Breast Cancer

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) Graded scale 0 and 1 – negative 2 – equivocal 3 – positive	Positivity occurs in 15-20% of breast cancer patients Predominantly high-grade tumors More common in African Americans – significant number have BRCA1 gene mutation Young age at onset Premenopausal women 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 ER/PR-positive, HER2-negative (node-positive) breast cancer HER2-positive breast cancer Triple-negative (TN) breast cancer	Scores report risk as low, intermediate, or high based on Molecular subtype of tumor Proliferation status Tumor size and node status Does not provide information about which chemotherapy regimen should be given if at high risk for distant recurrence
Genomic Health Oncotype DX (NCI)*	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 ER/PR-positive, HER2-negative (node-positive) breast cancer HER2-positive breast cancer Triple-negative (TN) breast cancer	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 ER/PR-positive, HER2-negative (node-positive) breast cancer HER2-positive breast cancer Triple-negative (TN) breast cancer	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 ER/PR-positive, HER2-negative (node-positive) breast cancer HER2-positive breast cancer Triple-negative (TN) breast cancer
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

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
- 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 (+)

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
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 recommendations (mammogram, clinical breast exam, breast self-exam) for women of average risk

Society	Mammogram	Clinical Breast Exam (CBE)	Breast Self-Exam (BSE)
AAFP (2016)	<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 (2015)	40-44 yrs – may choose to start annual screening 45-54 – annual screening ≥55 – every 2 years, as long as woman is in good health and is expected to live ≥10 yrs	Not recommended due to lack of evidence
ACOG (2011)	Every 2 yrs starting at 40 yrs Annually starting at 50 yrs	Annually at 40-45 yrs	Recommend monthly BSE
AGS (2008*)	Stop screening healthy women ≥85 yrs; ≥75 yrs consider life expectancy and quality of life when screening
USPSTF (2016)	Women age 40-49 yrs – decision to screen should be an individual one Women age 50-74 – screen every 2 years Women ≥75 yrs – no recommendation due to insufficient evidence	No recommendation	Recommend against teaching BSE
*Cited in AFP, 2008 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 (ASCO, 2007)
- All markers have low sensitivity and specificity when used in a screening setting
Hereditary breast and ovarian cancer (HBOC) genetic testing (National Cancer Institute)

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

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 member with breast, ovarian, pancreatic, and/or prostate cancer at any age

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

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 (Ovarian/Breast Ca) node 1139

Hereditary gene mutations

Gene Symbol	Inheritance	Cancer Association
ATM	AD	Breast
BARD1	AD	Breast, neuroblastoma
BRCA1	AD	Breast, ovarian, fallopian, peritoneal, pancreatic, prostate
BRCA2	AD	Breast, ovarian, fallopian, peritoneal, pancreatic, prostate, gallbladder, gastric, melanoma
BRIP1	AD	Breast, ovarian
CDH1	AD	Gastric, breast, prostate
CHEK2	AD	Breast, colorectal, prostate
EPCAM	AD	Colorectal, ovarian
MEN1	AD	Glucagonomas, gastrinomas, VIPomas, thymic, bronchial, gastric, breast
MLH1	AD	Ovarian, colorectal, endometrial, bladder, kidney
MSH2	AD	Ovarian, colorectal, endometrium, bladder, kidney
MSH6	AD	Ovarian, colorectal , endometrium, bladder, kidney
MUTYH	AR, AD	Colorectal (AR), gastric, breast, duodenal, endometrium (AD)
NBN	AD	Breast, ovarian
PALB2	AD	Breast, pancreatic
PTEN	AD	Thyroid, breast, endometrial
RAD51C	AD	Breast, ovarian
RAD51D	AD	Breast, ovarian
STK11	AD	Colorectal, pancreatic, breast, ovarian
TP53	AD	Breast, ovarian, brain, soft tissue and osteosarcomas, gastrointestinal, leukemia, lymphoma, adrenocortical carcinoma
AD = autosomal dominant; AR = autosomal recessive

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

Tamoxifen is an anti-estrogen drug used in treatment of 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
- 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
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
- 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

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

Recommended Use

Aid in prediction of response to anti-estrogen therapy

Stained and resulted by ARUP

Limitations

For paraffin-embedded, formalin-fixed tissue

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

Recommended Use

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

Recommended Use

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

Recommended Use

Measure protein overexpression

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

Recommended Use

Aid in prediction of response to HER2-directed therapy in patients with breast cancer

Use to confirm equivocal HercepTest IHC result (2+)

Limitations

FDA approved for formalin-fixed tissue only

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

Recommended Use

Triage for trastuzumab therapy when solid tissue unavailable

Limitations

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

PIK3CA Mutation Detection 2004510
Method: Polymerase Chain Reaction/Pyrosequencing

Recommended Use

Single gene assay

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

Predict 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

Recommended Use

May be an indicator of worse prognosis

Stained and resulted by ARUP

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Recommended Use

Histologic indication of tumor proliferation

Stained and resulted by ARUP

Cytology, Non-Gynecologic 2000623
Method: Microscopy

Recommended Use

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

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

Recommended Use

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

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

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

Analytical sensitivity and specificity of CGH – 99%

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

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

Recommended Use

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

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

Recommended Use

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

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

Recommended Use

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

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

Serial CTCs should be performed in the same laboratory

E-Cadherin by Immunohistochemistry 2003869
Method: Immunohistochemistry

Recommended Use

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

Recommended Use

Distinguish ovarian cancer from breast cancer

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

GATA3 by Immunohistochemistry 2012558
Method: Immunohistochemistry

Recommended Use

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/Primer Extension

Recommended Use

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

Limitations

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

Recommended Use

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%

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

Guidelines

Albert RH, Clark MM. Cancer Screening in the Older Patient. Am Fam Physician. Leawood, KS [Accessed: Apr 2016]

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: Apr 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 2016]

NCCN Clinical Practice Guidelines in Oncology, Breast Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Apr 2016]

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 [Accessed: Apr 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 [Accessed: Apr 2016]

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: Apr 2016]

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

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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®

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