Breast Cancer

  • Diagnosis
  • Screening
  • Monitoring
  • Pharmacogenetics
  • Background
  • Lab Tests
  • References
  • Related Content

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/CAP, 2013; NCCN, 2015)
          • 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
  • 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 (-)
      • Keratin 903 – more commonly used to differentiate usual ductal hyperplasia (UDH) from atypical ductal hyperplasias (ADH)/low-grade ductal carcinoma in situ (LG-DCIS)
        • Ductal (-)
        • Lobular (+)
      • CAM 5.2
        • Ductal – peripheral
        • Lobular – perinuclear

Prognosis

  • American Society of Clinical Oncology (ASCO)/National Academy of Clinical Biochemistry (NACB)/National Comprehensive Cancer Network (NCCN) recommend the following
    • ER/PR
      • ER positivity alone is a weak prognosis indicator; use in combination with progesterone
      • Two molecular subtypes – luminal A and luminal B
        • B has best prognosis
      • Positivity associated with improved prognosis when treated with anti-estrogen therapy (tamoxifen)
    • HER2
      • Positivity occurs in 15-20% of breast cancer patients
      • Graded scale of 0-3 for immunohistochemistry
        • 0 and 1 – negative
        • 2 – equivocal
        • 3 – positive
    • Triple-negative tumors (ER-/PR-/HER2/neu-)
      • More common in
        • African Americans – significant number have BRCA1 gene mutation
        • Young age at onset
        • Premenopausal women
      • Predominantly high-grade tumors
        • 75% have basal-like gene expression (CK5/14+, EGFR+) – worst prognosis of all breast cancer subtypes
      • Worst prognosis for breast cancer
  • Other markers
    • p53
      • Positivity may be associated with worse prognosis
      • Insufficient data to recommend use in disease management (ASCO, 2007)
    • 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
      • Insufficient data to recommend use in disease management (ASCO, 2007)
    • Ki-67 (MIB-1) – cell proliferative-associated antigen
      • Elevation associated with aggressive tumor behavior
      • Insufficient data to recommend use in disease management (ASCO, 2007)
    • uPA/PAI-1 (urokinase-type plasminogen activator/plasminogen-like activator inhibitor)
      • If both markers are low in node-negative patients, risk of relapse is low
    • 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
  • Prognostic panels include Prosigna, Oncotype DX, MammaPrint, MapQuant Dx, EndoPredict, Breast Cancer Index
    • Prosigna Breast Cancer Prognostic Gene Signature assay
      • Use to assess 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
      • Scores report risk as low, intermediate, or high based on
        • Molecular subtype of tumor
        • Proliferation status
        • Tumor size and node status
      • May help decrease overtreatment with chemotherapy
      • Does not provide information about which chemotherapy regimen should be given if at high risk for distant recurrence
    •  Genomic Health Oncotype DX (National Cancer Institute [NCI])
      • 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
  • 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
  • ​Breast cytology screening (eg, using ductal lavage) not yet recommended, but may be useful in high-risk patients
  • No tumor markers recommended in screening (American Society of Clinical Oncology [ASCO], 2007)
    • All markers have low sensitivity and specificity when used in a screening setting
  • Hereditary breast and ovarian cancer (HBOC) genetic testing

Symptoms in women with any of the following (Ovarian/Breast Ca) node 1191

Based on family history (in asymptomatic patient) (Ovarian/Breast Ca) node 913

  • Individuals with a family history of a known pathogenic mutation previously identified in a relative – perform targeted mutation testing

Hereditary gene mutations (Ovarian/Breast Ca) node 1139

  • Annual mammography
    • Most organizations (American Cancer Society, National Cancer Institute, American Medical Association, American Geriatrics Society) recommend annual screening beginning at 50 years (see table in Screening)
  • 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 (National Academy of Clinical Biochemistry [NACB], National Comprehensive Cancer Network [NCCN])
      • Cannot be used singly for monitoring breast cancer patients
        • Serial measurements are most useful
    • Carcinogenic embryonic antigen – use in conjunction with imaging, history, physical for monitoring therapy in metastatic disease (NACB, NCCN)
    • 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
  • Tamoxifen is an anti-estrogen drug used in treatment of estrogen receptor-positive (ER+) 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
  • 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, 2014)
    • BRCA1 or BRCA2 mutation
      • 1:500 – individuals from general population
      • 1:40 – Ashkenazi Jewish population
  • 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 (National Cancer Institute [NCI], 2014; SEER, 2014)
  • Sex – most common cancer in females
    • Rare in males (~2,000/year in U.S.) (NCI, 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
  • 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
    • Other rare tumors include phyllodes tumors, Paget disease of the breast, inflammatory breast cancer
    • Sarcoma or lymphoma (B cell and T/NK cell) is rare
  • 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

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Estrogen/Progesterone Receptor with Interpretation by Immunohistochemistry 0049210
Method: Immunohistochemistry

Limitations

For paraffin-embedded, formalin-fixed tissue

ERBB2 (HER2/neu) (HercepTest) by Immunohistochemistry, Tissue with Reflex to FISH if 2+ 0049178
Method: Immunohistochemistry

ERBB2 (HER2/neu) (HercepTest) with Interpretation by Immunohistochemistry, Tissue 0049174
Method: Immunohistochemistry

ERBB2 (HER2) (HercepTest) by Immunohistochemistry 2007332
Method: Immunohistochemistry

ERBB2 (HER2/neu) Gene Amplification by FISH, Tissue 2008603
Method: Fluorescence in situ Hybridization

Limitations

FDA approved for formalin-fixed tissue only

HER2/neu Quantitative by ELISA 2004672
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Limitations

Positive results are reliable; however, this serum assay has a 30% false-negative rate

PIK3CA Mutation Detection 2004510
Method: Polymerase Chain Reaction/Pyrosequencing

p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

DNA Cell Cycle Analysis - Ploidy and S-Phase 0095155
Method: Quantitative Flow Cytometry

Cytology, Non-Gynecologic 2000623
Method: Microscopy

Limitations

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

Limitations

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

Refer to Additional Technical Information document for list of genes tested

Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing and Deletion/Duplication 2011949
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations

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

Limitations

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

Limitations

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

Keratin 903 (K903) High Molecular Weight by Immunohistochemistry 2003978
Method: Immunohistochemistry

E-Cadherin by Immunohistochemistry 2003869
Method: Immunohistochemistry

Cytokeratin 8,18 Low Molecular Weight (CAM 5.2) by Immunohistochemistry 2003493
Method: Immunohistochemistry

PAX8 by Immunohistochemistry 2010787
Method: Immunohistochemistry

GATA3 by Immunohistochemistry 2012558
Method: Immunohistochemistry

Cytochrome P450 2D6 (CYP2D6) 14 Variants and Gene Duplication 0051232
Method: Polymerase Chain Reaction/Primer Extension

Limitations

Only the targeted CYP2D6 variants will be detected

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

Limitations

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

Additional Tests Available

ERBB2 (HER2/neu) (HercepTest) with Interpretation by Immunohistochemistry, Tissue 0049174
Method: Immunohistochemistry

Comments

Aids in prediction of response to trastuzumab (Herceptin) therapy in patients with breast cancer

Alternate test to confirm FISH result

Cytology, Fine Needle Aspirate 2000443
Method: Microscopy

Cancer Antigen-Breast (CA 15-3) 0080464
Method: Quantitative Electrochemiluminescent Immunoassay

Comments

Monitor therapy and identify disease recurrence in individuals with metastatic breast cancer

Do not use for diagnosis or screening of breast cancer

Cancer Antigen 27.29 0080392
Method: Quantitative Chemiluminescent Immunoassay

Comments

Monitor therapy and identify disease recurrence in individuals with a metastatic breast cancer diagnosis

Do not use for diagnosis or screening of breast cancer

Carcinoembryonic Antigen 0080080
Method: Quantitative Electrochemiluminescent Immunoassay

Comments

May be used to monitor stage II-III breast cancer

Serial testing should be used in conjunction with other clinical methods

Solid Tumor Mutation Panel by Next Generation Sequencing 2007991
Method: Massively Parallel Sequencing

Comments

Prognosis/treatment of individuals with solid tumor cancers at initial diagnosis or with refractory disease

For a full list of the targeted regions of the above genes, click here

Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing 2011954
Method: Polymerase Chain Reaction/ Sequencing

Comments

Up to 90% sensitivity for BRCA1 and BRCA2 mutations

Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Deletion/Duplication 2011915
Method: Multiplex Ligation-dependent Probe Amplification

Comments

This is a second tier test and REQUIRES PERMISSION from ARUP genetic counselor before ordering

Preferred initial test is the sequencing and deletion/duplication test

Clinical sensitivity – ~10% for BRCA1 and BRCA2 mutations

Refer to Additional Technical Information document for list of genes tested

Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes 2012032
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Comments

Preferred panel for confirming a diagnosis of a hereditary cancer with personal or family history consistent with features of more than one cancer syndrome

Refer to Additional Technical Information document for list of genes tested

Cancer Panel, Hereditary, Deletion/Duplication, 46 Genes 2010757
Method: Exonic Oligonucleotide-based CGH Microarray

Comments

Use to test known familial deletions/duplications in one of the 46 genes on the panel

Refer to Additional Technical Information document for list of genes tested

Guidelines

Clinical Preventive Service Recommendation - Breast Cancer. Am Fam Physician. Leawood, KS [Accessed: Nov 2015]

Dooley W, Ljung B, Veronesi U, Cazzaniga M, Elledge R, O'Shaughnessy J, Kuerer H, Hung D, Khan S, Phillips R, Ganz P, Euhus D, Esserman L, Haffty B, King B, Kelley M, Anderson M, Schmit P, Clark R, Kass F, Anderson B, Troyan S, Arias R, Quiring J, Love S, Page D, King E. 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

Hammond E, Hayes D, Dowsett M, Allred C, Hagerty K, Badve S, Fitzgibbons P, Francis G, Goldstein N, Hayes M, Hicks D, Lester S, Love R, Mangu P, McShane L, Miller K, Osborne K, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz J, Sweep F, Taube S, Torlakovic E, Valenstein P, Viale G, Visscher D, Wheeler T, Williams B, Wittliff J, Wolff A, 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 E. ASCO-CAP guidelines for breast predictive factor testing: an update. Appl Immunohistochem Mol Morphol. 2011; 19(6): 499-500. PubMed

Hampel H, Bennett R, Buchanan A, Pearlman R, Wiesner G, 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 M, Hayes D, Bast R, 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

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: Jun 2015]

NCCN Clinical Practice Guidelines in Oncology, Breast Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

Nelson H, Tyne K, Naik A, Bougatsos C, Chan B, Humphrey L, U.S. Preventive Services Task Force. Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2009; 151(10): 727-37, W237-42. PubMed

Oeffinger K, Fontham E, Etzioni R, Herzig A, Michaelson J, Shih Y, Walter L, Church T, Flowers C, LaMonte S, Wolf A, DeSantis C, Lortet-Tieulent J, Andrews K, Manassaram-Baptiste D, Saslow D, Smith R, Brawley O, 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: October 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

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: October 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

Wolff A, Hammond E, Hicks D, Dowsett M, McShane L, Allison K, Allred D, Bartlett J, Bilous M, Fitzgibbons P, Hanna W, Jenkins R, Mangu P, Paik S, Perez E, Press M, Spears P, Vance G, Viale G, Hayes D, 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: Nov 2015]

Duffy M, Evoy D, McDermott E. CA 15-3: uses and limitation as a biomarker for breast cancer. Clin Chim Acta. 2010; 411(23-24): 1869-74. PubMed

Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med. 2011; 135(1): 55-62. PubMed

Lalloo F, Evans D. 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 E, Dhesy-Thind S, Hagerty K, Mangu P, Temin S, Hanna W. Systematic review on hormone receptor testing in breast cancer. Appl Immunohistochem Mol Morphol. 2012; 20(3): 214-63. PubMed

Walsh T, Casadei S, Lee M, Pennil C, Nord A, Thornton A, Roeb W, Agnew K, Stray S, Wickramanayake A, Norquist B, Pennington K, Garcia R, King M, Swisher E. 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 D, Bernard P, Shawarby M, Al-Amri A, Hadi M. Distribution of molecular breast cancer subtypes in middle eastern-saudi arabian women: a pilot study. Ultrastruct Pathol. 2009; 33(4): 141-50. PubMed

Barker S, Bale S, Booker J, Buller A, Das S, Friedman K, Godwin A, Grody W, Highsmith E, Kant J, Lyon E, Mao R, Monaghan K, Payne D, Pratt V, Schrijver I, Shrimpton A, Spector E, Telatar M, Toji L, Weck K, Zehnbauer B, Kalman L. 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 T, Hawkes J, Quackenbush J, Robbins T, Palazzo J, Perou C, Bernard P. 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 R, Rodríguez-Lescure A, Ebbert M, Prat A, Munárriz B, Rowe L, Miller P, Ruiz-Borrego M, Anderson D, Lyons B, lvarez I, Dowell T, Wall D, Seguí M, Barley L, Boucher K, Alba E, Pappas L, Davis C, Aranda I, Fauron C, Stijleman I, Palacios J, Antón A, Carrasco E, Caballero R, Ellis M, Nielsen T, Perou C, Astill M, Bernard P, Martín M. PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. BMC Med Genomics. 2012; 5: 44. PubMed

Botkin J, Smith K, Croyle R, Baty B, Wylie J, Dutson D, Chan A, Hamann H, Lerman C, McDonald J, Venne V, Ward J, 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 B, Sweeney C, Habel L, Kwan M, Kroenke C, Weltzien E, Quesenberry C, Castillo A, Factor R, Kushi L, Bernard P. 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 L, Rugo H, Marcom K, Mayer E, Esteva F, Ma C, Liu M, Storniolo A, Rimawi M, Forero-Torres A, Wolff A, Hobday T, Ivanova A, Chiu W, Ferraro M, Burrows E, Bernard P, Hoadley K, Perou C, Winer E. 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 M, Chia S, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard P, Parker J, Perou C, Ellis M, Nielsen T. 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 C, Bernard P, Palazzo J. Cytokeratin profiles of male breast cancers. Histopathology. 2006; 49(4): 365-70. PubMed

Herschkowitz J, Simin K, Weigman V, Mikaelian I, Usary J, Hu Z, Rasmussen K, Jones L, Assefnia S, Chandrasekharan S, Backlund M, Yin Y, Khramtsov A, Bastein R, Quackenbush J, Glazer R, Brown P, Green J, Kopelovich L, Furth P, Palazzo J, Olopade O, Bernard P, Churchill G, Van Dyke T, Perou C. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007; 8(5): R76. PubMed

Hoadley K, Weigman V, Fan C, Sawyer L, He X, Troester M, Sartor C, Rieger-House T, Bernard P, Carey L, Perou C. EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics. 2007; 8: 258. PubMed

Hu Z, Fan C, Oh D, Marron J, He X, Qaqish B, Livasy C, Carey L, Reynolds E, Dressler L, Nobel A, Parker J, Ewend M, Sawyer L, Wu J, Liu Y, Nanda R, Tretiakova M, Orrico A, Dreher D, Palazzo J, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush J, Ellis M, Olopade O, Bernard P, Perou C. 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 M, 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 C, Sweeney C, Kwan M, Quesenberry C, Weltzien E, Habel L, Castillo A, Bernard P, Factor R, Kushi L, Caan B. Race and breast cancer survival by intrinsic subtype based on PAM50 gene expression. Breast Cancer Res Treat. 2014; 144(3): 689-99. PubMed

Layfield L, 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 L, Schmidt R. 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 L, Willmore-Payne C, Isom G, Holden J. 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 K, Ebbert M, Bernard P. TRIM29 functions as a tumor suppressor in nontumorigenic breast cells and invasive ER+ breast cancer. Am J Pathol. 2012; 180(2): 839-47. PubMed

Millson A, Suli A, Hartung L, Kunitake S, Bennett A, Nordberg M, Hanna W, Wittwer C, 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 M, Hayes T, Zheng S, Leal S, Frolov A, Ittmann M, Wheeler T, Prchal J. 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 J, Gauthier N, Bayer S, Ellis M, Parker J, Perou C, Szabo A, Bernard P. 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 K, Matissek S, Price R, Salama M, Janát-Amsbury M, Lim C. 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 J, Mullins M, Cheang M, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush J, Stijleman I, Palazzo J, Marron J, Nobel A, Mardis E, Nielsen T, Ellis M, Perou C, Bernard P. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009; 27(8): 1160-7. PubMed

Perreard L, Fan C, Quackenbush J, Mullins M, Gauthier N, Nelson E, Mone M, Hansen H, Buys S, Rasmussen K, Orrico A, Dreher D, Walters R, Parker J, Hu Z, He X, Palazzo J, Olopade O, Szabo A, Perou C, Bernard P. 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 M, Martín M, Parker J, Carrasco E, Caballero R, Tyldesley S, Gelmon K, Bernard P, Nielsen T, Perou C. 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 K, Rowe L, Bentz J. 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 W, Ogino S. DNA methylation in breast and colorectal cancers. Mod Pathol. 2008; 21(8): 1054; author reply 1054-5. PubMed

Schwartz G, Hughes K, Lynch H, Fabian C, Fentiman I, Robson M, Domchek S, Hartmann L, Holland R, Winchester D, 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

Slev P, Rawlins M, Roberts W. Performance characteristics of seven automated CA 15-3 assays. Am J Clin Pathol. 2006; 125(5): 752-7. PubMed

Sweeney C, Bernard P, Factor R, Kwan M, Habel L, Quesenberry C, Shakespear K, Weltzien E, Stijleman I, Davis C, Ebbert M, Castillo A, Kushi L, Caan B. 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 R, Byers T, Baumgartner K, Giuliano A, Herrick J, Murtaugh M, Samowitz W, Slattery M. 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

Willmore C, Holden J, Layfield L. 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 J, Zhou H, Gupta D, Hirschowitz S, Wittwer C, Layfield L. 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 L. 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 C. High-resolution DNA melting analysis: advancements and limitations. Hum Mutat. 2009; 30(6): 857-9. PubMed

Won J, Gao D, Chow C, Cheng J, Lau S, Ellis M, Perou C, Bernard P, Nielsen T. 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

Best, Hunter, PhD, Medical Director, Molecular Genetics; Director, High Complexity Platforms-NGS at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Bronner, Mary P., MD, Division Chief, Anatomic Pathology and Oncology at ARUP Laboratories; Professor of Anatomic Pathology, University of Utah

Geiersbach, Katherine, MD, FCAP, Medical Director, Solid Tumor Paraffin FISH, and Staff Pathologist, Molecular Oncology at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Gopez, Evelyn V., MD, Staff Cytopathologist at ARUP Laboratories; Associate Dean, Inclusion and Outreach, School of Medicine; Professor of Clinical Pathology, University of Utah

Gulbahce, H. Evin, MD, Staff Pathologist, Surgical Pathology and Oncology at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Heikal, Nahla, MD, MS, Assistant Medical Director, Immunology and Hemostasis/Thrombosis at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Lyon, Elaine, PhD, Medical Director, Genetics, and Co-Medical Director, Pharmacogenomics at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

McMillin, Gwendolyn A., BA, MA, PhD, Medical Director of Toxicology, Co-Medical Director of Pharmacogenomics at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Miller, Christine E., MS, LCGC, Genetic Counselor, Molecular Genetics at ARUP Laboratories; Faculty, Graduate Program in Genetic Counseling, University of Utah

Salama, Mohamed E., MD, Medical Director, Hematopathology and Immunohistochemistry Staining at ARUP Laboratories; Associate Professor of Clinical Pathology, Director of Hematopathology Fellowship Program, University of Utah

Samowitz, Wade S., MD, Medical Director, Solid Tumor Molecular Diagnostics and Histology, and Staff Pathologist, Anatomic Pathology at ARUP Laboratories; Professor of Anatomic Pathology, University of Utah

Vaughn, Cecily P., MS, R&D Senior Scientist, ARUP Institute for Clinical and Experimental Pathology, Anatomic Pathology Group

Wallander, Michelle L., PhD, R&D Investigator, ARUP Institute for Clinical and Experimental Pathology, Anatomic Pathology Group

Wittwer, Carl T., MD, PhD, Medical Director and Technical Vice President, General Flow Cytometry at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Last Update: January 2016