Breast Cancer

Diagnosis

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

Screening

  • Screening recommendations (mammogram, clinical breast exam, breast self-exam)

    Society

    Mammogram

    Clinical Breast Exam (CBE)

    Breast Self-Exam (BSE)

    AAFP (2009)

    <50 yrs – should be evaluated on individual basis  

    50-74 yrs – every 2 yrs

    Insufficient evidence to assess harms or benefits

    Recommend against teaching BSE

    ACS (2013)

    Annual screening for all women beginning at 40 yrs until no longer in good health

    Annual screening for all women beginning at 40 yrs until no longer in good health

    Every 3 yrs for women in their 20s and 30s; every year for women ≥40 yrs 

    Women should know how their breasts normally look and feel and report any breast change promptly to their health care provider

    BSE is an option for women starting in their 20s

    ACOG (2011)

    Every 2 yrs starting at 40 yrs

    Annually starting at 50 yrs

    Annually at 40-45 yrs

    Recommend monthly BSE

    AGS (2010)

    Stop screening healthy women ≥85 yrs; ≥75 yrs consider life expectancy and quality of life when screening

    USPSTF (2009)

    Recommend against routine screening mammography in women 40-49 yrs

    Biennial screening mammography for women 50-74 yrs

    No recommendation

    Recommend against teaching BSE

    USPSTF = U.S. Preventive Services Task Force; ACS = American Cancer Society; AAFP = American Academy of Family Physicians; AGS = American Geriatrics Society; ACOG = American Congress of Obstetricians and Gynecologists

  • 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
    • Breast cancer diagnosed by 45 yrs
    • Ovarian cancer
    • Two primary breast cancers, first diagnosed by 50 yrs
    • Breast cancer diagnosed by 50 yrs with ≥1 family members with breast cancer
    • Triple negative breast cancer diagnosed by 60 yrs
    • Breast cancer at any age with ≥1 family members with breast cancer diagnosed by 50 yrs
    • Breast cancer diagnosed at any age with ≥2 family members from the same side diagnosed with breast cancer at any age
    • Breast cancer at any age with ≥1 family members with ovarian cancer
    • Breast cancer diagnosed at any age with ≥2 family members with pancreatic or prostate cancer
    • Breast cancer diagnosed at any age and male family member with breast cancer
    • Breast cancer at any age and Ashkenazi Jewish ancestry
    Symptoms in men with any of the following
    • Breast cancer at any age
    • Pancreatic cancer or prostate cancer at any age with ≥2 family members with breast, ovarian, pancreatic, and/or prostate cancer at any age
    Based on family history (in asymptomatic patient)
    • For women with no Ashkenazi Jewish ancestry and family history of any of the following on the same side of the family
      • Two first-degree relatives diagnosed with breast cancer, one diagnosed at 50 yrs or younger
      • Three or more first-degree or second-degree  relatives diagnosed with breast cancer regardless of their age
      • A combination of first- and second-degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person)
      • A first-degree relative with bilateral breast cancer
      • A combination of two or more first- or second-degree relatives diagnosed with ovarian cancer regardless of age at diagnosis
      • A first- or second-degree relative diagnosed with both breast and ovarian cancer regardless of age at diagnosis
      • Breast cancer diagnosed in a male relative
    • For women with Ashkenazi Jewish ancestry and family history of any of the following
      • First-degree relative diagnosed with breast or ovarian cancer
      • Two second-degree relatives on the same side of the family diagnosed with breast or ovarian cancer
  • Individuals with a family history of a known pathogenic mutation previously identified in a relative – perform targeted mutation testing
  • Hereditary gene mutations
    Gene Symbol

    Inheritance

    Cancer Association

    ATMADBreast
    BARD1ADBreast, neuroblastoma
    BRCA1ADBreast, ovarian, fallopian, peritoneal, pancreatic, prostate
    BRCA2ADBreast, ovarian, fallopian, peritoneal, pancreatic, prostate, gallbladder, gastric, melanoma
    BRIP1ADBreast, ovarian
    CDH1ADGastric, breast, prostate
    CHEK2ADBreast, colorectal, prostate
    EPCAMADColorectal, ovarian
    MEN1ADGlucagonomas, gastrinomas, VIPomas, thymic, bronchial, gastric, breast
    MLH1ADOvarian, colorectal, endometrial, bladder, kidney
    MSH2ADOvarian, colorectal, endometrium, bladder, kidney
    MSH6ADOvarian, colorectal , endometrium, bladder, kidney
    MUTYHAR, ADColorectal (AR), gastric, breast, duodenal, endometrium (AD)
    NBNADBreast, ovarian
    PALB2ADBreast, pancreatic
    PTENADThyroid, breast, endometrial
    RAD51CADBreast, ovarian
    RAD51DADBreast, ovarian
    STK11ADColorectal, pancreatic, breast, ovarian
    TP53ADBreast, ovarian, brain, soft tissue and osteosarcomas, gastrointestinal, leukemia, lymphoma, adrenocortical carcinoma
    AD = autosomal dominant; AR = autosomal recessive

Monitoring

  • 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

Pharmacogenetics and Therapeutic Drug Monitoring

  • 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
      • Extensive metabolizer – no impairment
      • 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

Clinical Background

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
Test Name and Number Recommended Use Limitations Follow Up
Estrogen/Progesterone Receptor with Interpretation by Immunohistochemistry 0049210
Method: Immunohistochemistry

Aids 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

Aids in prediction of response to trastuzumab (Herceptin) therapy

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

Aids in prediction of response to trastuzumab (Herceptin) therapy

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

Aids in prediction of response to trastuzumab (Herceptin) therapy

Confirm equivocal HercepTest (2+) or IHC result

Measures gene amplification

Utilizes fluorescence, which limits visualization of tissue morphology

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

Single gene assay

Detects activating PIK3CA mutations in exons 9 and 20 associated with anti-EGFR therapy resistance

Predicts response to anti-EGFR and AKT/mTOR pathway therapies in a variety of malignancies, including breast cancer

   
p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry

Histologic prognosis of breast cancer

Determine treatment method for node-negative breast cancer

Stained and resulted by ARUP

   
Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Histologic prognostic indicator for node-negative breast cancer

Stained and resulted by ARUP

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

Prognostic indicator for node-negative breast cancer

Tumor-specific S-phase used when possible

Average histogram S-phase used

  • For diploid and some aneuploid tumors – where tumor and host S-phases cannot be separated
  • When percentage of aneuploid cells in histogram low – <25%
   
Cytology, Non-Gynecologic 2000623
Method: Microscopy

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 for confirmation of hereditary breast and ovarian cancer (HBOC) syndrome

Highest detection rate for HBOC syndrome but also highest likelihood of identifying variants of unknown significance

Clinical sensitivity – unknown

Analytical sensitivity and specificity of sequencing – 99% and 96%, respectively

Analytical sensitivity and specificity of CGH – 99%

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

 
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 for confirmation of HBOC

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

 
Ashkenazi Jewish (BRCA1 and BRCA2) 3 Mutations 2011958
Method: Polymerase Chain Reaction/Fragment Analysis

Predictive or diagnostic testing for heritable predisposition for breast or ovarian cancer in adults of Ashkenazi Jewish descent only

This test is used for detecting 3 common BRCA1 and BRCA2 mutations prevalent in individuals of Ashkenazi Jewish descent and REQUIRES PERMISSION from ARUPs genetic counselor before ordering

Preferred comprehensive test is BRCA1 and BRCA2 sequencing and deletion/duplication or familial mutation, targeted sequencing if a familial mutation is known

Clinical sensitivity – 97% for BRCA1 and BRCA2 mutations in Ashkenazi Jewish individuals

Detection rate of <1% for BRCA1 and BRCA2 mutations in individuals who are not of Ashkenazi Jewish descent

BRCA1 and BRCA2 gene mutations, other than those targeted, will not be detected

Rare diagnostic errors may occur due to primer site mutations

 
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 determine prognosis, assess treatment efficacy, and aid in treatment decisions for patients with metastatic breast cancer

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

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

Histologic diagnosis of adenocarcinomas of ductal origin in breast

Stained and returned to client pathologist for interpretation; consultation available if required

   
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

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

Histologic diagnosis 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

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

Pretherapeutic testing to identify individuals who should avoid or have different dosing of medications metabolized by CYP2D6, such as tamoxifen

Screening of individuals with personal or family history of adverse drug event or therapy failure when exposed to CYP2D6-metabolized drugs

Variants tested

  • 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)
  • Nonfunctional
    • *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

Clinical sensitivity – >95% in Caucasians; unknown in other ethnicities

CYP2D6 variants other than those listed in the table are not evaluated by this test

Phase and copy number of detected CYP2D6 variants may not be determined

Variants in other genes associated with drug metabolism or drug response will not be detected

Presence of other variants (eg, CYP2C19 and tamoxifen) may further impact drug metabolism

Drug metabolism may be affected by nongenetic factors (drug/drug interactions; conditions that impair renal or hepatic function)

Variant detection is not a substitute for therapeutic drug or clinical monitoring

Diagnostic errors can occur due to rare sequence variations

Genotype results should be interpreted in the context of the individual clinical situation

Consultation with a clinical pharmacy professional is recommended

 
Cytochrome P450 2C19 (CYP2C19) 9 Variants 0051104
Method: Polymerase Chain Reaction/DNA Hybridization/Electrochemical Detection

Pretherapeutic testing to identify individuals who should avoid or have different dosing of medications metabolized by CYP2C19, such as tamoxifen

Screening of individuals with personal or family history of adverse drug event or therapy failure when exposed to CYP2C19-metabolized drugs

Variants tested

  • Decreased function
    • *9 (c.431G>A)
    • *10 (c.680C>T)
  • Nonfunctional
    • *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, increased gene transcription)

Clinical sensitivity – ~99%  in Asians; ~87% in Caucasians

Only the targeted CYP2C19 mutations will be detected

Mutations in other genes associated with drug metabolism or drug response will not be detected

Drug metabolism may be affected by nongenetic factors

Mutation detection is not a substitute for therapeutic drug or clinical monitoring

Diagnostic errors can occur due to rare sequence variations

Genotype results should be interpreted in the context of the individual clinical situation

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
ERBB2 (HER2/neu) (HercepTest) with Interpretation by Immunohistochemistry, Tissue 0049174
Method: Immunohistochemistry

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

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

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

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

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

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

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

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

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

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