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*DNA-based classification. Understanding the specific details of a particular breast cancer may include looking at the cancer cell DNA by several different laboratory approaches. When specific DNA mutations or gene expression profiles are identified in the cancer cells this may guide the selection of treatments, either by targeting these changes, or by predicting from the DNA profile which non-targeted therapies are most effective.
*DNA-based classification. Understanding the specific details of a particular breast cancer may include looking at the cancer cell DNA by several different laboratory approaches. When specific DNA mutations or gene expression profiles are identified in the cancer cells this may guide the selection of treatments, either by targeting these changes, or by predicting from the DNA profile which non-targeted therapies are most effective.


*Other prognostic tools include Adjuvant!<ref name="pmid11181660">{{cite journal |author=Ravdin PM, Siminoff LA, Davis GJ, ''et al.'' |title=Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer |journal=J. Clin. Oncol. |volume=19 |issue=4 |pages=980–91 |year=2001 |month=February |pmid=11181660 |doi= |url=}}</ref><ref>http://www.adjuvantonline.com/use.jsp<ref> and PREDICT.<ref name="pmid20053270">{{cite journal |author=Wishart GC, Azzato EM, Greenberg DC, ''et al.'' |title=PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer |journal=Breast Cancer Res. |volume=12 |issue=1 |pages=R1 |year=2010 |pmid=20053270 |pmc=2880419 |doi=10.1186/bcr2464 |url=}}</ref>


===Histopathologic types===
===Histopathologic types===

Revision as of 02:52, 20 December 2010

Breast cancer classification divides breast cancer into several categories according to multiple different schemes, each based on different criteria and serving a different purpose. A typical description usually considers each of these aspects in turn: the histolopathological type, the grade of the tumor, the stage of the tumor, and the expression of proteins and genes. As knowledge of cancer cell biology develops these classifications are updated.

The practical purpose of classification is to describe each individual instance of breast cancer in a way that helps select which treatment approach is anticipated to have the best chance for a good outcome, with increased efficacy and low toxicity. Treatment algorithms rely on breast cancer classification to define specific subgroups that are each treated according to the best evidence available. Classification aspects must be carefully tested and validated, such that confounding effects are minimized, making them either true prognostic factors, which estimate disease outcomes such as disease-free or overall survival in the absence of therapy, or true predictive factors, which estimate the liklihood of response or lack of response to a specific treatment. [1]

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 is defined on the basis of physical exam findings, in that inflammatory breast cancer (IBC), a form of ductal carcinoma or malignant cancer in the ducts, is distinguished from other carcinomas by the inflamed appearance of the affected breast, which correlates with increased cancer aggressivity.[2]

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 histopathological type, grade, stage (TNM), receptor status, and the presence or absence of genes as determined by DNA testing:

  • Histopathology. Although breast cancer has many different 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.[3] Perineural and/or lymphovascular space invasion is usually considered as part of the histological description of a breast cancer, and when present may be associated with more aggressive disease.
  • Grade. Grading focuses on the appearance of the breast cancer cells compared to the appearance of normal breast tissue. Normal cells in an organ like the breast become differentiated, meaning that they take on specific shapes and forms that reflect their function as part of that organ. Cancerous cells lose that differentiation. In cancer, the cells that would normally line up in an orderly way to make up the milk ducts become disorganized. Cell division becomes uncontrolled. Cell nuclei become less uniform. Pathologists describe cells as well differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade) as the cells progressively lose the features seen in normal breast cells. Poorly differentiated cancers have a worse prognosis.
  • Stage. The TNM classification for 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 is a pre-malignant disease or marker (sometimes called DCIS: Ductal Carcinoma in Situ) .
    Stages 1–3 are defined as 'early' cancer and potentially curable.
    Stage 4 is defined as 'advanced' and/or 'metastatic' cancer and incurable.
  • Receptor status. Cells have receptors on their surface and in their cytoplasm and nucleus. Chemical messengers such as hormones 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.
  • DNA-based classification. Understanding the specific details of a particular breast cancer may include looking at the cancer cell DNA by several different laboratory approaches. When specific DNA mutations or gene expression profiles are identified in the cancer cells this may guide the selection of treatments, either by targeting these changes, or by predicting from the DNA profile which non-targeted therapies are most effective.


  • Other prognostic tools include Adjuvant![4]Cite error: A <ref> tag is missing the closing </ref> (see the help page).

Histopathologic types

Histopathologic classification is based upon characteristics seen upon light microscopy of biopsy specimens. The most common pathologic types of breast cancer are:

These three pathologic types represent approximately ¾ of breast cancer incidence.

The overall 5-year survival rate for both invasive ductal carcinoma and invasive lobular carcinoma were approximately 85% in 2003 according to a study in the USA.[6] Ductal carcinoma in situ, on the other hand, is itself harmless, but untreated, approximately 60 percent of low grade DCIS lesions will become invasive at 40 years follow-up.[7]

For an extensive list, the latest (2003) World Health Organization (WHO) classification of tumors of the breast[8] recommends the following pathological types, which includes benign (harmless) tumors along with malignant (cancerous) tumors:

Grading

Main article: Bloom-Richardson grade

The Bloom-Richardson grade is the most commonly used scoring system in the US, but other schemes such as the Nottingham score have also been widely applied. Grading schemes look at the similarity of breast cancer cells to normal breast tissue, and classify 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.

Staging

TNM (tumor, node, metastasis) system

Main article: TNM staging system

In outline, the TNM system classifies the cancer by several factors as described below, T for tumor, N for nodes, M for metastasis, and then aggregates TNM groups into overall stages as shown in the table. However, several factors are important when reviewing reports for individual breast cancers or when reading the medical literature- it is crucial to be aware that the criteria used in the TNM system have varied over time, sometimes fairly substantially, according to the different editions that AJCC[9] and UICC have released. 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 has been termed "stage migration." The technologies used to assign patients to particular categories have changed also, and it can be seen 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.

Tumor - The characteristics of cancer at its primary site of origin in the breast are used to determine tumor (or T) classification values (TX, T0, Tis, T1, T2, T3 or T4) which depend on the presence or absence of invasive cancer, the dimensions of the invasive cancer, and the presence or absence of invasion outside of the breast, for example to the skin of the breast, to the muscle or to the rib cage underneath:

  • TX - Primary tumor cannot be assessed.
  • T0 - No evidence of primary tumor.
  • Tis - Carcinoma in situ.
    • Tis (DCIS) - Ductal Carcinoma in situ.
    • Tis (LCIS) - Lobular Carcinoma in situ.
    • Tis (Paget's) - Paget's disease of the nipple with no tumor. Paget’s disease of the nipple is NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget's disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget's disease should still be noted.
  • T1 - Tumor 20 mm or less in its greatest dimension.
    • T1mi - Microinvasive tumor that is 1 mm or less in greatest dimension.
    • T1a - Tumor more than 1 mm but not more than 5 mm in its greatest dimension.
    • T1b - Tumor more than 5 mm but not more than 10 mm in its greatest dimension.
    • T1c - Tumor more than 10 mm but not more than 20 mm in its greatest dimension.
  • T2 - Tumor more than 20 mm but not more than 50 mm in its greatest dimension.
  • T3 - Tumor more than 50 mm in its greatest dimension.
  • T4 - Tumor of any size with direct extension to (a) chest wall or (b) skin as described below:
    • T4a - Extension to chest wall. By definition, adherence to, or invasion of, the pectoralis muscle alone does not qualify as T4.
    • T4b - Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange of the skin confined to the same breast which does not meet the criteria for inflammatory carcinoma. By definition, invasion of the dermis alone does not qualify as T4.
    • T4c - Both T4a and T4b.
    • T4d - Inflammatory breast cancer. Inflammatory carcinoma is restricted to cases with typical skin changes involving a third or more of the skin of the breast. While the histologic presence of invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a diagnosis of inflammatory breast cancer.

Lymph Node - The lymph node (or N) classification values (NX, N0, N1, N2 or N3) depend on the number, size and location of breast cancer cell deposits in various lymph nodes including in the armpit (axillary lymph nodes), the collar area (supraclavicular lymph nodes), and inside the chest (internal mammary lymph nodes.[10][11]) Within the armpit there are three levels of axillary lymph nodes, such that Level I is the bottom or outer level, below the lower edge of the pectoralis minor muscle; Level II is lying underneath the pectoralis minor muscle; and Level III is above the pectoralis minor muscle.

  • NX - regional lymph nodes cannot be assessed. Perhaps due to previous removal.
  • N0 - no regional lymph node metastasis. There are several N0 subsets:
  • pN0(i-): No regional lymph node metastases histologically, negative IHC
  • pN0(i+): Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC including ITC) where Isolated Tumor Cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section. ITCs may be detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated.
  • pN0(mol-): No regional lymph node metastases histologically, negative molecular findings (RT-PCR)
  • pN0(mol+): Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC
  • N1 - this refers to clinically staged N1 disease, defined as present in movable level I or level II axillary lymph nodes on the same side as the affected breast.
  • pN1 - this refers to pathologically staged lymph nodes, that have micrometastases; or metastases in 1 to 3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected, with the following characteristics:
  • pN1mi - Micrometastases (defined as greater than 0.2 mm and/or more than 200 cells, but none greater than 2 mm) or metastases in 1 to 3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected.
  • pN1a - Metastases in 1 to 3 axillary lymph nodes, at least one metastasis greater than 2 mm
  • pN1b - Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.
  • pN1c - Metastases in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.
  • N2 - metastasis to fixed regional axillary lymph nodes, or metastasis to the internal mammary lymph nodes, on the same side as the affected breast.
  • N3 - metastasis to supraclavicular lymph nodes or infraclavicular lymph nodes or metastasis to the internal mammary lymph nodes with metastasis to the axillary lymph nodes.

Metastases - There were traditionally three metastatic classification values (MX, M0 and M1) which principally depended on the absence of adequate information, the confirmed absence, or the presence, respectively, of breast cancer cells in locations other than the breast and lymph nodes (so-called distant metastases, e.g. to bone, brain, lung.) The MX classification was used by pathologists where clinical information about spread of cancer to other body sites was not available to them at the time the cancer pathology report was written. The present TNM report forms do not include the MX option, and, indeed, there is now no pathologic M0 stage as the staging forms direct the user to apply the clinical M category to complete stage group. There are now three options:

  • M0 - No clinical or radiographic evidence of distant metastases.
  • cM0(i+) - No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow or other non-regional nodal tissue that are no larger than 0.2 mm and which are not causing symptoms or signs of metastases.
  • M1 - Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm.

Overall stage grouping

The TNM descriptors for tumor T stage, node N involvement, and metastatic M stage can be combined into a single overall stage grouping number, also called Prognostic Group, labelled Stage 0 to IV. A summary of the AJCC and UICC 7th edition from 2010 is shown:

Tumor T Stage Node N Stage Metastatic M Stage Overall Stage / Prognostic Group
Tis N0 M0 0
T1 (includes T1mi) N0 M0 IA
T0 or T1 N1mi M0 IB
T0-1 N1 M0 IIA
T2 N0 M0 IIA
T2 N1 M0 IIB
T3 N0 M0 IIB
T0-T2 N2 M0 IIIA
T3 N1-N2 M0 IIIA
T4 N0-N2 M0 IIIB
any T N3 M0 IIIC
any T any N M1 (this does NOT include cM0(+) IV


The following table shows historical data from a textbook with publication date 2007 May. The staging edition and primary reference for the outcome data needs to be identified.

Stages Features[12] Overall 5-year survival historically[12]
Stage 0 Ductal (DCIS) or lobular carcinoma in situ (LCIS) without microinvasion 92%
Stage I Invasive carcinoma of 2cm or less in diameter (including invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), as well as DCIS and LCIS with microinvasion) without lymph node involvement or metastases of less than 0.02 cm in diameter 87%
Stage II Invasive carcinoma (mainly IDC and ILC)
  • of 5 cm or less in diameter with up to three involved axillary nodes, or
  • greater than 5 cm but without lymph node involvement.
 75%
Stage III Invasive carcinoma (mainly IDC and ILC) 46%
Stage IV Any T Any N M1; Any breast cancer showing distant metastasis 13%

Receptor status

The receptor status of breast cancers has traditionally been identified by immunohistochemistry, which stains the cells based on the presence of estrogen receptors (ER), progestin receptors (PR) and HER2 receptors. This remains the commonest method of testing for receptor status, but DNA based analyses can categorize breast cancers into groups based on gene profiles that correspond to receptor status.
Receptor status is used to divide breast cancer into several molecular classes:

  1. Basal-like, which are ER-, PR- and HER2- (triple negative, TN). Most BRCA1 breast cancers are basal-like TN.
  2. Luminal A, which are ER+ and low grade
  3. Luminal B, which are ER+ but often high grade
  4. HER2+, which have amplified ERBB2 [13]
  5. Claudin-low, a more recently described class that is often triple-negative but which may be distinct in that this subset of TN also has low cell-cell junction protein and has frequent lymphocytic infiltration.

Receptor status is a critical assessment for all breast cancers as it determines the suitability of using targeted treatments such as tamoxifen and or trastuzumab. These treatments are now some of the most effective adjuvant treatments of breast cancer. Estrogen receptor positive (ER+) cancer cells depend on estrogen for their growth, so they can be treated with drugs to reduce either the effect of estrogen (e.g. tamoxifen) or the actual level of estrogen (e.g. aromatase inhibitors), and generally have a better prognosis. Generally, prior to modern treatments, HER+ had a worse prognosis,[13] 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.[14] Conversely, triple negative cancer (i.e. no positive receptors), lacking targeted treatments now has a comparatively poor prognosis.[15][16]

Other immunohistochemical tests

Among many immunohistochemical tests that may further stratify prognosis, BCL2 has shown promise in preliminary studies.[17]

DNA classification

Traditional DNA classification was based on the general observation that cells that are dividing more quickly have a worse prognosis, and relied on either the presence of protein Ki67 or the percentage of cancer cell DNA in S phase. These methods, and scoring systems that used DNA ploidy, are used much less often now, as their predictive and prognostic power was less substantial than other classification schemes such as the TNM stage. In contrast, modern DNA analyses are increasingly relevant in defining underlying cancer biology and in helping choose treatments.[18][19][20][21]

HER2/neu status can be analyzed by fluorescent in-situ hybridization (FISH) assays, which have a higher correlation than receptor immunohistochemistry with response to trastuzumab, a targeted therapy.

DNA microarrays have compared normal cells to breast cancer cells and found differences in the expression of hundreds of genes. Although the significance of many of those genetic differences is unknown, independent analyses by different research groups has found that certain groups of genes have a tendency to co-express. These co-expressing clusters have included hormone receptor-related genes, HER2-related genes, a group of basal-like genes, and proliferation genes. As might therefore be anticipated, there is considerable similarity between the receptor and microarray classifications, but assignment of individual tumors is by no means identical. By way of illustration, some analyses have suggested that approximately 75% of receptor classified triple-negative (TN) basal-like tumors have the expected DNA expression profile, and a similar 75% of tumors with a typical basal-like DNA expression profile are receptor TN as well. This means that 25% of triple-negative (TN) basal-like tumors as defined by one or other classification are excluded from the alternative classification's results. Which classification scheme more reliably assorts patients to effective therapies is under investigation.

Several commercially marketed DNA microarray tests analyze clusters of certain genes and may help decide which possible treatment is most effective for a particular cancer.[22] These tests are presently of potential use mainly in estrogen-receptor positive cancers, and their use in that subset of breast cancers is supported by Level II evidence or Level III evidence. One test, Oncotype DX, is supported by Level II evidence. Current rules do not mandate approval by the U.S. Food and Drug Administration (FDA) for these tests if performed at a single, company-operated laboratory[23] and, accordingly, the Oncotype DX assay is not specifically FDA approved. Oncotype DX has been endorsed by the American Society of Clinical Oncology. Clinical trial 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 chemotherapy and so it may be appropriate to choose to avoid the associated treatment side effects. In intermediate risk breast cancer, Oncotype may improve the risk assessment that is derived from routine clinical variables.[24][25] Although supported by Level III evidence, MammaPrint, sometimes also known as the Amsterdam or 70-gene profile, is approved by the FDA, as Agendia, the manufacturer of the test system, applied for FDA clearance even though it was not required to do so. [26] The evidence for Oncotype was assessed favorably by the California Technology Assessment Forum (CTAF) in 2006, while the available evidence for Mammaprint had not yet fulfilled all CTAF criteria in 2010.[27] Two other tests also have Level III evidence: Theros and MapQuant Dx. No tests have been verified by Level I evidence, defined as being derived from a prospective, randomized controlled trial where patients who used the test had a better outcome than those who did not. Acquiring extensive Level I evidence would be clinically and ethically challenging. However, several validation approaches[28][29] are being actively pursued. Oncotype DX is being evaluted in node negative, estrogen-receptor positive breast cancer in a prospective trial, the Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx),[30] launched 2006 May and that has already enrolled 10,000 people [31] with intermediate results on the test. Oncotype is also being evaluated in node positive, estrogen-receptor positive breast cancer in a Milan/European trial. Mammaprint is being evaluated in the Microarray In Node negative Disease may Avoid ChemoTherapy trial (MINDACT).[32][33] 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".[13]

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.[34] [35] Expression of genes that regulate tubulin may help predict the activity of taxanes.

Various DNA results are being incorporated in the design of clinical trials of new medicines. Specific genes such as p53, NME1, BRCA and PIK3CA/Akt may be associated with responsiveness of the cancer cells to innovative research pharmaceuticals. BRCA1 and BRCA2 polymorphic variants can increase the risk of breast cancer, and these cancers tend to express a profile 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, respond to treatment with PARP inhibitors[36] 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.[37] mTOR inhibitors such as everolimus may show more effect in PIK3CA/Akt e9 mutants than in e20 mutants or wild types.[38]

DNA methylation patterns can epigenetically affect gene expression in breast cancer and may contribute to some of the observed differences between genetic subtypes.[39]

Clinical investigations have looked at whether testing for variant genotype polymorphic alleles of several genes can predict whether or not to prescribe tamoxifen, based on 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 [40][41] and testing for the CYP2C19*2 polymorphism gave counterintuitive results.[42] The medical utility of potential biomarkers of tamoxifen responsiveness such as HOXB13, [43] PAX2, [44] and estrogen receptor (ER) alpha and beta isoforms interaction with SRC3 [45][46] have all yet to be fully defined.

References

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  2. ^ Giordano SH, Hortobagyi GN (2003). "Inflammatory breast cancer: clinical progress and the main problems that must be addressed". Breast Cancer Res. 5 (6): 284–8. doi:10.1186/bcr608. PMID 14580242. {{cite journal}}: Unknown parameter |pmtc= ignored (help)CS1 maint: unflagged free DOI (link)
  3. ^ Merck Manual, Professional Edition, Ch. 253, Breast Cancer.
  4. ^ Ravdin PM, Siminoff LA, Davis GJ; et al. (2001). "Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer". J. Clin. Oncol. 19 (4): 980–91. PMID 11181660. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b c Percentage values are from United States statistics 2004. Subtype specific incidences are taken from Table 6 (invasive) and Table 3 (in situ) from Eheman CR, Shaw KM, Ryerson AB, Miller JW, Ajani UA, White MC (2009). "The changing incidence of in situ and invasive ductal and lobular breast carcinomas: United States, 1999-2004". Cancer Epidemiol. Biomarkers Prev. 18 (6): 1763–9. doi:10.1158/1055-9965.EPI-08-1082. PMID 19454615. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link). 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 [1]
  6. ^ NOTE: Number really refers to invasive ductal carcinoma, despite title. Arpino G, Bardou VJ, Clark GM, Elledge RM (2004). "Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome". Breast Cancer Res. 6 (3): R149–56. doi:10.1186/bcr767. PMC 400666. PMID 15084238.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  7. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1186/bcr842, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1186/bcr842 instead. [2]
  8. ^ Peter Devilee; Fattaneh A. Tavassoli (2003). World Health Organization: Tumours of the Breast and Female Genital Organs. Oxford [Oxfordshire]: Oxford University Press. ISBN 92-832-2412-4.{{cite book}}: CS1 maint: multiple names: authors list (link)
  9. ^ Originally: Greene, FL, Page, DL, Fleming, ID, et al. American Joint Committee on Cancer. AJCC Staging Handbook. 6th edition. New York: Springer-Verlag; 2002:Pp. 223-240. Updated according to: American Joint Committee on Cancer homepage. Current edition applies to staging performed on and after 2010 January 1.
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  11. ^ Scatarige JC, Boxen I, Smathers RL (1990). "Internal mammary lymphadenopathy: imaging of a vital lymphatic pathway in breast cancer". Radiographics. 10 (5): 857–70. PMID 2217975. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) available as full text article with multiple images at http://radiographics.rsna.org/content/10/5/857.full.pdf
  12. ^ a b Unless else specified in boxes the reference is: Chapter 19 - The Female Genital System and Breast, page 749 in: Kumar V, Abbas AK, Fausto N, Mitchell R. (2007 May). Robbins Basic Pathology. Philadelphia: Saunders. p. 960. ISBN 1-4160-2973-7. {{cite book}}: Check date values in: |year= (help)CS1 maint: multiple names: authors list (link) 8th edition.
  13. ^ a b c Molecular origin of cancer: gene-expression signatures in breast cancer, Christos Sotirou and Lajos Pusztai, N Engl J Med 360:790 (2009 Feb 19)
  14. ^ Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2+ breast cancer. N Engl J Med. 2005; 353:1673-1684 and supplementary appendix.
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  16. ^ "Understanding and Treating Triple-Negative Breast Cancer". Cancer Network. Retrieved 2010-05-08.
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