Breast Cancer
- Key Points
- Diagnosis
- Screening
- Monitoring
- Pharmacogenetics
- Background
- Lab Tests
- References
- Related Topics
- Videos
| American Society of Clinical Oncology 2016 Prognostic Marker Recommendations | ||
|---|---|---|
|
Non-Panel Prognostic Markers |
||
|
Marker |
Indication/Description |
Positivity/Prognosis |
|
ER/PR (Estrogen/progesterone) |
ER and PR status should be determined on all invasive breast cancers and breast cancer recurrences (ASCO, 2010) |
ER positivity alone is a weak prognostic indicator; use in combination with PR  Two molecular subtypes – luminal A and luminal B; B has best prognosis  Positivity associated with improved prognosis when treated with anti-estrogen therapy (eg, tamoxifen) |
|
HER2 (Human epidermal growth factor receptor 2) |
HER2 status (HER2 negative or positive) should be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive) (ASCO, 2013) Â Graded scale
|
Positivity occurs in 15-20% of breast cancer patients Predominantly high-grade tumors More common in
75% have basal-like gene expression (CK5/14+, EGFR+) – worst prognosis of all breast cancer subtypes Worst prognosis for breast cancer |
|
uPA/PAI-1 (Urokinase-type plasminogen activator/plasminogen-like activator inhibitor) |
May be used in ER/PR-positive , HER2-negative (node-negative) women with early breast cancer to guide decisions on adjuvant therapy |
 |
|
IHC4 (Immunohistochemistry 4) |
Do not use in women who are ER/PR-positive, HER2-negative (node-negative or node-positive) for adjuvant decisions |
 |
|
Ki-67 (MIB-1) (Cell proliferative-associated antigen) |
Do not use to guide choice on adjuvant chemotherapy |
Elevation associated with aggressive tumor behavior |
|
Prognostic Panels |
||
|
Panel |
Indication |
Description |
|
Prosigna Breast Cancer Prognostic Gene Signature assay* |
May be used in ER/PR-positive, HER2-negative (node-negative) breast cancer in conjunction with other clinicopathologic variables to guide decisions on adjuvant systemic therapy Do not use in the following
|
Scores report risk as low, intermediate, or high based on
Does not provide information about which chemotherapy regimen should be given if at high risk for distant recurrence |
|
Genomic Health Oncotype DX (NCI)* Â |
May be used in ER/PR-positive, HER2-negative (node-negative) breast cancer to guide decisions on adjuvant systemic chemotherapy Do not use in the following
|
21 gene recurrence score TAILORx (Trial for Assigning Individualized Options for Treatment [Rx]) – study of genes associated with recurrence risk for use in determining most effective treatment options Helps to predict effectiveness of tamoxifen alone in postmenopausal women with node-negative, ER+, early stage breast cancer |
|
EndoPredict* |
May be used in ER/PR-positive, HER2-negative (node-negative) breast cancer to guide decisions on adjuvant systemic chemotherapy Do not use in the following
|
12 gene risk score |
|
Breast Cancer Index* |
May be used in ER/PR-positive, HER2-negative (node-negative) breast cancer to guide decisions on adjuvant systemic therapy Do not use in the following
|
 |
|
MammaPrint |
Do not use in ER/PR positive, HER2 negative (node-positive or node-negative) |
70 gene panel |
|
*FDA approved for use in early stage (stage I-III), node-positive breast cancer, but not guideline recommended |
||
Â
Indications for Testing
- Malignant histology compatible with breast cancer
Histology
- Therapeutic decisions are made using combination of the following tumor features
- Histologic grade – includes nuclear probe and mitotic index
- Estrogen receptor (ER) and progesterone receptor (PR) status
- HER2 (ERBB2) status
- Methods for initial HER2 determination – immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or dual in situ hybridization (ISH)
- Concordance between IHC and dual ISH/FISH may vary due to subjective interpretation
- Dual ISH includes fluorescence or Bright-field assays; most current dual ISH assays consist of two differentially labeled probes, one for HER2 and one for chromosome 17 centromere
- IHC or dual ISH/FISH may be used in initial evaluation for HER2 status
- Equivocal results should be resolved with alternate test (ASCO/College of American Pathologists [CAP], 2013; National Comprehensive Cancer Network [NCCN], 2016)
- Equivocal (2+) IHC – dual ISH/FISH recommended follow-up test
- Equivocal dual ISH/FISH – follow-up testing options
- Repeat dual ISH/FISH on same specimen using an alternative control probe
- IHC for HER2 expression status using the same block or a different block from the same specimen, if not already performed
- Repeat testing (dual ISH/FISH or IHC) on a different specimen from patient’s tumor
- Methods for initial HER2 determination – immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or dual in situ hybridization (ISH)
- For metastatic disease – ASCO (2016) recommends retesting available tumor tissue for ER, PR, and HER2 status
- Other immunohistochemical staining
- Immunoreactivity of normal breast epithelium
- Luminal: CK 7, CK 8, CK 18, CK 19
- Basal cells: CK 5/6, CK 14, CK 17
- Myoepithelial cells: CK 5, CK 14, CK 17, SMA, calponin, p63
- IHC staining may be used to differentiate ductal versus lobular carcinoma
- E-cadherin
- Ductal (+)
- Lobular (-)
- CK 5/6 – sometimes used to differentiate usual ductal hyperplasia (UDH) from atypical ductal hyperplasias (ADH)/low-grade ductal carcinoma in situ (LG-DCIS)
- Ductal (-)
- Lobular (+)
- E-cadherin
- Immunoreactivity of normal breast epithelium
Prognosis
- ASCO 2016 prognostic marker recommendations – refer to Key Points section
- Other markers
- p53
- Positivity may be associated with worse prognosis
- Aneuploid and high S-phase tumors
- Associated with worse prognosis in node-negative cancers
- Low S-phase and diploid DNA content associated with better prognosis​
- PIK3CA gene mutation
- Associated with shorter breast cancer-specific and disease-free survival
- FGFR2 gene mutation
- ~1% of breast cancers show copy number gains in the FGFR2 gene
- Reported in triple-negative breast cancers (negative for ER, PR, and HER2 expression)
- Patients whose tumors demonstrate FGFR2 gene amplification may benefit from FGFR2-targeting antibodies or FGFR-specific tyrosine kinase inhibitors
- SWOG RxPONDER trial – determine if chemotherapy need can be based on risk scores
- p53
- Minimally invasive disease detection helps determine risk or presence of metastatic disease and includes measures of tumor cells in
- Bone marrow
- Axillary nodes/sentinel nodes
- Systemically (circulating tumor cells [CTCs])
- Most helpful in prognosis of advanced disease
- Should not be used for diagnosis or treatment decisions
- Annual mammography
- Most organizations (ACS, NCI, AMA, AGS) recommend annual screening beginning at 50 years (see table in Screening section)
- Annual gynecological examination for patients receiving tamoxifen therapy due to increased risk of endometrial cancer
- Endometrial ultrasound and biopsy indicated in patients with abnormal vaginal bleeding or atypical endometrial cells on a PAP smear
- Cancer markers
- CA 15-3 and CA 27.29
- May be used to monitor advanced disease in conjunction with diagnostic imaging, history, physical (NCCN, 2016)
- Cannot be used singly for monitoring breast cancer patients
- Serial measurements are most useful, using the same marker sequentially
- Carcinogenic embryonic antigen – use in conjunction with imaging, history, physical for monitoring therapy in metastatic disease (NCCN, 2016)
- Circulating tumor cell count – use to determine prognosis, assess treatment efficacy, and aid in treatment decisions for patients with metastatic breast cancer
- HER2 (serum) – preliminary evidence suggests potential value in monitoring trastuzumab therapy in advanced disease
- CA 15-3 and CA 27.29
- Tamoxifen is an anti-estrogen drug used in treatment of ER+Â breast cancer
- Tamoxifen metabolites, particularly endoxifen and 4-hydroxy-tamoxifen, bind the estrogen receptors and suppress breast cancer cell proliferation
- Cytochrome P450 2D6 (CYP2D6) and tamoxifen
- Metabolism of tamoxifen to endoxifen depends on a CYP2D6-mediated reaction
- Decreased metabolite production (due to nonfunctional or poorly functional CYP2D6) could put patients at risk for recurrence of breast cancer
- CYP2D6 genotype is associated with the following phenotypes
- Poor metabolizer – little or no metabolism; alternate drug recommended
- Intermediate metabolizer – possible impaired metabolism
- Ultrarapid metabolizer – faster-than-normal metabolism; implications for tamoxifen therapy not well-characterized
- NCCN (2015), ASCO (2016) do not recommend routine CYP2D6 genotyping to determine optimal adjuvant endocrine strategy
- Cytochrome P450 2C19 (CYP2C19) and tamoxifen
- Metabolism of tamoxifen to 4-hydroxy-tamoxifen can be accelerated by the presence of the CYP2C19*17 allele that confers an ultrarapid metabolizer phenotype
- Tamoxifen metabolism is also affected by concomitant administration of selective serotonin reuptake inhibitors (SSRIs) and other strong inhibitors of CYP2D6
- Strong inhibitors of CYP2D6 should be avoided in patients taking tamoxifen
Primary carcinoma of the breast, the most common type of breast malignancy, usually begins as a neoplastic proliferation of epithelial cells lining the ducts or lobules of the breast.
Epidemiology
- Incidence – ~235,000 new cases of breast cancer diagnosed in U.S. per year (NCCN, 2016)
- BRCA1 or BRCA2 mutation
- 1:500 – individuals from general population
- 1:40 – Ashkenazi Jewish population
- BRCA1 or BRCA2 mutation
- Prevalence – increases with age
- Sporadic breast cancer usually occurs after age 50
- Breast cancer commonly occurs before age 50 in BRCA1 and BRCA2 mutation carriers
- Median age at diagnosis – 61 years (SEER, 2014)
- Sex – most common cancer in females
- Rare in males (~2,000/year in U.S.) (SEER, 2014)
Risk Factors
- Associated with only a minority of cases
- Gene mutations – BRCA1, BRCA2 most common; several other genes likely involved (see Screening section)
- BRCA1 and BRCA2 mutations believed to cause 20-60% of all hereditary breast cancers
- 5-10% of all breast cancer and 10-15% of ovarian cancers are caused by BRCA1 or BRCA2 mutations
- BRCA mutation database (University of Utah Huntsman Cancer Institute (HCI), WHO International Agency for Research on Cancer (IARC), University of Utah Department of Pathology and ARUP Laboratories)
- Early menarche
- Late menopause
- First childbirth at >30 years
- Menopausal hormonal replacement therapy
- Chest radiation at <30 years
- Moderate alcohol intake
- Family history of breast cancer
- Previous exposure to chest radiation
- See the National Cancer Institute for the Breast Cancer Risk Assessment Tool  (based on the GAIL model) to further estimate breast cancer risk
Pathophysiology
- Tumors are usually epithelial cell in origin
- Noninvasive forms may be present alone or in association with invasive carcinoma
Clinical Presentation
- Breast mass
- Nipple discharge
- Breast asymmetry
- Retraction of nipple, skin changes
- Redness or tenderness – inflammatory breast cancer
Estrogen/Progesterone Receptor with Interpretation by Immunohistochemistry 0049210
Method: Immunohistochemistry
Aid in prediction of response to anti-estrogen therapy
Stained and resulted by ARUP
For paraffin-embedded, formalin-fixed tissue
ERBB2 (HER2/neu) (HercepTest) by Immunohistochemistry, Tissue with Reflex to FISH if 2+ 0049178
Method: Immunohistochemistry
Aid in prediction of response to HER2-directed therapy in patients with breast cancer
Alternate test to confirm equivocal dual in situ hybridization (ISH) or fluorescence in situ hybridization (FISH) result
Measure protein expression
Reflex pattern – if ERBB2 (HercepTest) result is 2+, then FISH is added
ERBB2 (HER2/neu) (HercepTest) with Interpretation by Immunohistochemistry, Tissue 0049174
Method: Immunohistochemistry
Aid in prediction of response to HER2-directed therapy in patients with breast or gastric cancer
Alternate test to confirm equivocal FISH result
Measure protein expression
ERBB2 (HER2) (HercepTest) by Immunohistochemistry 2007332
Method: Immunohistochemistry
Measure protein overexpression
ERBB2 (HER2/neu) Gene Amplification by FISH, Tissue 2008603
Method: Fluorescence in situ Hybridization
Aid in prediction of response to HER2-directed therapy in patients with breast cancer
Use to confirm equivocal HercepTest IHC result (2+)
FDA approved for formalin-fixed tissue only
HER2/neu Quantitative by ELISA 2004672
Method: Quantitative Enzyme-Linked Immunosorbent Assay
Triage for trastuzumab therapy when solid tissue unavailable
Positive results are reliable; however, this serum assay has a 30% false-negative rate
PIK3CA Mutation Detection 2004510
Method: Polymerase Chain Reaction/Pyrosequencing
Predict response to anti-EGFR and AKT/mTOR pathway therapies in a variety of malignancies, including breast cancer
Detect activating PIK3CA mutations in exons 9 and 20 associated with anti-EGFR therapy resistance
Single gene assay
p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry
May be an indicator of worse prognosis
Stained and resulted by ARUP
Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry
Histologic indication of tumor proliferation
Stained and resulted by ARUP
Cytology, Non-Gynecologic 2000623
Method: Microscopy
This test is used for all nongynecologic sources EXCEPT specimens obtained by fine needle aspiration; for FNA specimens, refer to fine needle aspirate test
Cytomorphologic screening for breast cancer cells and precursor lesions
Potential risk-assessment tool
Known false negatives and false positives
Breast and Ovarian Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 20 Genes 2012026
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Preferred first-tier genetic test to diagnose a hereditary cancer syndrome related to breast and ovarian cancer, including HBOC, if a known familial variant has NOT been previously identified
When a relative has been previously tested, see familial mutation targeted sequencing test
Highest detection rate for HBOC syndrome but also highest likelihood of identifying variants of unknown significance
Genes tested – ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53
Refer to Additional Technical Information document for further content
Clinical sensitivity – unknown
Deep intronic and regulatory mutations, breakpoints for large deletions/duplications, sequence changes in EPCAM, exons 11-15 of CHEK2 will not be evaluated with the exception of the c.1100delC mutation, and deletions/duplications (exon 1 in CDH1, MSH2, and RAD51D; exons 4,6, 7 in STK11; exon 8 in PTEN; exon 12 in ATM) will not be determined or evaluated
Small deletions or insertions may not be detected
Diagnostic errors can occur due to rare sequence variations
Â
Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing and Deletion/Duplication 2011949
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Acceptable first-tier genetic test to confirm HBOC syndrome
When a relative has been previously tested, see familial mutation targeted sequencing test
Only the BRCA1 and BRCA2 genes are assayed
Clinical sensitivity – ~20-60% sensitivity for HBOC syndrome
Analytical sensitivity and specificity of sequencing – 99% and 96%, respectively
Rare diagnostic errors can occur due to primer or probe site mutations
Regulatory region mutations and deep intronic mutations will not be detected
Genes causing HBOC syndrome, other than BRCA1 and BRCA2, are not tested
Deletion/duplication breakpoints will not be determined
Prosigna Breast Cancer Prognostic Gene Signature 2010248
Method: Hybridization/gene expression
Assess the risk of distant recurrence in post- or perimenopausal women with early stage (stage I or stage II), hormone receptor-positive (ER+ and/or PR+) breast cancer
Useful in both node-negative and node-positive (1-3 nodes) disease
May help decrease overtreatment with chemotherapy
Minimum 10% tumor required
Test is intended for women with hormone receptor-positive breast cancer only
Not intended to provide information about what chemotherapy regimen should be given if at high risk for distant recurrence
Circulating Tumor Cell Count 0093399
Method: Immunomagnetic Separation/Immunofluorescent Stain/Computer Assisted Analysis
Use to prognosticate, assess treatment efficacy, and manage treatment decisions for patients with metastatic breast cancer
Use in metastatic tumors in conjunction with clinical data and imaging to monitor response to therapy and disease progression
Cutoffs vary by tumor cell type
CTC is not as accurate as imaging in assessing whether a patient has progressive disease
Doxorubicin therapy patients – allow at least 7 days following administration of dose before testing
Not detected – CTCs that do not express EpCAM; CTCs that express EpCAM but not cytokeratins 8, 18, and 19
Serial CTCs should be performed in the same laboratory
E-Cadherin by Immunohistochemistry 2003869
Method: Immunohistochemistry
Histologic diagnosis of morphologic subtype of breast cancer
Stained and returned to client pathologist for interpretation; consultation available if required
PAX8 by Immunohistochemistry 2010787
Method: Immunohistochemistry
Distinguish ovarian cancer from breast cancer
Stained and returned to client pathologist for interpretation; consultation available if required
GATA3 by Immunohistochemistry 2012558
Method: Immunohistochemistry
Breast marker
Can be used in a panel of antibodies for diagnosis of unknown primary carcinoma when carcinomas of the breast or bladder are a possibility; the pattern of reactivity should be nuclear
Stained and returned to client pathologist for interpretation; consultation available if required
Cytochrome P450 2D6 (CYP2D6) 14 Variants and Gene Duplication 0051232
Method: Polymerase Chain Reaction/Fluorescence Monitoring
Â
Assess genetic risk of abnormal drug metabolism for drugs metabolized by CYP2D6
Investigate genetic causes that might contribute to a personal or family history of an adverse drug event or therapeutic failure involving a drug metabolized by CYP2D6
May aid in drug selection and dose planning for drugs metabolized by CYP2D6
Clinical sensitivity – drug dependent
Analytical sensitivity/specificity – >99%
Variants tested (variants are numbered according to M33388 sequence)
- Functional
- *2 (2850C>T)
- *2A (-1584C>G; 2850C>T)
- Decreased function
- *9 (2613-5delAGA)
- *10 (100C>T)
- *17 (1023C>T)
- *29 (1659G>A)
- *41 (2988G>A)
- Non-functional
- *3 (2549delA)
- *4 (1846G>A)
- *5 (gene deletion)
- *6 (1707delT)
- *7 (2935A>C)
- *8 (1758G>T)
- *12 (124G>A)
- *14 (1758G>A)
- Increased function
- Duplicated functional alleles
Only the targeted CYP2D6 variants will be detected by this panel
Diagnostic errors can occur due to rare sequence variations
Risk of therapeutic failure or adverse reactions with CYP2D6 substrates may be affected by genetic and nongenetic factors that are not detected by this test
This result does not replace the need for therapeutic drug or clinical monitoring
It is not always possible to identify which allele is duplicated when a CYP2D6 duplication is detected
Cytochrome P450 2C19, CYP2C19 - 9 Variants 2012769
Method: Polymerase Chain Reaction/Fluorescence Monitoring
Assess genetic risk of abnormal drug metabolism for drugs metabolized by CYP219
Investigate genetic causes that might contribute to a personal or family history of an adverse drug event or therapeutic failure involving a drug metabolized by CYP2C19
May aid in drug selection and dose planning for drugs metabolized by CYP2C19
Variants detected
- Decreased function
- *9 (c.431G>A)
- *10 (c.680C>T)
- No function
- *2 (c.681G>A)
- *3 (c.636G>A)
- *4 (c.1A>G)
- *6 (c.395G>A)
- *7 (c.819+2T>A)
- *8 (c.358T>C)
- Increased function
- *17 (c.-806C>T)
Clinical sensitivity – drug dependent
Analytical sensitivity/specificity – >99%Â
Only the targeted CYP2C19 mutations will be detected
Diagnostic errors can occur due to rare sequence variations
Risk of therapeutic failure or adverse reactions with CYP2C19 substrates may be affected by genetic and nongenetic factors that are not detected by this test
This result does not replace the need for therapeutic drug or clinical monitoring
Guidelines
Albert RH, Clark MM. Cancer Screening in the Older Patient. Am Fam Physician. Leawood, KS [Accessed: Dec2016]
American College of Obstetricians-Gynecologists. Practice bulletin no. 122: Breast cancer screening. Obstet Gynecol. 2011; 118(2 Pt 1): 372-82. PubMed
Clinical Preventive Service Recommendation - Breast Cancer. Am Fam Physician. Leawood, KS [Accessed: Dec 2016]
Hammond EH, Hayes DF, Dowsett M, Allred C, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne K, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams B, Wittliff JL, Wolff AC, American Society of Clinical Oncology, College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010; 134(7): e48-72. PubMed
Hammond EH. ASCO-CAP guidelines for breast predictive factor testing: an update. Appl Immunohistochem Mol Morphol. 2011; 19(6): 499-500. PubMed
Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1): 70-87. PubMed
Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC, American Society of Clinical Oncology. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007; 25(33): 5287-312. PubMed
Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, Hammond EH, Kuderer NM, Liu MC, Mennel RG, Van Poznak C, Bast RC, Hayes DF. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016; 34(10): 1134-50. PubMed
NCCN Clinical Practice Guidelines in Oncology, Breast and Ovarian Cancer Genetic/Familial High-Risk Assessment: Breast and Ovarian . National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Apr 2017]
NCCN Clinical Practice Guidelines in Oncology, Breast Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Apr 2017]
Oeffinger KC, Fontham ET, Etzioni R, Herzig A, Michaelson JS, Shih YT, Walter LC, Church TR, Flowers CR, LaMonte SJ, Wolf AM, DeSantis C, Lortet-Tieulent J, Andrews K, Manassaram-Baptiste D, Saslow D, Smith RA, Brawley OW, Wender R, American Cancer Society. Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society. JAMA. 2015; 314(15): 1599-614. PubMed
Protocol for the Examination of Specimens from Patients with Ductal Carcinoma In Situ (DCIS) of the Breast. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: December 2013. College of American Pathologists (CAP). Northfield, IL [Revised Dec 2013; Accessed: Dec 2016]
Protocol for the Examination of Specimens from Patients with Invasive Carcinoma of the Breast. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Revised Jan 2016; Accessed: Dec2016]
Siu AL, U.S. Preventive Services Task Force. Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016; 164(4): 279-96. PubMed
Van Poznak C, Somerfield MR, Bast RC, Cristofanilli M, Goetz MP, Gonzalez-Angulo AM, Hicks DG, Hill EG, Liu MC, Lucas W, Mayer IA, Mennel RG, Symmans WF, Hayes DF, Harris LN. Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2015; 33(24): 2695-704. PubMed
Wolff AC, Hammond EH, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical Oncology, College of American Pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013; 31(31): 3997-4013. PubMed
General References
Breast Cancer Risk Assessment Tool. National Cancer Institute. Bethesda, MD [Accessed: Feb 2017]
Dooley WC, Ljung BM, Veronesi U, Cazzaniga M, Elledge RM, O'Shaughnessy JA, Kuerer HM, Hung DT, Khan SA, Phillips RF, Ganz PA, Euhus DM, Esserman LJ, Haffty BG, King BL, Kelley MC, Anderson MM, Schmit PJ, Clark RR, Kass FC, Anderson BO, Troyan SL, Arias RD, Quiring JN, Love SM, Page DL, King EB. Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. J Natl Cancer Inst. 2001; 93(21): 1624-32. PubMed
Duffy MJ, Evoy D, McDermott EW. CA 15-3: uses and limitation as a biomarker for breast cancer. Clin Chim Acta. 2010; 411(23-24): 1869-74. PubMed
Duffy MJ, Walsh S, McDermott EW, Crown J. Biomarkers in Breast Cancer: Where Are We and Where Are We Going Adv Clin Chem. 2015; 71: 1-23. PubMed
Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med. 2011; 135(1): 55-62. PubMed
Lalloo F, Evans DG. Familial breast cancer. Clin Genet. 2012; 82(2): 105-14. PubMed
López-Muñoz E, Méndez-Montes M. Markers of circulating breast cancer cells. Adv Clin Chem. 2013; 61: 175-224. PubMed
Nofech-Mozes S, Vella ET, Dhesy-Thind S, Hagerty KL, Mangu PB, Temin S, Hanna WM. Systematic review on hormone receptor testing in breast cancer. Appl Immunohistochem Mol Morphol. 2012; 20(3): 214-63. PubMed
Ramsey SD, Henry L, Gralow JR, Mirick DK, Barlow W, Etzioni R, Mummy D, Thariani R, Veenstra DL. Tumor marker usage and medical care costs among older early-stage breast cancer survivors. J Clin Oncol. 2015; 33(2): 149-55. PubMed
Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King M, Swisher EM. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011; 108(44): 18032-7. PubMed
References from the ARUP Institute for Clinical and Experimental Pathology®
Al-Tamimi DM, Bernard PS, Shawarby MA, Al-Amri AM, Hadi MA. Distribution of molecular breast cancer subtypes in middle eastern-saudi arabian women: a pilot study. Ultrastruct Pathol. 2009; 33(4): 141-50. PubMed
Barker SD, Bale S, Booker J, Buller A, Das S, Friedman K, Godwin AK, Grody WW, Highsmith E, Kant JA, Lyon E, Mao R, Monaghan KG, Payne DA, Pratt VM, Schrijver I, Shrimpton AE, Spector E, Telatar M, Toji L, Weck K, Zehnbauer B, Kalman LV. Development and characterization of reference materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2 genetic testing. J Mol Diagn. 2009; 11(6): 553-61. PubMed
Bastien R, Lewis TB, Hawkes JE, Quackenbush JF, Robbins TC, Palazzo J, Perou CM, Bernard PS. High-throughput amplicon scanning of the TP53 gene in breast cancer using high-resolution fluorescent melting curve analyses and automatic mutation calling. Hum Mutat. 2008; 29(5): 757-64. PubMed
Bastien RR, RodrÃguez-Lescure A, Ebbert MT, Prat A, Munárriz B, Rowe L, Miller P, Ruiz-Borrego M, Anderson D, Lyons B, lvarez IÃ, Dowell T, Wall D, Seguà MÃ, Barley L, Boucher KM, Alba E, Pappas L, Davis CA, Aranda I, Fauron C, Stijleman IJ, Palacios J, Antón A, Carrasco E, Caballero R, Ellis MJ, Nielsen TO, Perou CM, Astill M, Bernard PS, MartÃn M. PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. BMC Med Genomics. 2012; 5: 44. PubMed
Botkin JR, Smith KR, Croyle RT, Baty BJ, Wylie JE, Dutson D, Chan A, Hamann HA, Lerman C, McDonald J, Venne V, Ward JH, Lyon E. Genetic testing for a BRCA1 mutation: prophylactic surgery and screening behavior in women 2 years post testing. Am J Med Genet A. 2003; 118A(3): 201-9. PubMed
Caan BJ, Sweeney C, Habel LA, Kwan ML, Kroenke CH, Weltzien EK, Quesenberry CP, Castillo A, Factor RE, Kushi LH, Bernard PS. Intrinsic subtypes from the PAM50 gene expression assay in a population-based breast cancer survivor cohort: prognostication of short- and long-term outcomes. Cancer Epidemiol Biomarkers Prev. 2014; 23(5): 725-34. PubMed
Carey LA, Rugo HS, Marcom K, Mayer EL, Esteva FJ, Ma CX, Liu MC, Storniolo AM, Rimawi MF, Forero-Torres A, Wolff AC, Hobday TJ, Ivanova A, Chiu W, Ferraro M, Burrows E, Bernard PS, Hoadley KA, Perou CM, Winer EP. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol. 2012; 30(21): 2615-23. PubMed
Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009; 101(10): 736-50. PubMed
Ciocca V, Bombonati A, Gatalica Z, Di Pasquale M, Milos A, Ruiz-Orrico A, Dreher D, Folch N, Monzon F, Santeusanio G, Perou CM, Bernard PS, Palazzo JP. Cytokeratin profiles of male breast cancers. Histopathology. 2006; 49(4): 365-70. PubMed
Factor RE, Schmidt RL, Chadwick BE, Witt BJ, Morgan M, Neumayer LA, Layfield LJ. Axillary lymph node FNA in women with breast cancer is a highly accurate procedure, so why are core biopsies being done Diagn Cytopathol. 2015; 43(6): 510-2. PubMed
Geiersbach KB, Willmore-Payne C, Pasi AV, Paxton CN, Werner TL, Xu X, Wittwer CT, Gulbahce E, Downs-Kelly E. Genomic Copy Number Analysis of HER2-Equivocal Breast Cancers. Am J Clin Pathol. 2016; 146(4): 439-47. PubMed
Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007; 8(5): R76. PubMed
Hoadley KA, Weigman VJ, Fan C, Sawyer LR, He X, Troester MA, Sartor CI, Rieger-House T, Bernard PS, Carey LA, Perou CM. EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics. 2007; 8: 258. PubMed
Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Orrico AR, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS, Perou CM. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006; 7: 96. PubMed
Kallak K, Baumgart J, Evers S, Poromaa S, Moby L, Kask K, Norjavaara E, Kushnir MM, Bergquist J, Nilsson K. Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients. Climacteric. 2012; 15(5): 473-80. PubMed
Kroenke CH, Sweeney C, Kwan ML, Quesenberry CP, Weltzien EK, Habel LA, Castillo A, Bernard PS, Factor RE, Kushi LH, Caan BJ. Race and breast cancer survival by intrinsic subtype based on PAM50 gene expression. Breast Cancer Res Treat. 2014; 144(3): 689-99. PubMed
Kwan ML, Bernard PS, Kroenke CH, Factor RE, Habel LA, Weltzien EK, Castillo A, Gunderson EP, Maxfield KS, Stijleman IJ, Langholz BM, Quesenberry CP, Kushi LH, Sweeney C, Caan BJ. Breastfeeding, PAM50 tumor subtype, and breast cancer prognosis and survival J Natl Cancer Inst. 2015; 107(7): PubMed
Kwan ML, Kroenke CH, Sweeney C, Bernard PS, Weltzien EK, Castillo A, Factor RE, Maxfield KS, Stijleman IJ, Kushi LH, Quesenberry CP, Habel LA, Caan BJ. Association of high obesity with PAM50 breast cancer intrinsic subtypes and gene expression BMC Cancer. 2015; 15: 278. PubMed
Layfield LJ, Lewis C. In situ and invasive components of mammary adenocarcinoma: comparison of Her-2/neu status. Anal Quant Cytol Histol. 2007; 29(4): 239-43. PubMed
Layfield LJ, Schmidt RL. HER2/neu gene amplification heterogeneity: the significance of cells with a 3:1 HER2/CEP17 ratio. Appl Immunohistochem Mol Morphol. 2012; 20(6): 543-9. PubMed
Layfield LJ, Willmore-Payne C, Isom G, Holden JA. Monoplex LightCycler polymerase chain reaction quantitation of the HER2 gene for quality assurance of HER2/neu testing by immunohistochemistry and fluorescence in situ hybridization. Appl Immunohistochem Mol Morphol. 2008; 16(6): 562-7. PubMed
Liu J, Welm B, Boucher KM, Ebbert MT, Bernard PS. TRIM29 functions as a tumor suppressor in nontumorigenic breast cells and invasive ER+ breast cancer. Am J Pathol. 2012; 180(2): 839-47. PubMed
MartÃn M, Brase JC, Ruiz A, Prat A, Kronenwett R, Calvo L, Petry C, Bernard PS, Ruiz-Borrego M, Weber KE, Rodriguez CA, Alvarez IM, Segui MA, Perou CM, Casas M, Carrasco E, Caballero R, RodrÃguez-Lescure A. Prognostic ability of EndoPredict compared to research-based versions of the PAM50 risk of recurrence (ROR) scores in node-positive, estrogen receptor-positive, and HER2-negative breast cancer. A GEICAM/9906 sub-study. Breast Cancer Res Treat. 2016; 156(1): 81-9. PubMed
Millson A, Suli A, Hartung L, Kunitake S, Bennett A, Nordberg MC, Hanna W, Wittwer CT, Seth A, Lyon E. Comparison of two quantitative polymerase chain reaction methods for detecting HER2/neu amplification. J Mol Diagn. 2003; 5(3): 184-90. PubMed
Mims MP, Hayes TG, Zheng S, Leal SM, Frolov A, Ittmann MM, Wheeler TM, Prchal JT. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res. 2006; 66(3): 1880; author reply 1880-1. PubMed
Mullins M, Perreard L, Quackenbush JF, Gauthier N, Bayer S, Ellis M, Parker J, Perou CM, Szabo A, Bernard PS. Agreement in breast cancer classification between microarray and quantitative reverse transcription PCR from fresh-frozen and formalin-fixed, paraffin-embedded tissues. Clin Chem. 2007; 53(7): 1273-9. PubMed
Okal A, Matissek KJ, Matissek SJ, Price R, Salama ME, Janát-Amsbury MM, Lim CS. Re-engineered p53 activates apoptosis in vivo and causes primary tumor regression in a dominant negative breast cancer xenograft model. Gene Ther. 2014; 21(10): 903-12. PubMed
Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009; 27(8): 1160-7. PubMed
Perreard L, Fan C, Quackenbush JF, Mullins M, Gauthier NP, Nelson E, Mone M, Hansen H, Buys SS, Rasmussen K, Orrico AR, Dreher D, Walters R, Parker J, Hu Z, He X, Palazzo JP, Olopade OI, Szabo A, Perou CM, Bernard PS. Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay. Breast Cancer Res. 2006; 8(2): R23. PubMed
Prat A, Cheang MC, MartÃn M, Parker JS, Carrasco E, Caballero R, Tyldesley S, Gelmon K, Bernard PS, Nielsen TO, Perou CM. Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer. J Clin Oncol. 2013; 31(2): 203-9. PubMed
Proctor KA, Rowe LR, Bentz JS. Cytologic features of nipple aspirate fluid using an automated non-invasive collection device: a prospective observational study. BMC Womens Health. 2005; 5: 10. PubMed
Samowitz WS, Ogino S. DNA methylation in breast and colorectal cancers. Mod Pathol. 2008; 21(8): 1054; author reply 1054-5. PubMed
Schwartz GF, Hughes KS, Lynch HT, Fabian CJ, Fentiman IS, Robson ME, Domchek SM, Hartmann LC, Holland R, Winchester DJ, Consensus Conference Committee The International Consensus Conference Committee. Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007. Cancer. 2008; 113(10): 2627-37. PubMed
Sheffield BS, Kos Z, Asleh-Aburaya K, Wang XQ, Leung S, Gao D, Won J, Chow C, Rachamadugu R, Stijleman I, Wolber R, Gilks B, Myles N, Thomson T, Hayes MM, Bernard PS, Nielsen TO, Chia SK. Molecular subtype profiling of invasive breast cancers weakly positive for estrogen receptor. Breast Cancer Res Treat. 2016; 155(3): 483-90. PubMed
Slev PR, Rawlins ML, Roberts WL. Performance characteristics of seven automated CA 15-3 assays. Am J Clin Pathol. 2006; 125(5): 752-7. PubMed
Sweeney C, Bernard PS, Factor RE, Kwan ML, Habel LA, Quesenberry CP, Shakespear K, Weltzien EK, Stijleman IJ, Davis CA, Ebbert MT, Castillo A, Kushi LH, Caan BJ. Intrinsic subtypes from PAM50 gene expression assay in a population-based breast cancer cohort: differences by age, race, and tumor characteristics. Cancer Epidemiol Biomarkers Prev. 2014; 23(5): 714-24. PubMed
Sweeney C, Wolff RK, Byers T, Baumgartner KB, Giuliano AR, Herrick JS, Murtaugh MA, Samowitz WS, Slattery ML. Genetic admixture among Hispanics and candidate gene polymorphisms: potential for confounding in a breast cancer study? Cancer Epidemiol Biomarkers Prev. 2007; 16(1): 142-50. PubMed
Thompson MD, Grubbs CJ, Bode AM, Reid JM, McGovern R, Bernard PS, Stijleman IJ, Green JE, Bennett C, Juliana M, Moeinpour F, Steele VE, Lubet RA. Lack of effect of metformin on mammary carcinogenesis in nondiabetic rat and mouse models Cancer Prev Res (Phila). 2015; 8(3): 231-9. PubMed
Wallden B, Storhoff J, Nielsen T, Dowidar N, Schaper C, Ferree S, Liu S, Leung S, Geiss G, Snider J, Vickery T, Davies SR, Mardis ER, Gnant M, Sestak I, Ellis MJ, Perou CM, Bernard PS, Parker JS. Development and verification of the PAM50-based Prosigna breast cancer gene signature assay BMC Med Genomics. 2015; 8: 54. PubMed
Willmore C, Holden JA, Layfield LJ. Correlation of HER2 gene amplification with immunohistochemistry in breast cancer as determined by a novel monoplex polymerase chain reaction assay. Appl Immunohistochem Mol Morphol. 2005; 13(4): 333-41. PubMed
Willmore-Payne C, Holden JA, Zhou H, Gupta D, Hirschowitz S, Wittwer CT, Layfield LJ. Evaluation of Her-2/neu gene status in osteosarcoma by fluorescence in situ hybridization and multiplex and monoplex polymerase chain reactions. Arch Pathol Lab Med. 2006; 130(5): 691-8. PubMed
Willmore-Payne C, Metzger K, Layfield LJ. Effects of fixative and fixation protocols on assessment of Her-2/neu oncogene amplification status by fluorescence in situ hybridization. Appl Immunohistochem Mol Morphol. 2007; 15(1): 84-7. PubMed
Wittwer CT. High-resolution DNA melting analysis: advancements and limitations. Hum Mutat. 2009; 30(6): 857-9. PubMed
Won JR, Gao D, Chow C, Cheng J, Lau SY, Ellis MJ, Perou CM, Bernard PS, Nielsen TO. A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard. Mod Pathol. 2013; 26(11): 1438-50. PubMed
Medical Reviewers
Breast Predictive Factor Update - Elizabeth H.Hammond, MD, FCAP (FREE CME credit) (37 min)
Clinical Next-Gen Sequencing for Solid Tumors: What, How, Why, and When? - Christopher Corless, MD, PhD (FREE CME credit) (48 min)
Hereditary Breast and Ovarian Cancer and Genetic Testing - Rong Mao, MD, and Gwendolyn A. McMillin, PhD, DABCC (CC, TC) (FREE CME credit) (23 min)
Intraductal Proliferative Lesions of the Breast - Juan Rosai, MD (FREE CME credit) (48 min)
Laboratory Testing for HER2 Status in Breast Cancer - Katherine Geiersbach, MD, FCAP, FACMG (FREE CME credit) (38 min)
Molecular Oncology: The Role of Next-Generation, Sequencing-Based Gene Panels in Solid Tumors - Allie Grossmann, MD, PhD (60 min)
Molecular Testing in Breast Cancer: An Oncologist’s Perspective - Adam Cohen, MD (FREE CME credit) (52 min)
Next Generation Sequencing for Solid Tumors Diagnostics: Current Practice and New Developments - Larissa V. Furtado, MD (FREE CME credit) (62 min)
Pharmacogenetics of CYP-Mediated Drug Metabolism - Gwendolyn A. McMillin, PhD (FREE CME credit) (25 min)
Prognostic Gene Expression Tests for Early Stage Breast Cancer - Philip S. Bernard, MD (FREE CME credit) (22 min)
Risk Mitigation in Breast Predictive Factor Testing - Elizabeth H. Hammond, MD, FCAP (FREE CME credit) (34 min)
Spindle Cell Lesions of the Breast - Erinn Downs-Kelly, DO, MS (FREE CME credit) (60 min)
Spotlight on Testing: Genetic Testing for Hereditary Breast and Ovarian Cancer Syndrome - Hunter Best, PhD (4 min)
Surprise! Breast Tumors with Unexpected Final Pathology - Rachel E. Factor, MD, MHS (FREE CME credit) (36 min)
Updates in Margin Status and Lymph Node Dissection - Leigh Neumayer, MD, MS, FACS (FREE CME credit) (44 min)
Utility of Whole Genome Arrays for the Detection of Clinically Relevant Imbalances and Homozygosity in the Constitutional and Hematologic Malignancies Setting - Sarah South, PhD, FACMG (50 min)
Last Update: May 2017