
* [[Fibromatosis]] (aggressive)
* [[Inflammatory myofibroblastic tumor]]
* [[Lipoma]]
** [[Angiolipoma]]
* [[Granular cell tumour]]
* [[Neurofibroma]]
* [[Schwannoma]]
* [[Angiosarcoma]]
* [[Liposarcoma]]
* [[Rhabdomyosarcoma]]
* [[Osteosarcoma]]
* [[Leiomyoma]]
* [[Leiomyosarcoma]]

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Tumors of the male breast
* [[Gynecomastia]] (benign)
* [[Carcinoma]] (See [[Male breast cancer]] section on types of breast cancer)
** [[In situ]]
** [[Invasive (cancer)|Invasive]]

Malignant lymphoma
* [[Non-Hodgkin lymphoma]]

Metastatic tumors to the breast from other places in the body

Precursor lesions
* Lobular neoplasia
** [[lobular carcinoma in situ]]
* Intraductal proliferative lesions
** Usual ductal [[hyperplasia]]
** Flat epithelial hyperplasia
** [[Atypical ductal hyperplasia]]
** [[Ductal carcinoma in situ]]
** [[Pure apocrine carcinoma of the breast#Apocrine ductal carcinoma in situ|Apocrine ductal carcinoma in situ]] 
* Microinvasive carcinoma
* [[Intraductal papilloma|Intraductal papillary neoplasms]]
** Central [[papilloma]]
** Peripheral papilloma
** Atypical papilloma
** Intraductal papillary carcinoma
** Intracystic papillary carcinoma

Benign epithelial lesions
* [[Adenosis]], including variants
** [[Sclerosis (medicine)|Sclerosing]] adenosis
** [[Apocrine]] [[adenosis]]
** Blunt duct [[adenosis]]
** Microglandular [[adenosis]]
** Adenomyoepithelial [[adenosis]]
* Radial scar / complex [[Sclerosis (medicine)|sclerosing]] lesion
* [[Adenoma]]s
** [[Tubular adenoma]]
** [[Lactating]] adenoma
** [[Apocrine]] adenoma
** [[Pleomorphic adenoma]]
** Ductal adenoma

Myoepithelial lesions
* Myoepitheliosis
* Adenomyoepithelial adenosis
* [[Adenomyoepithelioma of the breast|Adenomyoepithelioma]]
* Malignant myoepithelioma

Fibroepithelial tumours
* [[Fibroadenoma]]
* [[Phyllodes tumour]]
** [[Benign]]
** [[Borderline (cancer)|Borderline]]
** [[Malignant]]
* Periductal stromal [[sarcoma]], low-grade
* Mammary [[hamartoma]]

Benign tumors of the nipple
* [[Nipple adenoma]]
* [[Syringoma]]tous adenoma
* [[Paget's disease of the breast|Paget's disease]] of the nipple
Malignant tumors of the nipple
* [[Paget's disease of the breast|Paget's disease]] of the nipple

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{{anchor|Nottingham system}}

== Grade ==

The grading of a cancer in the breast depends on the microscopic similarity of breast cancer cells to normal breast tissue, and classifies the cancer as well differentiated (low-grade), moderately differentiated (intermediate-grade), and poorly differentiated (high-grade), reflecting progressively less normal appearing cells that have a worsening prognosis. Although grading is fundamentally based on how biopsied, cultured cells behave, in practice the grading of a given cancer is derived by assessing the cellular appearance of the tumor. The closer the appearance of the cancer cells to normal cells, the slower their growth and the better the prognosis. If cells are not well differentiated, they will appear immature, will divide more rapidly, and will tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale used).

The Nottingham system<ref>{{cite journal |last1= Elston |first1= CW |last2= Ellis |first2= IO |title= Pathologic prognostic factors in breast cancer. I. The value of histological grades in breast cancer. Experience from a large study with long-term follow-up |journal= Histopathology |year= 1991 |volume= 19 |issue= 5 |pages= 403–10 |pmid= 1757079 |doi=10.1111/j.1365-2559.1991.tb00229.x|s2cid= 17622089 }} {{cite journal |title= Republished |year= 2002 |doi= 10.1046/j.1365-2559.2002.14892.x | volume=41 |journal=Histopathology |pages=154–161|s2cid= 208083532 }}</ref> is recommended for breast cancer grading.<ref>{{cite web|title=What is the Nottingham combined histologic grade (modified Scarff-Bloom-Richardson grade) system for breast tumors?|url=https://www.medscape.com/answers/1668113-181367/what-is-the-nottingham-combined-histologic-grade-modified-scarff-bloom-richardson-grade-system-for-breast-tumors|author=Oudai Hassan|website=[[Medscape]]|access-date=2 October 2019|archive-date=30 November 2020|archive-url=https://web.archive.org/web/20201130023022/https://www.medscape.com/answers/1668113-181367/what-is-the-nottingham-combined-histologic-grade-modified-scarff-bloom-richardson-grade-system-for-breast-tumors|url-status=live}} Updated: 20 March 2019</ref> The Nottingham system is also called the Bloom–Richardson–Elston system (BRE),<ref>{{cite journal | vauthors = Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H, Spichtin H, Maurer R, Mirlacher M, Köchli O, Zuber M, Dieterich H, Mross F, Wilber K, Simon R, Sauter G | display-authors = 6 | title= Prognostic relevance of gene amplifications and coamplifications in breast cancer | journal=Cancer Research | volume=64 | issue=23 | date = December 2004 | pages= 8534–8540| doi= 10.1158/0008-5472.CAN-04-1945| pmid= 15574759| doi-access=free| author1-link= Khawla Al Khuraya }}</ref> or the Elston-Ellis modification<ref>{{cite journal | author = Elston CW, Ellis IO | title = Pathologic prognostic factors in breast cancer. I. The value of histological grades in breast cancer. Experience from a large study with long-term follow-up | journal = Histopathology | volume = 1991 | issue = 19| pages = 403–410 }}</ref> of the Scarff-Bloom-Richardson grading system.<ref name="BloomRichardson1957">{{Cite journal | last1 = Bloom | first1 = H.J. | last2 = Richardson | first2 = W.W. | title = Histological grading and prognosis in breast cancer; A study of 1409 cases of which 359 have been followed for 15 years | journal = British Journal of Cancer | volume = 11 | issue = 3 | pages = 359–77 | year = 1957 | pmid = 13499785 | pmc = 2073885 | doi=10.1038/bjc.1957.43}}</ref><ref name="Genestie1998">{{Cite journal | vauthors = Genestie C, Zafrani B, Asselain B, Fourquet A, Rozan S, Validire P, Vincent-Salomon A, Sastre-Garau X | display-authors = 6 | title = Comparison of the prognostic value of Scarff-Bloom-Richardson and Nottingham histological grades in a series of 825 cases of breast cancer: Major importance of the mitotic count as a component of both grading systems | journal = Anticancer Research | volume = 18 | issue = 1B | pages = 571–6 | year = 1998 | pmid = 9568179 }}</ref> It grades breast carcinomas by adding up scores for [[#Tubule formation|tubule formation]], [[#Nuclear pleomorphism|nuclear pleomorphism]], and [[#Mitotic count|mitotic count]], each of which is given 1 to 3 points. The scores for each of these three criteria are then added together to give an [[#Overall grade|overall final score and corresponding grade]]. It is not applicable to medullary carcinomas which are histologically high-grade by definition, while being clinically low-grade if lymph nodes are negative.<ref>{{cite web|url=http://surgpathcriteria.stanford.edu/breast/medcabr/grading.html|title=Medullary Carcinoma of the Breast|website=Stanford Medicine|access-date=31 December 2020|archive-date=8 September 2020|archive-url=https://web.archive.org/web/20200908111707/http://surgpathcriteria.stanford.edu/breast/medcabr/grading.html|url-status=live}}</ref> It is also not applicable to metaplastic carcinomas.<ref>{{cite web|url=http://surgpathcriteria.stanford.edu/breast/metacabr/grading.html|title=Metaplastic Carcinoma of the Breast|website=Stanford Medicine|access-date=31 December 2020|archive-date=8 September 2020|archive-url=https://web.archive.org/web/20200908112435/http://surgpathcriteria.stanford.edu/breast/metacabr/grading.html|url-status=live}}</ref>

The grading criteria are as follows:

=== Tubule formation ===
[[File:Tubule formation score in the Nottingham system.jpg|thumb|300px|Tubule formation score in the Nottingham system]]
This [[parameter]] 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.<ref name="PujaniSharma2014">{{cite journal|last1=Pujani|first1=Mukta|last2=Sharma|first2=KiranLata|last3=Srivastava|first3=AN|last4=Singh|first4=US|last5=Bansal|first5=Cherry|title=Grading systems in the cytological diagnosis of breast cancer: A review|journal=Journal of Cancer Research and Therapeutics|volume=10|issue=4|year=2014|pages=839–845|issn=0973-1482|doi=10.4103/0973-1482.140979|pmid=25579516|doi-access=free}}</ref>
* 1 point: tubular formation in more than 75% of the tumor (it may in addition be termed "majority of tumor")
* 2 points: tubular formation in 10 to 75% of the tumor ("moderate")
* 3 points: tubular formation in less than 10% of the tumor ("little or none")

=== Nuclear pleomorphism ===
This [[parameter]] assesses whether the [[cell nucleus|cell nuclei]] are uniform like those in normal breast duct epithelial cells, or whether they are larger, darker, or irregular ([[pleomorphism (cytology)|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 [[Atypia|cellular abnormalities]] should be evaluated.
* 1 point: nuclei with minimal or mild variation in size and shape
* 2 points: nuclei with moderate variation in size and shape
* 3 points: nuclei with marked variation in size and shape
<gallery mode="packed" heights="180">
File:Micrograph of ductal carcinoma with mild nuclear pleomorphism.jpg|Ductal carcinoma with mild nuclear pleomorphism.
File:Micrograph of invasive ductal carcinoma of tubular type with moderate nuclear pleomorphism (crop).jpg|Invasive ductal carcinoma with moderate nuclear pleomorphism.
File:Histopathology of invasive lobular carcinoma with moderate nuclear pleomorphism.jpg|Invasive lobular carcinoma with moderate nuclear pleomorphism.
File:Micrograph of invasive ductal carcinoma with marked nuclear pleomorphism.jpg|Invasive ductal carcinoma with marked nuclear pleomorphism.
</gallery>

=== Mitotic count ===
[[File:Mitosis appearances in breast cancer.jpg|thumb|Mitosis appearances in breast cancer]]
This [[parameter]] assesses how many [[mitotic]] figures (dividing cells) the pathologist sees in 10x high power microscope field. One of the hallmarks of cancer is that cells divide uncontrollably. The more cells that are dividing, the worse the cancer.

Note: Mitotic figures are counted only at the periphery of the tumor, and counting should begin in the most mitotically active areas.

{|class="wikitable"
|+ Mitotic count per 10 [[high-power field]]s (HPFs)<ref>{{cite web|url=http://surgpathcriteria.stanford.edu/breast/infductcabr/grading.html|title=Infiltrating Ductal Carcinoma of the Breast (Carcinoma of No Special Type)|website=[[Stanford University School of Medicine]]|access-date=2 October 2019|archive-date=11 September 2019|archive-url=https://web.archive.org/web/20190911054536/http://surgpathcriteria.stanford.edu/breast/infductcabr/grading.html|url-status=live}}</ref>
!colspan=5| Area per HPF !!rowspan=2| Score
|-
! 0.096&nbsp;mm<sup>2</sup><ref name=HPF group=notes>Area per [[high-power field]] for some microscope types:
* Olympus BX50, BX40 or BH2 or AO or Nikon with 15x eyepiece: 0.096 mm<sup>2</sup>
* AO with 10x eyepiece: 0.12 mm<sup>2</sup>
* Nikon or Olympus with 10x eyepiece: 0.16 mm<sup>2</sup>
* Leitz Ortholux: 0.27 mm<sup>2</sup>
* Leitz Diaplan: 0.31 mm<sup>2</sup><br />- {{cite web|url=http://surgpathcriteria.stanford.edu/breast/infductcabr/grading.html|title=Infiltrating Ductal Carcinoma of the Breast (Carcinoma of No Special Type)|website=[[Stanford University School of Medicine]]|access-date=2 October 2019|archive-date=11 September 2019|archive-url=https://web.archive.org/web/20190911054536/http://surgpathcriteria.stanford.edu/breast/infductcabr/grading.html|url-status=live}}</ref> !! 0.12&nbsp;mm<sup>2</sup><ref name=HPF group=notes/> !! 0.16&nbsp;mm<sup>2</sup><ref name=HPF group=notes/> !! 0.27&nbsp;mm<sup>2</sup><ref name=HPF group=notes/> !! 0.31&nbsp;mm<sup>2</sup><ref name=HPF group=notes/>
|-
| 0-3 || 0-4 || 0-5 || 0-9 || 0-11 || 1
|-
| 4-7 || 5-8 || 6-10 || 10-19 || 12-22 || 2
|-
| >7 || >8 || >10 || >19 || >22 || 3
|}

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

[[cancer staging|Staging]]<ref name="whatis20100505">What is Cancer Staging? American Joint Committee on Cancer 2010 May 5.http://www.cancerstaging.org/mission/whatis.html {{Webarchive|url=https://web.archive.org/web/20130827005207/http://cancerstaging.org/mission/whatis.html |date=27 August 2013 }}</ref> 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.<ref name="whatis20100505" /> 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.<ref name="NCI-stage">National Cancer Institute. Stage Information for Breast Cancer.http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page3 {{Webarchive|url=https://web.archive.org/web/20110608001256/http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page3 |date=8 June 2011 }}</ref>

Staging information that is obtained prior to surgery, for example by mammography, x-rays and CT scans, is called clinical staging and staging by surgery is known as pathological staging.

Pathologic staging is more accurate than clinical staging, but clinical staging is the first and sometimes the only staging type. For example, if clinical staging reveals stage IV disease, extensive surgery may not be helpful, and (appropriately) incomplete pathological staging information will be obtained.

The [[American Joint Committee on Cancer]] (AJCC) and the [[International Union Against Cancer]] (UICC) recommend [[TNM staging system|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.

===Primary Tumor (T)===
Tumor&nbsp;– The [[tumor]] values (TX, T0, Tis, T1, T2, T3 or T4) depend on the cancer at the primary site of origin in the breast, as follows:<ref name=Alkabban2019>Originally copied from {{cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK482286/|title=Cancer, Breast|author=Fadi M. Alkabban|author2=Troy Ferguson|chapter=Breast Cancer|via=[[National Center for Biotechnology Information]]|year=2021|publisher=StatPearls|pmid=29493913 |access-date=4 October 2019|archive-date=24 December 2020|archive-url=https://web.archive.org/web/20201224165512/https://www.ncbi.nlm.nih.gov/books/NBK482286/|url-status=live}} Last Update: 4 June 2019. [http://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License] {{Webarchive|url=https://web.archive.org/web/20151121114042/http://creativecommons.org/licenses/by/4.0/ |date=21 November 2015 }}</ref>

* TX: inability to assess that site
* Tis: [[ductal carcinoma in situ]] (DCIS), [[lobular carcinoma in situ]] (LCIS) or [[Paget's disease of the breast|Paget's disease]]
* T1: Less than 2&nbsp;cm
:* T1a: 0.1 to 0.5 cm
:* T1b: 0.5 to 1.0 cm
:* T1c: 1.0 to 2.0 cm
* T2: 2 to 5&nbsp;cm
* T3: Larger than 5&nbsp;cm
* T4
:* T4a: Chest wall involvement
:* T4b: Skin involvement
:* T4c: Both 4a and 4b
:* T4d: [[Inflammatory breast cancer]], a clinical circumstance where typical skin changes involve at least a third of the breast.

===Regional Lymph Nodes (N)===
Lymph Node&nbsp;– 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 ([[axilla|axillary lymph nodes]]), the collar area ([[supraclavicular fossa|supraclavicular lymph nodes]]), and inside the chest (internal mammary lymph nodes.)<ref name="pmid3347753">{{cite journal |vauthors=Scatarige JC, Fishman EK, Zinreich ES, Brem RF, Almaraz R |title=Internal mammary lymphadenopathy in breast carcinoma: CT appraisal of anatomic distribution |journal=Radiology |volume=167 |issue=1 |pages=89–91 |date=April 1988 |pmid=3347753 |doi= 10.1148/radiology.167.1.3347753}}</ref><ref name="pmid2217975">{{cite journal |vauthors=Scatarige JC, Boxen I, Smathers RL |title=Internal mammary lymphadenopathy: imaging of a vital lymphatic pathway in breast cancer |journal=Radiographics |volume=10 |issue=5 |pages=857–70 |date=September 1990 |pmid=2217975 |doi= 10.1148/radiographics.10.5.2217975|doi-access=free }} available as full text article with multiple images at http://radiographics.rsna.org/content/10/5/857.full.pdf</ref> 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 ([[wikt:apex|apical]]) axilla which is above the pectoralis minor muscle. Each stage is as follows:<ref name=Alkabban2019/>
* N0: There is some nuance to the official definitions for N0 disease, which includes:
:* N0(i+) : Isolated Tumor Cell clusters (ITC), which are small clusters of cells not greater than 0.2&nbsp;mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section, whether detected by [[H&E stain|routine histology]] or [[immunohistochemistry]].<ref name=medscape>{{cite journal|url=https://emedicine.medscape.com/article/2007112-overview|title=Breast Cancer Staging|website=medscape|author=Joseph A Sparano, MD|date=6 October 2021|access-date=21 August 2020|archive-date=13 September 2020|archive-url=https://web.archive.org/web/20200913010841/https://emedicine.medscape.com/article/2007112-overview|url-status=live}} Updated: 8 June 2019</ref>
:* N0(mol-): regional lymph nodes have no metastases histologically, but have positive molecular findings ([[RT-PCR]]).<ref name=medscape/>
* N1: Metastases in 1-3 axillary lymph nodes and/or in internal mammary nodes; and/or in clinically negative internal mammary nodes with [[micrometastasis]], or macrometastasis on sentinel lymph node biopsy.<ref name=medscape/>
:* N1mi: Micrometastasis, that is, lymph node clusters at least 2 mm or 200 cells, but less than 2.0 mm.<ref name=medscape/> At least one carcinoma focus over 2.0 mm is called "Lymph node metastasis". If one node qualifies as metastasis, all other nodes even with smaller foci are counted as metastases as well.
* N2: Fixed/matted ipsilateral axillary nodes.
* N3
:* N3a – Ipsilateral infraclavicular nodes
:* N3b – Ipsilateral internal mammary nodes
:* N3c – Ipsilateral supraclavicular nodes

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

===Overall stage===
A combination of T, N and M, as follows:<ref name=Alkabban2019/>
* Stage 0: Tis
* Stage I: T1N0
* Stage II: T2N0, T3N0 T0N1, T1N1, or T2N1
* Stage III: Invasion into skin and/or ribs, matted lymph nodes, T3N1, T0N2, T1N2, T2N2, T3N2, AnyT N3, T4 any N, locally advanced breast cancer
* Stage IV: M1, advanced breast cancer

{|class="wikitable floatright"
|+ Breast&nbsp;cancer prognosis&nbsp;by&nbsp;stage<ref name="pmid36387150">Data from: {{cite journal| author1=Mangone L | author2=Marinelli F | author3=Bisceglia I | author4=Braghiroli MB | author5=Damato A | author6=Pinto C| title=Five-year relative survival by stage of breast and colon cancers in northern Italy. | journal=Front Oncol | year= 2022 | volume= 12 | issue=  | pages= 982461 | pmid=36387150 | doi=10.3389/fonc.2022.982461 | pmc=9659859 | doi-access=free }} </ref>
! Stage !! 5-year<br>survival
|-
! Stage 0
| 100%
|-
! Stage I
| 100%
|-
! Stage II
| 90%
|-
! Stage III
| 70%
|-
! Stage IV
| 30%
|}

==== Staging and prognosis ====
The impact of different stages on outcome can be appreciated in the following table, taken from patient data in the 2013-2015 period, and using the [[TNM staging system|AJCC 8th edition]] for staging.<ref name="pmid36387150"/> It does not show the influence of important additional factors such as [[estrogen receptor]] (ER) or [[HER2/neu]] receptor status, and does not reflect the impact of newer treatments.

==== Previous editions ====
Although TNM classification is an internationally agreed system, it has gradually evolved through its different editions; the dates of publication and of adoption for use of AJCC editions is summarized in the table in this article; past editions are available from AJCC for web download.<ref name="pastEd">American Joint Committee on Cancer. Past Editions of the AJCC Cancer Staging Manual available at {{cite web |url=http://www.cancerstaging.org/products/pasteditions.html |title=American Joint Committee on Cancer: Publications & Electronic Products: Past Editions of the AJCC Cancer Staging Manual |access-date=3 January 2011 |url-status=dead |archive-url=https://web.archive.org/web/20110106025146/http://www.cancerstaging.org/products/pasteditions.html |archive-date=6 January 2011 }}</ref>

Several factors are important when reviewing reports for individual breast cancers or when reading the medical literature, and applying staging data.

{|class="wikitable floatright" style="text-align:center;font-size:90%;width:56%;margin-left:1em"
|-
! AJCC edition !! published<ref name="pastEd" /> !! went into effect<ref name="pastEd" /> !! Breast cancer <br />link(s) and page numbers <br />in the original
|-
! 7
| 2009
| 2010
| AJCC<ref name="AJCC7-BR" /> or NCI<ref name="NCI-stage" />
|-
! 6
| 2002
| 2003
| AJCC;<ref name="AJCC6-BR">AJCC Cancer Staging Manual 6th edition; Chapter 25; Breast Cancer&nbsp;– original pages 223-240 http://www.cancerstaging.org/products/csmanual6ed-4.pdf {{Webarchive|url=https://web.archive.org/web/20110928053645/http://www.cancerstaging.org/products/csmanual6ed-4.pdf |date=28 September 2011 }}</ref> original pages 223-240
|-
! 5
| 1997
| 1998
| AJCC;<ref name="AJCC5-BR">AJCC Cancer Staging Manual 5th edition; Chapter 25; Breast Cancer&nbsp;– original pages 171-180 http://www.cancerstaging.org/products/csmanual5ed_4.pdf {{Webarchive|url=https://web.archive.org/web/20110928054414/http://www.cancerstaging.org/products/csmanual5ed_4.pdf |date=28 September 2011 }}</ref> original pages 171-180
|-
! 4
| 1992
| 1993
| AJCC;<ref name="AJCC4-BR">AJCC Cancer Staging Manual 4th edition; Chapter 25; Breast Cancer&nbsp;– original pages 149-154 http://www.cancerstaging.org/products/csmanual4ed_2.pdf {{Webarchive|url=https://web.archive.org/web/20110928054641/http://www.cancerstaging.org/products/csmanual4ed_2.pdf |date=28 September 2011 }}</ref> original pages 149-154
|-
! 3
| 1988
| 1989
| AJCC;<ref name="AJCC3-BR">AJCC Cancer Staging Manual 3rd edition; 1988; Chapter 23; Breast Cancer-original pages 145-150 http://www.cancerstaging.org/products/csmanual3ed_2.pdf {{Webarchive|url=https://web.archive.org/web/20110928054856/http://www.cancerstaging.org/products/csmanual3ed_2.pdf |date=28 September 2011 }}</ref> original pages 145-150
|-
! 2
| 1983
| 1984
| AJCC;<ref name="AJCC2-BR">AJCC Cancer Staging Manual 2nd edition; 1983; Chapter 21; Breast Cancer-original pages 127-134 http://www.cancerstaging.org/products/csmanual2ed.pdf {{Webarchive|url=https://web.archive.org/web/20110928054155/http://www.cancerstaging.org/products/csmanual2ed.pdf |date=28 September 2011 }}</ref> original pages 127-134
|-
! 1
| 1977
| 1978
| AJCC;<ref name="AJCC1-BR">AJCC Cancer Staging Manual 1977; Chapter 12; Breast Cancer-original pages 101-108 http://www.cancerstaging.org/products/csmanual1ed.pdf {{Webarchive|url=https://web.archive.org/web/20110928053853/http://www.cancerstaging.org/products/csmanual1ed.pdf |date=28 September 2011 }}</ref> 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 [[Union for International Cancer Control|UICC]] have released.<ref name="pastEd" /> 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 [[Cancer staging|
"stage migration"]].<ref name="pmid4000199">{{Cite journal | last1 = Feinstein | first1 = A. R. | last2 = Sosin | first2 = D. M. | last3 = Wells | first3 = C. K. | doi = 10.1056/NEJM198506203122504 | title = The Will Rogers Phenomenon | journal = New England Journal of Medicine | volume = 312 | issue = 25 | pages = 1604–1608 | year = 1985 | pmid = 4000199}}</ref> For example, differences in the 1998 and 2003 categories resulted in many cancers being assigned differently, with apparent improvement in survival rates.<ref name="pmid12947058">{{Cite journal | vauthors = Woodward WA, Strom EA, Tucker SL, McNeese MD, Perkins GH, Schechter NR, Singletary SE, Theriault RL, Hortobagyi GN, Hunt KK, Buchholz TA | display-authors = 6 | title = Changes in the 2003 American Joint Committee on Cancer staging for breast cancer dramatically affect stage-specific survival | journal = Journal of Clinical Oncology | volume = 21 | issue = 17 | pages = 3244–3248 | date = September 2003 | pmid = 12947058 | doi = 10.1200/JCO.2003.03.052 }}</ref>

As a practical matter, reports often use the staging edition that was in place when the study began, rather than the date of acceptance or publication. However, it is worth checking whether the author updated the staging system during the study, or modified the usual classification rules for specific use in the investigation.

A different effect on staging arises from evolving technologies that are used to assign patients to particular categories, such that increasingly sensitive methods tend to cause individual cancers to be reassigned to higher stages, making it improper to compare that cancer's prognosis to the historical expectations for that stage.

Finally, of course, a further important consideration is the effect of improving treatments over time as well.

Previous editions featured three [[metastatic]] values (MX, M0 and M1) which referred respectively to absence of adequate information, the confirmed absence, or the presence of breast cancer cells in locations other than the breast and regional lymph nodes, such as to bone, brain, lung.

AJCC has provided web accessible poster versions of the current versions of these copyrighted TNM descriptors and groups,<ref name="AJCC7-BR">AJCC Cancer Staging Manual, 7th edition, updated Cancer Staging Posters.http://www.cancerstaging.org/staging/posters/breast8.5x11.pdf {{Webarchive|url=https://web.archive.org/web/20110626124046/http://www.cancerstaging.org/staging/posters/breast8.5x11.pdf |date=26 June 2011 }}</ref> and readers should refer to that up to date, accurate information<ref name="AJCC7-BR" /> or to the [[National Cancer Institute]] (NCI)<ref name="NCI-stage" /> or [[National Comprehensive Cancer Network]]<ref name="NCCN-Breast2011-2" /> sites which reprints these with AJCC permission.

For accurate, complete, current details refer to the accessible copyrighted documentation from AJCC,<ref name="AJCC7-BR" /> or to the authorized documentation from NCI<ref name="NCI-stage" /> or [[National Comprehensive Cancer Network|NCCN]];<ref name="NCCN-Breast2011-2" /> for past editions refer to AJCC.<ref name="pastEd" />

== Receptor status ==
The [[receptor (biochemistry)|receptor]] status of [[breast cancer]]s has traditionally been identified by [[immunohistochemistry]] (IHC), which stains the cells based on the presence of [[estrogen]] [[estrogen receptor|receptors]] (ER), [[progesterone receptor]]s (PR) and [[HER2]]. This remains the most common method of testing for receptor status, but DNA [[DNA microarray|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 [[#MammaPrint and BluePrint|following section]].

Receptor status is a critical assessment for all breast cancers as it determines the suitability of using [[Targeted therapy|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, [[HER2|HER+]] had a worse prognosis,<ref name="sotirou">{{cite journal | author = Sotirou Christos, Pusztai Lajos | title = Molecular origin of cancer: gene-expression signatures in breast cancer | url = http://content.nejm.org/cgi/content/full/360/8/790 | journal = The New England Journal of Medicine | year = 2009 | volume = 360 | issue = 8 | pages = 790–800 | doi = 10.1056/NEJMra0801289 | pmid = 19228622 | access-date = 16 June 2010 | archive-date = 5 January 2010 | archive-url = https://web.archive.org/web/20100105062336/http://content.nejm.org/cgi/content/full/360/8/790 | url-status = live | url-access = subscription }}</ref> 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.<ref>{{cite journal | vauthors = Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N | display-authors = 6 | date = October 2005 | title = Trastuzumab plus adjuvant chemotherapy for operable HER2+ breast cancer | pmid = 16236738 | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1673–1684 | doi= 10.1056/NEJMoa052122 | s2cid = 9534884 | doi-access = free }}</ref> Conversely, [[triple-negative breast cancer|triple negative cancer]] (i.e. no positive receptors), lacking targeted treatments, now has a comparatively poor [[prognosis]].<ref>{{cite journal | vauthors = Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA | display-authors = 6 | date = August 2007 |title= Triple-negative breast cancer: clinical features and patterns of recurrence |journal= Clinical Cancer Research |pmid= 17671126 |volume= 13 |issue= 15 Pt 1 |pages= 4429–4434 |doi= 10.1158/1078-0432.CCR-06-3045| doi-access= free | title-link = doi }}</ref><ref>{{cite web |url=http://www.cancernetwork.com/display/article/10165/1340727?pageNumber=1 |title=Understanding and Treating Triple-Negative Breast Cancer |publisher=Cancer Network |access-date=8 May 2010 |archive-date=9 June 2010 |archive-url=https://web.archive.org/web/20100609023341/http://www.cancernetwork.com/display/article/10165/1340727?pageNumber=1 |url-status=live }}</ref>

[[Androgen receptor]] is expressed in 80-90% of ER+ breast cancers and 40% of "triple negative" breast cancers. Activation of androgen receptors appears to suppress breast cancer growth in ER+ cancer while in ER- breast it appears to act as growth promoter. Efforts are underway to utilize this as prognostic marker and treatment.<ref name=Lehman_2011/><ref name=Hu_2011>{{Cite journal | vauthors = Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, Marotti JD, Hankinson SE, Colditz GA, Tamimi RM | display-authors = 6 | doi = 10.1158/1078-0432.CCR-10-2021 | title = Androgen receptor expression and breast cancer survival in postmenopausal women | journal = Clinical Cancer Research | volume = 17 | issue = 7 | pages = 1867–1874 | year = 2011 | pmid = 21325075 | pmc =3076683 }}</ref>

=== Molecular subtype ===
[[receptor (biochemistry)|Receptor]] status was traditionally considered by reviewing each individual receptor ([[Estrogen receptor|ER]], [[Progesterone receptor|PR]], [[HER2]]) in turn, but newer approaches look at these together, along with the [[tumor]] [[#Grade|grade]], to categorize [[breast cancer]] into several conceptual molecular classes<ref name="Prat2011">{{Cite journal | last1 = Prat | first1 = A. | last2 = Perou | first2 = C. M. | doi = 10.1016/j.molonc.2010.11.003 | title = Deconstructing the molecular portraits of breast cancer | journal = Molecular Oncology | volume = 5 | issue = 1 | pages = 5–23 | year = 2011 | pmid = 21147047 | pmc = 5528267}}</ref> that have different [[prognosis|prognoses]]<ref name="NCCN-Breast2011-2">{{cite web |title=National Comprehensive Cancer Network (NCCN) guidelines, Breast Cancer Version 2.2011 |url=http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf |access-date=3 July 2011 |archive-date=24 March 2009 |archive-url=https://web.archive.org/web/20090324025716/http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf |url-status=live }}</ref> and may have different responses to specific therapies.<ref name="Geyer2009">{{Cite journal | last1 = Geyer | first1 = F. C. | last2 = Marchiò | first2 = C. | last3 = Reis-Filho | first3 = J. S. | doi = 10.1080/00313020802563536 | title = The role of molecular analysis in breast cancer | journal = Pathology | volume = 41 | issue = 1 | pages = 77–88 | year = 2009 | pmid = 19089743 | s2cid = 39374813 }}</ref> [[DNA microarrays]] have assisted this approach, as discussed in the [[#DNA microarrays|following section]]. Proposed molecular subtypes include:
* Basal-like: ER-, PR- and HER2-; also called [[triple negative breast cancer]] (TNBC).<ref name="Perou2011">{{Cite journal | last1 = Perou | first1 = C. M. | title = Molecular Stratification of Triple-Negative Breast Cancers | journal = The Oncologist | volume = 16 | pages = 61–70 | year = 2011 | doi = 10.1634/theoncologist.2011-S1-61| pmid = 21278442 | doi-access = free }}</ref> Most [[BRCA1]] breast cancers are basal-like TNBC.
* Luminal A: ER+ and low grade
* Luminal B: ER+ but often high grade
* Luminal ER-/AR+: (overlapping with apocrine and so called molecular apocrine) - recently identified androgen responsive subtype which may respond to antihormonal treatment with [[bicalutamide]]<ref name=Lehman_2011>{{Cite journal | vauthors = Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA | display-authors = 6 | doi = 10.1172/JCI45014 | title = Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies | journal = Journal of Clinical Investigation | volume = 121 | issue = 7 | pages = 2750–2767 | date = July 2011 | pmid = 21633166 | pmc =3127435 }}</ref>
* ERBB2/HER2-amplified: has overexpressed [[HER2/neu]]<ref name="sotirou"/>
* Normal breast-like<ref name="NCCN-Breast2011-2" /><ref name="Prat2011" /><ref name="Ross2009">{{Cite journal | last1 = Ross | first1 = J. S. | title = Multigene Classifiers, Prognostic Factors, and Predictors of Breast Cancer Clinical Outcome | doi = 10.1097/PAP.0b013e3181a9d4bf | journal = Advances in Anatomic Pathology | volume = 16 | issue = 4 | pages = 204–215 | year = 2009 | pmid = 19546609 | s2cid = 37465636 | doi-access = free }}</ref>
* [[Claudin]]-low: a more recently described class; often triple-negative, but distinct in that there is low expression of [[Tight junction protein 1|cell-cell junction proteins]]<ref name="Perou2011" /> including [[E-cadherin]]<ref name="Perou2011" /> and frequently there is infiltration with [[lymphocyte]]s.<ref name="Prat2011" /><ref name="Herschkowitz2011">{{Cite journal | vauthors = Herschkowitz JI, Zhao W, Zhang M, Usary J, Murrow G, Edwards D, Knezevic J, Greene SB, Darr D, Troester MA, Hilsenbeck SG, Medina D, Perou CM, Rosen JM | display-authors = 6 | title = Breast Cancer Special Feature: Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells | doi = 10.1073/pnas.1018862108 | journal = Proceedings of the National Academy of Sciences | volume = 109 | issue = 8 | pages = 2778–2783 | date = February 2012 | pmid = 21633010| pmc = 3286979| doi-access = free | title-link = doi }}</ref><ref name="Harrell2011">{{Cite journal | vauthors = Harrell JC, Prat A, Parker JS, Fan C, He X, Carey L, Anders C, Ewend M, Perou CM | display-authors = 6 | title = Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse | doi = 10.1007/s10549-011-1619-7 | journal = Breast Cancer Research and Treatment | date = April 2012 | pmid = 21671017 | volume=132 | issue=2 | pmc=3303043 | pages=523–535 }}</ref>

{|class=wikitable
|+ Comparison of molecular subtypes of breast cancer.<ref name="TsangTse2020">{{cite journal|last1=Tsang|first1=Julia Y.S.|last2=Tse|first2=Gary M.|title=Molecular Classification of Breast Cancer|journal=Advances in Anatomic Pathology|volume=27|issue=1|year=2020|pages=27–35|issn=1072-4109|doi=10.1097/PAP.0000000000000232|pmid=31045583|s2cid=143423297}}</ref>
! !! Luminal A !! Luminal B !! ERBB2/HER2-amplified !! Basal-like
|-
! Overall gene expression
| High expression of:
* Luminal epithelial genes
* ER-related genes
| Compared to Luminal A, higher expression of:
* Proliferation-related genes
* HER2-related genes
Lower expression of:
* Luminal epithelial genes
* ER-related genes
|
* High expression of HER2-related genes
* Low expression of ER-related genes
| High expression of:
* Basal epithelial-related genes
* proliferation-related genes
Low expression of:
* HER2-related genes
* ER-related genes
|-
! [[Light microscopy]] types
|
* Tubular carcinoma
* Low grade invasive ductal carcinoma
* Classic invasive lobular carcinoma
|
* Invasive ductal carcinoma
* Micropapillary carcinoma
* Pleomorphic invasive lobular carcinoma
|
* High grade invasive ductal carcinoma
* Pleomorphic invasive lobular carcinoma
|
* High grade invasive ductal carcinoma
* Metaplastic carcinoma
* [[Medullary carcinoma of the breast|Medullary carcinoma]]
* Adenoid cystic carcinoma
|-
! [[Immunohistochemistry]]
|
* Estrogen receptor positive
* Progesterone receptor positive in at least 20% of cases
* HER2 negative
* Low Ki-67
|
* Estrogen receptor positive
* Progesterone receptor positive in less than 20% of cases
* HER2 positive or high Ki-67
|
* HER2 positive
* Estrogen and progesterone receptor negative
|
* HER2, estrogen and progesterone receptor negative
|-
! Gene mutations
|
* PI3KCA
* MAPK3K1
* GATA3
* CCDN1 amplification
|
Similar to luminal A but:
* TP53 inactivation
* Rb inactivation
* Myc-related transcription
* FOXM1-related transcription
|
* HER2 amplicon and corresponding [[signaling pathway]] signature
|
* TP53
* RB1 loss
* BRCA1 loss
* MYC amplification
* PI3K/AKT pathway oversignaling
|}

== DNA classification ==

=== Traditional DNA classification ===
Traditional [[DNA]] [[Categorization|classification]] was based on the general observation that cells that are [[mitosis|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 staging system|TNM stage]]. In contrast, modern DNA analyses are increasingly relevant in defining underlying [[cancer]] biology and in helping choose treatments.<ref name="pmid10963602">{{cite journal | vauthors = Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D | display-authors = 6 |title=Molecular portraits of human breast tumours |journal=Nature |volume=406 |issue=6797 |pages=747–752 |date=August 2000 |pmid=10963602 |doi=10.1038/35021093 | bibcode = 2000Natur.406..747P |s2cid=1280204 | url = https://cdr.lib.unc.edu/downloads/p5547t54k }}</ref><ref name="pmid16518056">{{cite journal |vauthors=Nagasaki K, Miki Y |title=Gene expression profiling of breast cancer |journal=Breast Cancer |volume=13 |issue=1 |pages=2–7 |year=2006 |pmid=16518056 |doi= 10.2325/jbcs.13.2|s2cid=6255927 }}</ref><ref name="pmid20130425">{{cite journal |vauthors=Normanno N, De Luca A, Carotenuto P, Lamura L, Oliva I, D'Alessio A |title=Prognostic applications of gene expression signatures in breast cancer |journal=Oncology |volume=77 |pages=2–8 |year=2009 |issue=Suppl 1 |pmid=20130425 |doi=10.1159/000258489 |s2cid=21011879 }}</ref><ref name="pmid20576095">{{cite journal | vauthors = Jönsson G, Staaf J, Vallon-Christersson J, Ringnér M, Holm K, Hegardt C, Gunnarsson H, Fagerholm R, Strand C, Agnarsson BA, Kilpivaara O, Luts L, Heikkilä P, Aittomäki K, Blomqvist C, Loman N, Malmström P, Olsson H, Johannsson OT, Arason A, Nevanlinna H, Barkardottir RB, Borg A | display-authors = 6 |title=Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics |journal=Breast Cancer Research |volume=12 |issue=3 |pages=R42 |year=2010 |pmid=20576095 |pmc=2917037 |doi=10.1186/bcr2596 | doi-access = free }}</ref>

=== HER2/neu ===
[[HER2/neu]] status can be analyzed by [[fluorescent in-situ hybridization]] (FISH) assays.<ref name="NCCN-Breast2011-2" /> 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.<ref name="NCCN-Breast2011-2" />

=== DNA microarrays ===

==== Background ====
[[File:Bc-classification.png|right|thumb|Molecular classification of breast cancer from mRNA expression profiles]]
[[DNA microarrays]] have compared normal cells to breast cancer cells and found differences in the expression of hundreds of [[gene]]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 [[Genetic cluster|clusters]] have included [[hormone]] [[receptor (biochemistry)|receptor-related]] genes, [[HER2]]-related genes, a group of basal-like genes, and [[Cell proliferation|proliferation]] genes. As might therefore be anticipated, there is considerable similarity between the receptor and microarray classifications, but assignment of individual tumors is by no means identical. By way of illustration, some analyses have suggested that approximately 75% of receptor classified [[triple-negative breast cancer]]s (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 in a different way to emphasize things, this means that 25% of triple-negative breast cancer (TNBC) basal-like tumors as defined by one or other classification are excluded from the alternative classification's results. Which classification scheme (receptor [[immunohistochemistry|IHC]] or [[DNA microarrays|DNA expression profile]]) more reliably assorts particular cancers to effective therapies is under investigation.

Several commercially marketed [[DNA microarray]] tests analyze [[Genetic cluster|clusters]] of [[gene]]s and may help decide which possible treatment is most effective for a particular [[cancer]].<ref name="pmid20065178">{{cite journal |vauthors=Sparano JA, Solin LJ |title=Defining the clinical utility of gene expression assays in breast cancer: the intersection of science and art in clinical decision making |journal=Journal of Clinical Oncology |volume=28 |issue=10 |pages=1625–7 |date=April 2010 |pmid=20065178 |doi=10.1200/JCO.2009.25.2882 |doi-access=free }}</ref> The use of these assays in [[breast cancer]]s is supported by [[Evidence-based medicine#US Preventive Services Task Force|Level II evidence]] or [[Evidence-based medicine#US Preventive Services Task Force|Level III evidence]]. No tests have been verified by [[Evidence-based medicine#US Preventive Services Task Force|Level I evidence]], which is rigorously defined as being derived from a [[prospective cohort study|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<ref name="pmid20392785">{{cite journal |vauthors=Mandrekar SJ, Sargent DJ |title=Predictive biomarker validation in practice: lessons from real trials |journal=Clin Trials |volume=7 |issue=5 |pages=567–73 |date=October 2010|pmid=20392785|doi=10.1177/1740774510368574 |pmc=3913192}}</ref><ref name="pmid20981123">{{cite journal |vauthors=Pharoah PD, Caldas C |title=Genetics: How to validate a breast cancer prognostic signature |journal=Nat Rev Clin Oncol |volume=7 |issue=11 |pages=615–6 |date=November 2010|pmid=20981123|doi=10.1038/nrclinonc.2010.142 |s2cid=32411967 }}</ref> are being actively pursued.

Numerous genetic profiles have been developed.<ref name="Ross2008">{{Cite journal | last1 = Ross | first1 = J. S. | last2 = Hatzis | first2 = C. | last3 = Symmans | first3 = W. F. | last4 = Pusztai | first4 = L. | last5 = Hortobagyi | first5 = G. N. | title = Commercialized Multigene Predictors of Clinical Outcome for Breast Cancer | doi = 10.1634/theoncologist.2007-0248 | journal = The Oncologist | volume = 13 | issue = 5 | pages = 477–493 | year = 2008 | pmid = 18515733| s2cid = 19435207 | doi-access = free }}</ref><ref name="Albain2009">{{Cite journal | last1 = Albain | first1 = K. S. | last2 = Paik | first2 = S. | last3 = Van't Veer | first3 = L.| author3-link = Laura J. van't Veer| title = Prediction of adjuvant chemotherapy benefit in endocrine responsive, early breast cancer using multigene assays | doi = 10.1016/S0960-9776(09)70290-5 | journal = The Breast | volume = 18 | pages = S141–S145 | year = 2009 | pmid = 19914534 | doi-access = free }}</ref> The most heavily marketed are:
* [[Oncotype DX]] is supported by [[Evidence-based medicine#US Preventive Services Task Force|Level II evidence]], and was originally designed for use in [[estrogen]] [[estrogen receptor|receptor]] (ER) positive tumors,<ref name="Fan2006">{{Cite journal | vauthors = Fan C, Oh DS, Wessels L, Weigelt B, Nuyten DS, Nobel AB, van't Veer LJ, Perou CM | display-authors = 6 | doi = 10.1056/NEJMoa052933 | title = Concordance among gene-expression-based predictors for breast cancer | journal = New England Journal of Medicine | volume = 355 | issue = 6 | pages = 560–569 | date = August 2006 | pmid = 16899776 | doi-access = free }}</ref> and has been endorsed by the [[American Society of Clinical Oncology]] (ASCO)<ref name="Ross2008" /><ref name="Harris2007">{{Cite journal | vauthors = Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC | display-authors = 6 | doi = 10.1200/JCO.2007.14.2364 | collaboration = ((American Society of Clinical Oncology)) | title = American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer | journal = Journal of Clinical Oncology | volume = 25 | issue = 33 | pages = 5287–5312 | date = November 2007 | pmid = 17954709| pmc = 2793754 }}</ref> and the [[National Comprehensive Cancer Network|NCCN]].<ref name="NCCN-Breast2011-2" />
* [[MammaPrint]] is supported only by [[Evidence-based medicine#US Preventive Services Task Force|Level III evidence]], can be performed on [[estrogen]] [[estrogen receptor|receptor]] (ER) positive and negative tumors, and has [[Food and Drug Administration|FDA]] approval.
* Two other tests also only have [[Evidence-based medicine#US Preventive Services Task Force|Level III evidence]]: Theros and MapQuant Dx.<ref name="Hareyanon2008">Armen Hareyanon. MapQuant Dx Genomic Grade Test Identifies Breast Cancer Patients. 2 June 2008 http://www.emaxhealth.com/98/22731.html {{Webarchive|url=https://web.archive.org/web/20110929104509/http://www.emaxhealth.com/98/22731.html |date=29 September 2011 }}</ref><ref name="Filho2011">{{Cite journal | last1 = Filho | first1 = O. M. | last2 = Ignatiadis | first2 = M. | last3 = Sotiriou | first3 = C. | doi = 10.1016/j.critrevonc.2010.01.011 | title = Genomic Grade Index: An important tool for assessing breast cancer tumor grade and prognosis | journal = Critical Reviews in Oncology/Hematology | volume = 77 | issue = 1 | pages = 20–29 | year = 2011 | pmid = 20138540 }}</ref><ref name="FilhoASCO2011">{{cite web|url=http://www.ipsogen.com/uploads/media/MQ_Feasibility_ASCO2011-Poster.pdf |title=Select your country: Qiagen Marseille |work=ipsogen.com |access-date=12 December 2015 |url-status=dead |archive-url=https://web.archive.org/web/20120326130929/http://www.ipsogen.com/uploads/media/MQ_Feasibility_ASCO2011-Poster.pdf |archive-date=26 March 2012 }}</ref>

These multigene assays, some partially and some completely commercialized, have been scientifically reviewed to compare them with other standard [[#Overview|breast cancer classification]] methods such as [[#Grade|grade]] and [[#Receptor status|receptor status]].<ref name="Ross2009" /><ref name="Albain2009" /> Although these [[DNA microarray|gene-expression profiles]] look at different individual [[gene]]s, they seem to classify a given [[tumor]] into similar [[risk]] groups and thus provide [[Inter-rater reliability|concordant]] predictions of outcome.<ref name="NCCN-Breast2011-2" /><ref name="Fan2006" />

Although there is considerable evidence that these tests can refine the treatment decisions in a meaningful proportion of breast cancers<ref name="Ross2008" /><ref name="Albain2009" /> they are fairly expensive; proposed selection criteria for which particular tumors may benefit by being interrogated by these assays<ref name="NCCN-Breast2011-2" /> remain [[Controversy|controversial]], particularly with [[lymph node]] positive cancers.<ref name="NCCN-Breast2011-2" /> 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".<ref name="sotirou" />

==== Oncotype DX ====
Oncotype DX assesses 16 cancer-related [[gene]]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 receptor|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.

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 (oncology)|hormonal therapy]] found a strong correlation of the Oncotype [[Cancer#Classification|classification]] with the likelihood of a [[Response Evaluation Criteria in Solid Tumors|complete response]] (CR) to the presurgical chemotherapy.<ref name="pmid16145055">{{cite journal | vauthors = Gianni L, Zambetti M, Clark K, Baker J, Cronin M, Wu J, Mariani G, Rodriguez J, Carcangiu M, Watson D, Valagussa P, Rouzier R, Symmans WF, Ross JS, Hortobagyi GN, Pusztai L, Shak S | display-authors = 6 |title=Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer |journal=Journal of Clinical Oncology |volume=23 |issue=29 |pages=7265–7277 |date=October 2005 |pmid=16145055 |doi=10.1200/JCO.2005.02.0818 |doi-access=free }}</ref>

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.<ref name="pmid20665886">{{cite journal| vauthors = Kelly CM, Krishnamurthy S, Bianchini G, Litton JK, Gonzalez-Angulo AM, Hortobagyi GN, Pusztai L | display-authors = 6 |title=Utility of oncotype DX risk estimates in clinically intermediate risk hormone receptor-positive, HER2-normal, grade II, lymph node-negative breast cancers |journal=Cancer |volume=116 |issue=22 |pages=5161–5167 |date=November 2010 |pmid=20665886 |doi=10.1002/cncr.25269 |doi-access=free | title-link=doi }}</ref> Results from both the US<ref name="Lo2010">{{Cite journal | vauthors = Lo SS, Mumby PB, Norton J, Rychlik K, Smerage J, Kash J, Chew HK, Gaynor ER, Hayes DF, Epstein A, Albain KS | display-authors = 6 | doi = 10.1200/JCO.2008.20.2119 | title = Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection | journal = Journal of Clinical Oncology | volume = 28 | issue = 10 | pages = 1671–1676 | date = April 2010 | pmid = 20065191 | doi-access = free | title-link = doi }}</ref> and internationally<ref name="Albanell2011">{{Cite journal | last1 = Albanell | first1 = J. | last2 = González | first2 = A. | last3 = Ruiz-Borrego | first3 = M. | last4 = Alba | first4 = E. | last5 = García-Saenz | first5 = J. A. | last6 = Corominas | first6 = J. M. | last7 = Burgues | first7 = O. | last8 = Furio | first8 = V. | last9 = Rojo | first9 = A. | last10 = Palacios | first10 = J. | last11 = Bermejo | first11 = B. | last12 = Martínez-García | first12 = M. | last13 = Limon | first13 = M. L. | last14 = Muñoz | first14 = A. S. | last15 = Martín | first15 = M. | last16 = Tusquets | first16 = I. | last17 = Rojo | first17 = F. | last18 = Colomer | first18 = R. | last19 = Faull | first19 = I. | last20 = Lluch | first20 = A. | title = Prospective transGEICAM study of the impact of the 21-gene Recurrence Score assay and traditional clinicopathological factors on adjuvant clinical decision making in women with estrogen receptor-positive (ER+) node-negative breast cancer | doi = 10.1093/annonc/mdr278 | journal = Annals of Oncology | year = 2011 | pmid = 21652577 | volume=23 | issue=3 | pages=625–631| doi-access = free | hdl = 10630/29523 | hdl-access = free }}</ref> suggest that Oncotype may assist in treatment decisions.<ref>New Mexico OncologyHematology Consultants, Ltd. Copyright held by CancerConsultants Breast Cancer Information Center. European Study Reports that Oncotype DX Influences Breast Cancer Treatment Decisions. Posted 2010 October 17, accessioned 2010 Dec 19 and 2, 011 July 3 at http://nmcancercenter.org/european-study-reports-that-oncotype-dx%C2%AE-influences-breast-cancer-treatment-decisions/ {{Webarchive|url=https://web.archive.org/web/20120328071347/http://www.nmcancercenter.org/european-study-reports-that-oncotype-dx%C2%AE-influences-breast-cancer-treatment-decisions/ |date=28 March 2012 }}</ref>

Oncotype DX has been endorsed by the [[American Society of Clinical Oncology]] (ASCO)<ref name="Ross2008" /><ref name="Harris2007"/> and the [[National Comprehensive Cancer Network]] (NCCN).<ref name="NCCN-Breast2011-2" /> The NCCN Panel considers the 21-gene assay as an option when evaluating certain [[tumor]]s<ref name="NCCN-Breast2011-2" /> to assist in estimating likelihood of recurrence and benefit from [[chemotherapy]], emphasizing that the recurrence score should be used along with other breast cancer [[#Overview|classification]] elements when [[Stratified medicine|stratifying]] [[risk]].<ref name="NCCN-Breast2011-2" /> Oncotype fulfilled all California Technology Assessment Forum (CTAF) criteria in October 2006.<ref name="Tice-CTAF2010" /> 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<ref name="FDA20070214">NCI Cancer Bulletin FDA Update 2007 February 14, Volume 4, Number 7 as Retrieved 17 October 2010 at http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2007/021407/page5 {{Webarchive|url=https://web.archive.org/web/20101222095153/http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2007/021407/page5 |date=22 December 2010 }}</ref> 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.<ref name="FDA20070214" />

==== MammaPrint and BluePrint ====
{{main|MammaPrint}}
The MammaPrint gene pattern is a commercial-stage 70-[[gene]] panel marketed by Agendia,<ref name="AgendiaCompanyCharacterization">The mission of Agendia. Agendia web isite.http://www.agendia.com/pages/mission/86.php {{Webarchive|url=https://web.archive.org/web/20131123011254/http://www.agendia.com/pages/mission/86.php |date=23 November 2013 }}</ref> that was developed in patients under age 55 years who had [[lymph node]] negative [[breast cancer]]s [[#Stage|(N0)]].<ref name="Tice-CTAF2010">Tice JA. The 70-Gene Signature (MammaPrint) as a Guide for the Management of Early Stage Breast Cancer. California Technology Assessment Forum. 2010 June 2nd. Full text accessioned 2010 Dec 19 at http://www.ctaf.org/content/assessments/detail/?id=1178 {{Webarchive|url=https://web.archive.org/web/20110725212101/http://www.ctaf.org/content/assessments/detail/?id=1178 |date=25 July 2011 }}</ref> The commercial test is marketed for use in breast cancer irrespective of [[estrogen]] [[estrogen receptor|receptor]] (ER) status.<ref name="Tice-CTAF2010" /> The test is run on formalin fixed, paraffin-embedded tissue. MammaPrint traditionally used rapidly frozen tissue<ref name="NCCN-Breast2011-2" /> but a room temperature, molecular [[Fixation (histology)|fixative]] is available for use within 60 minutes of obtaining fresh tissue samples.<ref name="AgendiaOrderingSymphony">Ordering Symphony is a simple process. Agendia web site.http://www.agendia.com/pages/ordering_symphony/38.php {{Webarchive|url=https://web.archive.org/web/20110605081140/http://www.agendia.com/pages/ordering_symphony/38.php |date=5 June 2011 }}</ref>

A summary of [[clinical trial]]s using MammaPrint is included in the [[MammaPrint|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.<ref name="Tice-CTAF2010" /> MammaPrint has 5 [[Food and Drug Administration|FDA]] clearances and is the only FDA cleared microarray assay available. To be eligible for the MammaPrint [[DNA microarray|gene expression profile]], a breast cancer should have the following characteristics: [[#Stage|stage]] 1 or 2, tumor size less than 5.0&nbsp;cm, [[estrogen]] [[estrogen receptor|receptor]] positive (ER+) or estrogen receptor negative (ER-). In the US, the tumor should also be [[lymph node]] [[#Stage|negative (N0)]], but internationally the test may be performed if the lymph node status is negative or positive with up to 3 nodes.<ref name="AgendiaEligIntern">MammaPrint Patient Eligibility Internationally (Outside of the USA) http://www.agendia.com/pages/patient_eligibility_internationally/317.php {{Webarchive|url=https://web.archive.org/web/20110605080927/http://www.agendia.com/pages/patient_eligibility_internationally/317.php |date=5 June 2011 }}</ref>

One method of assessing the molecular subtype of a [[breast cancer]] is by BluePrint,<ref name="AgendiaBluePrint">Introducing BluePrint: A Molecular Subtyping Profile for Breast Cancer. Agendia web site.http://www.agendia.com/pages/blueprint/324.php {{Webarchive|url=https://web.archive.org/web/20110903082626/http://www.agendia.com/pages/blueprint/324.php |date=3 September 2011 }}</ref> a commercial-stage 80-gene panel marketed by Agendia, either as a standalone test, or combined with the [[MammaPrint]] gene profile.

=== Other DNA assays and choice of treatment ===
The choice of established chemotherapy medications, if chemotherapy is needed, may also be affected by DNA assays that predict relative resistance or sensitivity. [[Topoisomerase II]] (TOP2A) expression predicts whether [[doxorubicin]] is relatively useful.<ref>{{cite journal | vauthors = MacGrogan G, Rudolph P, Mascarel I, Mauriac L, Durand M, Avril A, Dilhuydy JM, Robert J, Mathoulin-Pélissier S, Picot V, Floquet A, Sierankowski G, Coindre JM | display-authors = 6 | date = August 2003 | title = DNA topoisomerase II alfa expression and the response to primary chemotherapy in breast cancer | journal = British Journal of Cancer | volume = 89 | issue = 4 | pages = 666–671 | doi = 10.1038/sj.bjc.6601185 | pmid = 12915875 | pmc = 2376904 | doi-access = free | title-link = doi }}</ref><ref>Gene Review TOP2A&nbsp;– topoisomerase (DNA) II alpha 170kDa Homo sapiens as Retrieved 18 October 2010 [https://web.archive.org/web/20101114095323/http://www.wikigenes.org/e/gene/e/7153.html]</ref> 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.<ref name="Alvarez2010">{{Cite journal | last1 = Alvarez | first1 = R. H. | last2 = Valero | first2 = V. | last3 = Hortobagyi | first3 = G. N. | doi = 10.1200/JCO.2009.25.4011 | title = Emerging Targeted Therapies for Breast Cancer | journal = Journal of Clinical Oncology | volume = 28 | issue = 20 | pages = 3366–3379 | year = 2010 | pmid = 20530283 }}</ref> 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]] [[Polymorphism (biology)|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]]<ref>Tutt A J Clin Onc 2009; 27(suppl 15): abst CRA501</ref> 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.<ref name="pmid20631063">{{cite journal | vauthors = Issaeva N, Thomas HD, Djureinovic T, Djurenovic T, Jaspers JE, Stoimenov I, Kyle S, Pedley N, Gottipati P, Zur R, Sleeth K, Chatzakos V, Mulligan EA, Lundin C, Gubanova E, Kersbergen A, Harris AL, Sharma RA, Rottenberg S, Curtin NJ, Helleday T | display-authors = 6 |title=6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance |journal=Cancer Research |volume=70 |issue=15 |pages=6268–6276 |date=August 2010 |pmid=20631063 |pmc=2913123 |doi=10.1158/0008-5472.CAN-09-3416 }} Correction published at Correction: 6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance Cancer Res 2010 October 1;70:7734</ref> [[mTOR]] inhibitors such as [[everolimus]] may show more effect in PIK3CA/Akt e9 mutants than in e20 mutants or wild types.<ref>{{cite journal | vauthors = Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS | display-authors = 6 | title = Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer | date = June 2009 | journal = Journal of Clinical Oncology | volume = 27 | issue = 16 | pages = 2630–2637 | doi = 10.1200/JCO.2008.18.8391 | pmid = 19380449 | doi-access = free }}</ref>

[[DNA methylation]] patterns can [[Epigenetics|epigenetically]] affect gene expression in breast cancer and may contribute to some of the observed differences between genetic subtypes.<ref name="pmid21092249">{{cite journal | vauthors = D'Anello L, Sansone P, Storci G, Mitrugno V, D'Uva G, Chieco P, Bonafé M | display-authors = 6 |title=Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells |journal=Molecular Cancer |volume=9 |page=300 |date = November 2010 |pmid=21092249 |pmc=3002335 |doi=10.1186/1476-4598-9-300 | doi-access = free }}</ref>

Tumors overexpressing the [[Wnt signaling pathway]] co-receptor [[LRP6|low-density lipoprotein receptor-related protein 6]] (LRP6) may represent a distinct subtype of breast cancer and a potential treatment target.<ref name="Liu2010">{{Cite journal | last1 = Liu | first1 = C. -C. | last2 = Prior | first2 = J. | last3 = Piwnica-Worms | first3 = D. | last4 = Bu | first4 = G. | title = LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy | doi = 10.1073/pnas.0911220107 | journal = Proceedings of the National Academy of Sciences | volume = 107 | issue = 11 | pages = 5136–5141 | year = 2010 | pmid = 20194742 | pmc =2841938 | bibcode = 2010PNAS..107.5136L | doi-access = free }}</ref>

Numerous clinical investigations looked at whether testing for [[SNP genotyping|variant genotype]] [[Polymorphism (biology)|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.<ref>{{cite web | last1=Rae | first1=JM | last2=Drury | first2=S | last3=Hayes | first3=DF | display-authors=etal | title=Lack of Correlation between Gene Variants in Tamoxifen Metabolizing Enymes with Primary Endpoints in the ATAC Trial. 33rd Annual San Antonio Breast Cancer Symposium (SABCS): abstract S1-7 | date=9 December 2010 | accessdate=17 December 2010 | url=http://www.abstracts2view.com/sabcs10/view.php?nu=SABCS10L_1093&terms= | archiveurl=https://web.archive.org/web/20110811162448/http://www.abstracts2view.com/sabcs10/view.php?nu=SABCS10L_1093 |archivedate=11 August 2011 }}</ref><ref>{{cite web | last1=Leyland-Jones | first1=B | last2=Regan | first2=MM | last3=Bouzyk | first3=M | display-authors=etal | title=Outcome According to CYP2D6 Genotype among Postmenopausal Women with Endocrine-Responsive Early Invasive Breast Cancer Randomized in the BIG 1-98 Trial. 33rd Annual San Antonio Breast Cancer Symposium (SABCS): abstract S1-8 | date= 9 December 2010 | accessdate=17 December 2010 | url=http://www.abstracts2view.com/sabcs10/view.php?nu=SABCS10L_556&terms= | archiveurl=https://web.archive.org/web/20110707075854/http://www.abstracts2view.com/sabcs10/view.php?nu=SABCS10L_556&terms= |archivedate=7 July 2011 }}</ref> Testing for the [[CYP2C19|CYP2C19*2]] polymorphism gave counterintuitive results.<ref>{{cite journal | vauthors = Ruiter R, Bijl MJ, van Schaik RH, Berns EM, Hofman A, Coebergh JW, van Noord C, Visser LE, Stricker BH | display-authors = 6 | date = October 2010 | title = CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen | journal = Pharmacogenomics | volume = 11 | issue = 10| pages = 1367–1375 | doi=10.2217/pgs.10.112| pmid = 21047200 }}</ref> The medical utility of potential [[Biomarker (medicine)|biomarkers]] of tamoxifen responsiveness such as [[HOXB13]],<ref>{{cite journal | vauthors = Jerevall PL, Jansson A, Fornander T, Skoog L, Nordenskjöld B, Stål O | year = 2010 | title = Predictive relevance of HOXB13 protein expression for tamoxifen benefit in breast cancer | journal = Breast Cancer Research | volume = 12 | issue = 4 | page = 206 | doi=10.1186/bcr2612| pmid = 20649975 | pmc = 2949642 | doi-access = free }}</ref> [[PAX2]],<ref>{{cite web |url=http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093 |title=Study sheds new light on tamoxifen resistance |publisher=CORDIS : News |date=13 November 2008 |access-date=14 November 2008 |archive-date=20 February 2009 |archive-url=https://web.archive.org/web/20090220060249/http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093 |url-status=dead }}<br />{{cite journal | vauthors = Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS | display-authors = 6 |title=Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen |journal=Nature |volume=456 |issue=7222 |pages=663–666 |date=December 2008 |pmid=19005469 |pmc=2920208 |doi=10.1038/nature07483 | doi-access = free | title-link = doi | bibcode = 2008Natur.456..663H }}</ref> and estrogen receptor (ER) alpha and beta [[isoforms]] interaction with [[Nuclear receptor coactivator 3|SRC3]]<ref name="pmid17158759">{{cite journal |vauthors=Mc Ilroy M, Fleming FJ, Buggy Y, Hill AD, Young LS |title=Tamoxifen-induced ER-alpha-SRC-3 interaction in HER2 positive human breast cancer; a possible mechanism for ER isoform specific recurrence |journal=Endocr. Relat. Cancer |volume=13 |issue=4 |pages=1135–45 |date=December 2006 |pmid=17158759 |doi=10.1677/erc.1.01222 |doi-access=free }}</ref><ref name="pmid19456271">{{cite journal |vauthors=Spears M, Bartlett J |title=The potential role of estrogen receptors and the SRC family as targets for the treatment of breast cancer |journal=Expert Opin. Ther. Targets |volume=13 |issue=6 |pages=665–74 |date=June 2009 |pmid=19456271 |doi=10.1517/14728220902911509 |s2cid=39034059 }}</ref> have all yet{{when?|date=August 2022}} to be fully defined.

== Other classification approaches ==

=== Computer models ===
Computer models consider several traditional factors concurrently to derive individual survival predictions and calculations of potential treatment benefits. The validated [[algorithm]]s can present visually appealing graphics that assist in treatment decisions. In addition, other classifications of breast cancers do exist and no uniform system has been consistently adopted worldwide. <!-- image requested -->

Adjuvant! is based on US [[cohort study|cohorts]]<ref name="pmid11181660">{{cite journal | vauthors = Ravdin PM, Siminoff LA, Davis GJ, Mercer MB, Hewlett J, Gerson N, Parker HL | display-authors = 6 |title=Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer |journal=Journal of Clinical Oncology |volume=19 |issue=4|pages=980–991 |date=February 2001 |pmid=11181660|doi=10.1200/JCO.2001.19.4.980 }}</ref> and presents colored bar charts that display information that may assist in decisions regarding [[systemic effect|systemic]] [[adjuvant]] therapies. Successful validation was seen with Canadian<ref name="pmid15837986">{{cite journal | vauthors = Olivotto IA, Bajdik CD, Ravdin PM, Speers CH, Coldman AJ, Norris BD, Davis GJ, Chia SK, Gelmon KA | display-authors = 6 |title=Population-based validation of the prognostic model ADJUVANT! for early breast cancer |journal=Journal of Clinical Oncology |volume=23 |issue=12 |pages=2716–2725|date=April 2005 |pmid=15837986 |doi=10.1200/JCO.2005.06.178 |s2cid=27080534 |doi-access=free }}</ref> and Dutch<ref name="pmid19801202">{{cite journal | vauthors = Mook S, Schmidt MK, Rutgers EJ, van de Velde AO, Visser O, Rutgers SM, Armstrong N, van't Veer LJ, Ravdin PM | display-authors = 6 |title=Calibration and discriminatory accuracy of prognosis calculation for breast cancer with the online Adjuvant! program: a hospital-based retrospective cohort study |journal=Lancet Oncology |volume=10 |issue=11 |pages=1070–1076 |date=November 2009 |pmid=19801202|doi=10.1016/S1470-2045(09)70254-2 }}</ref> cohorts. Adjuvant! seemed less applicable to a British cohort<ref name="pmid19724274">{{cite journal|vauthors=Campbell HE, Taylor MA, Harris AL, Gray AM |title=An investigation into the performance of the Adjuvant! Online prognostic programme in early breast cancer for a cohort of patients in the United Kingdom |journal=Br. J. Cancer |volume=101 |issue=7 |pages=1074–84 |date=October 2009 |pmid=19724274|pmc=2768087 |doi=10.1038/sj.bjc.6605283 }}</ref> and accordingly PREDICT is being developed in the United Kingdom.<ref name="pmid20053270">{{cite journal | vauthors = Wishart GC, Azzato EM, Greenberg DC, Rashbass J, Kearins O, Lawrence G, Caldas C, Pharoah PD | display-authors = 6 |title=PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer |journal=Breast Cancer Research |volume=12 |issue=1 |pages=R1 |year=2010 |pmid=20053270 |pmc=2880419 |doi=10.1186/bcr2464 | doi-access = free }}</ref>

=== Other immunohistochemical tests ===
Among the [[immunohistochemistry|immunohistochemical]] tests that may further stratify [[prognosis]], [[BCL2]] has shown promise in preliminary studies.<ref name="pmid20664598">{{cite journal | vauthors = Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J, Baglietto L, Severi G, Giles GG, McLean CA, Callagy G, Green AR, Ellis I, Gelmon K, Turashvili G, Leung S, Aparicio S, Huntsman D, Caldas C, Pharoah P | display-authors = 6 |title=BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received |journal=British Journal of Cancer |volume=103 |issue=5 |pages=668–75 |date=August 2010 |pmid=20664598 |pmc=2938244 |doi=10.1038/sj.bjc.6605736 }}</ref>

=== Van Nuys prognostic index ===

The USC/Van Nuys prognostic index (VNPI) classifies [[ductal carcinoma in situ]] (DCIS) into dissimilar risk categories that may be treated accordingly.<ref>{{cite journal | author = Silverstein Melvin J., Lagios Michael D. | year = 2010| title = Choosing Treatment for Patients With Ductal Carcinoma In Situ: Fine Tuning the University of Southern California/Van Nuys Prognostic Index | journal = J Natl Cancer Inst Monogr | volume = 2010 | issue = 41| pages = 193–196 | doi = 10.1093/jncimonographs/lgq040 | pmid = 20956828| pmc = 5161065| doi-access = free }}</ref>

==Notes==
{{reflist|group="notes"}}

== References ==
{{Reflist}}

{{Breast neoplasia}}
{{Portal bar|Medicine}}
{{Authority control}}

[[Category:Breast neoplasia]]
[[Category:Breast cancer]]
[[Category:Cancer staging]]
[[Category:Medical classification]]
[[Category:Classification systems]]