Breast Cancer

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. Histology is the primary method of diagnosis, while markers, such as ER/PR and HER2, can suggest prognosis.

Tabs Content

Clinical Overview

Key Points

American Society of Clinical Oncology 2016 Prognostic Marker Recommendations

Nonpanel 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	n/a
IHC4 (Immunohistochemistry 4)	Do not use in women who are ER/PR-positive, HER2-negative (node-negative or node-positive) for adjuvant decisions	n/a
Ki-67 (MIB-1) (Cell proliferative-associated antigen)	Do not use to guide choice on adjuvant chemotherapy	Elevation associated with aggressive tumor behavior
n/a, not available

Prognostic Panels
Panel	Indication	Description
Prosigna Breast Cancer Prognostic Gene Signature assay^a	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)^a	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^a	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^a	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	n/a
MammaPrint	Do not use in ER/PR positive, HER2 negative (node-positive or node-negative)	70 gene panel
^aFDA approved for use in early stage (stage I-III), node-positive breast cancer, but not guideline recommended n/a, not available

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/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
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
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 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 yrs – annual screening ≥55 yrs– every 2 yrs, as long as woman is in good health and is expected to live ≥10 yrs	Not recommended due to lack of evidence
ACOG (2017)	Offer starting at 40 yrs; initiate at 40-49 yrs after counseling and if patient desires Recommend by no later than 50 yrs Screen every 1-2 yrs based on shared decision making	May be offered after shared decision making Every 1-3 yrs for women 25-39 yrs Annually for women ≥40 yrs	Not recommended in average-risk women
AGS (2008^a)	Stop screening healthy women ≥85 yrs; for those ≥75 yrs, consider life expectancy and quality of life when screening
USPSTF (2016)	Women 40-49 yrs – decision to screen should be an individual one Women 50-74 yrs – screen every 2 yrs Women ≥75 yrs – no recommendation due to insufficient evidence	No recommendation	Recommend against teaching BSE
^aCited in AAFP, 2008 AAFP, American Academy of Family Physicians; ACOG, American Congress of Obstetricians and Gynecologists; ACS, American Cancer Society; AGS, American Geriatrics Society; USPSTF, U.S. Preventive Services Task Force

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)

Indications for testing in individuals with any of the following

Indications for testing in individuals with any of the following (NCCN, 2018)

Breast cancer or high-grade prostate cancer diagnosed at any age and Ashkenazi Jewish ancestry
Breast cancer diagnosed by 50 years
Triple-negative breast cancer diagnosed by 60 years
Two breast cancer primaries diagnosed at any age
Breast cancer diagnosed at any age and one or more close blood relatives with breast cancer diagnosed by 50 years, invasive ovarian cancer, male breast cancer, pancreatic cancer, or high-grade or metastatic prostate cancer
Breast cancer diagnosed at any age and two or more close blood relatives with breast cancer at any age
Ovarian cancer, pancreatic cancer, or metastatic prostate cancer diagnosis at any age

Indications for testing in asymptomatic patient with either of the following (NCCN, 2018)

One or more first- or second-degree relatives with breast cancer diagnosed by 45 years, ovarian cancer, male breast cancer, pancreatic cancer, metastatic prostate cancer, two or more breast cancer primaries in the same family member, or two or more family members with breast cancer primaries on the same side of the family with at least one diagnosed by 50 years
Personal and/or family history on the same side of the family with three or more diagnoses of
- Breast cancer, sarcoma, adrenocortical carcinoma, brain tumor, leukemia
- Colon cancer, endometrial cancer, thyroid cancer, kidney cancer, dermatologic manifestations, macrocephaly, hamartomatous polyps of gastrointestinal tract
- Lobular breast cancer, diffuse gastric cancer
- Breast cancer, gastrointestinal cancer or hamartomatous polyps, ovarian sex chord tumors, pancreatic cancer, testicular sertoli cell tumors, or childhood skin pigmentation

Perform targeted testing in individuals with (NCCN, 2018)

Known pathogenic or likely pathogenic variant in a cancer susceptibility gene within the family
Known pathogenic or likely pathogenic variant in a cancer susceptibility gene found on tumor testing

Hereditary gene mutations

Hereditary Gene Mutations
Gene Symbol	Inheritance	Cancer Association
ATM	AD, AR	Breast, possible increased risk for colorectal (AD) Ataxia telangiectasia (AR)
BARD1	AD	Breast, neuroblastoma
BRCA1	AD	Breast, ovarian, fallopian, peritoneal, pancreatic, prostate; hereditary breast and ovarian cancer (HBOC) syndrome
BRCA2	AD, AR	Breast, ovarian, fallopian, peritoneal, pancreatic, prostate, gallbladder, gastric, melanoma; HBOC syndrome (AD) Fanconi anemia, complementation group J (AR)
BRIP1	AD, AR	Ovarian, possible increased risk for breast (AD) Fanconi anemia, complementation group J (AR)
CDH1	AD	Gastric, breast, prostate
CHEK2	AD	Breast, colorectal, prostate
EPCAM	AD	Colorectal, ovarian; Lynch syndrome
MEN1	AD	Glucagonomas, gastrinomas, VIPomas, thymic, bronchial, gastric, breast; multiple endocrine neoplasia type 1 (MEN1)
MLH1	AD, AR	Ovarian, colorectal, endometrial, gastric, bladder, kidney; Lynch syndrome (AD) Constitutional mismatch repair deficiency (AR)
MSH2	AD, AR	Ovarian, colorectal, endometrium, gastric, bladder, kidney; Lynch syndrome (AD) Constitutional mismatch repair deficiency (AR)
MSH6	AD, AR	Ovarian, colorectal, endometrium, gastric, bladder, kidney; Lynch syndrome (AD) Constitutional mismatch repair deficiency (AR)
MUTYH	AD, AR	Colorectal, MUTYH-associated polyposis (MAP) (AR) Possible increased risk for gastric, breast, duodenal, endometrium (AD)
NBN	AD, AR	Breast, possible increased risk for ovarian (AD) Nijmegen breakage syndrome (AR)
PALB2	AD, AR	Breast, pancreatic, possible increased risk for ovarian (AD) Fanconi anemia, complementation group N (AR)
PTEN	AD	Breast, thyroid, endometrial, colorectal; PTEN hamartoma tumor syndrome/Cowden syndrome
RAD51C	AD, AR	Ovarian, possible increased risk for breast (AD) Fanconi anemia, complementation group O (AR)
RAD51D	AD	Ovarian, possible increased risk for breast
STK11	AD	Breast, colorectal, stomach, pancreatic, ovarian; Peutz-Jeghers syndrome
TP53	AD	Breast, ovarian, brain, soft tissue and osteosarcomas, gastrointestinal, leukemia, lymphoma, adrenocortical carcinoma; Li Fraumeni syndrome
AD, autosomal dominant; AR, autosomal recessive

Monitoring

Annual mammography
- Most organizations (ACS, NCI, AMA, AGS) 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 (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

Pharmacogenetics

Cytochrome P450 2D6 (CYP2D6) and tamoxifen

Tamoxifen is an antiestrogen 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; 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
Neither the National Comprehensive Cancer Network (NCCN, 2017) nor the American Society of Clinical Oncology (ASCO, 2016) recommend CYP2D6 genotyping to determine optimal adjuvant tamoxifen strategy
Multivariant panel – used to detect the 15 most common variants involved in changes in metabolism

*CYP2D6* Genotyping Variants Tested
Allele Designation	Nucleotide Change (Numbered According to M33388 Sequence)	Reference Sequence Identifier	Predicted Enzyme Activity	Predicted Activity Score
*2	2850C>T	rs16947	Functional (normal)	1
*2A	-1584C>G; 2850C>T	rs1080985, rs16947	Functional (normal)	1
*3	2549delA	rs35742686	No function	0
*4	1846G>A	rs3892097	No function	0
*5	Gene deletion		No function	0
*6	1707delT	rs5030655	No function	0
*7	2935A>C	rs5030867	No function	0
*8	1758G>T	rs5030865	No function	0
*9	2613-5delAGA	rs5030656	Decreased function	0.5
*10	100C>T	rs1065852	Decreased function	0.5
*12	124G>A	rs5030862	No function	1
*14	1758G>A	rs5030865	No function	1
*17	1023C>T	rs28371706	Decreased function	0.5
*29	1659G>A	rs59421388	Decreased function	0.5
*36	10 carrying a CYP2D7*-derived exon 9 conversion		No function	0
*41	2988G>A	rs28371725	Decreased function	0.5
Duplication of functional alleles			Increased function	>1

Clinical Pharmacogenetics Implementation Consortium (CPIC) provides recommendations for tamoxifen dosing and for use of concomitant CYP2D6 inhibitors based on genotype results (Goetz, 2018)
- Poor metabolizer (only no functional alleles) – lower endoxifen concentrations; higher risk of breast cancer recurrence
  - Recommend aromatase inhibitors for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women due to poor efficacy and increased risk of relapse of breast cancer with tamoxifen
- Intermediate metabolizer (one decreased function and one no function allele) – lower endoxifen concentrations; higher risk of breast cancer recurrence
  - Avoid CYP2D6 strong to weak inhibitors
  - Consider using aromatase inhibitors for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women due to poor efficacy and increased risk of relapse of breast cancer with tamoxifen
- Normal or intermediate metabolizer (controversial) (two decreased function alleles or one normal function and one no function allele) – lower endoxifen concentrations; higher risk of breast cancer recurrence
  - Avoid CYP2D6 strong to weak inhibitors
  - Consider using aromatase inhibitors for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women due to poor efficacy and increased risk of relapse of breast cancer with tamoxifen
- Normal metabolizer (two normal function alleles or one normal function and one decreased function allele) – therapeutic endoxifen concentrations
  - Avoid moderate and strong CYP2D6 inhibitors
  - Initiate therapy with recommended standard of care dosing
- Ultrarapid metabolizer (duplications of functional alleles) – therapeutic endoxifen concentrations
  - Avoid moderate and strong CYP2D6 inhibitors
  - Initiate therapy with recommended standard of care dosing
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

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

Background

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)
- 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 associated with a hereditary cause
- 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

ARUP Lab Tests

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 with Reflex, 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+)

Reflex pattern – breast tissue results of FISH group 2, 3, or 4 will be reflexed to ERBB2 (HER2/neu) (HercepTest) with interpretation by immunohistochemistry; gastric and other nonbreast tissue results of "equivocal" will be reflexed to an alternate probe in an effort to resolve amplification status

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

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

Hereditary Breast and Ovarian Cancer Panel, Sequencing and Deletion/Duplication 2012026
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Recommended Use

Recommended test to confirm a diagnosis of hereditary breast and/or ovarian cancer in individuals with a personal or family history of breast and/or ovarian cancer

When a relative has a previously identified pathogenic sequence variant, see familial mutation targeted sequencing test

Refer to the Test Fact Sheet for full list of genes tested

Limitations

Refer to Test Fact Sheet for full list of limitations

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

Recommended test to confirm hereditary breast and ovarian cancer (HBOC) syndrome

When a relative has a previously identified pathogenic sequence variant, see familial mutation targeted sequencing test

Only the BRCA1 and BRCA2 genes are assayed

Limitations

Refer to the Test Fact Sheet for full limitations

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) 15 Variants and Gene Duplication 2014547
Method: Polymerase Chain Reaction/Fluorescence Monitoring

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

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)
- *36 (*10 carrying a CYP2D7-derived exon 9 conversion)
Increased function
- Duplicated functional alleles

Limitations

Only the targeted CYP2D6 variants will be detected by this panel

Combination of *5 (gene deletion) and gene duplication cannot be specifically identified; combination is not expected to adversely affect the prediction of activity score or phenotype

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

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

Test Fact Sheet(s)

Hereditary Breast and Ovarian Cancer

Hereditary Cancer Panel

Medical Experts

Bayrak-Toydemir, Pinar, MD, PhD, Medical Director, Molecular Genetics and Genomics at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Bernard, Philip S., MD, Medical Director, Molecular Oncology at ARUP Laboratories; Associate Professor of Anatomic Pathology, University of Utah

Chadwick, Barbara E., MD, Medical Director, Cytology, and Staff Pathologist, Surgical Pathology at ARUP Laboratories; Assistant Professor of Anatomic Pathology, University of Utah

Factor, Rachel E., MD, MHS, Medical Director, Anatomic Pathology and Cytology; Assistant Professor of Pathology, Director of Breast Pathology, Co-Director of the Cytopathology Fellowship Prgoram, University of Utah

Lyon, Elaine, PhD, FACMG, Medical Director, Molecular Genetics and Genomics, Medical Director, Pharmacogenomics at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Mao, Rong, MD, FACMG, Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

McMillin, Gwendolyn A., PhD, Medical Director, Toxicology, and Medical Director, Pharmacogenetics, at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

References

Guidelines

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
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
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General References

Breast Cancer Risk Assessment Tool. National Cancer Institute. Bethesda, MD [Accessed: Jul 2018]

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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

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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^®

Bastien RR, Rodríguez-Lescure A, Ebbert MT, Prat A, Munárriz B, Rowe L, Miller P, Ruiz-Borrego M, Anderson D, Lyons B, Álvarez I, Dowell T, Wall D, Seguí M, Barley L, Boucher KM, Alba E, Pappas L, Davis CA, Aranda I, Fauron C, Stijleman IJ, Palacios J, Antón A, Carrasco E, Caballero R, Ellis MJ, Nielsen TO, Perou CM, Astill M, Bernard PS, Martín M. PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. BMC Med Genomics. 2012; 5: 44. PubMed

Caan BJ, Sweeney C, Habel LA, Kwan ML, Kroenke CH, Weltzien EK, Quesenberry CP, Castillo A, Factor RE, Kushi LH, Bernard PS. Intrinsic subtypes from the PAM50 gene expression assay in a population-based breast cancer survivor cohort: prognostication of short- and long-term outcomes. Cancer Epidemiol Biomarkers Prev. 2014; 23(5): 725-34. PubMed

Carey LA, Rugo HS, Marcom K, Mayer EL, Esteva FJ, Ma CX, Liu MC, Storniolo AM, Rimawi MF, Forero-Torres A, Wolff AC, Hobday TJ, Ivanova A, Chiu W, Ferraro M, Burrows E, Bernard PS, Hoadley KA, Perou CM, Winer EP. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol. 2012; 30(21): 2615-23. PubMed

Cohen AL, Factor RE, Mooney K, Salama ME, Wade M, Serpico V, Ostrander E, Nelson E, Porretta J, Matsen C, Bernard P, Boucher K, Neumayer L. POWERPIINC (PreOperative Window of Endocrine TheRapy Provides Information to Increase Compliance) trial: Changes in tumor proliferation index and quality of life with 7 days of preoperative tamoxifen. Breast. 2017; 31: 219-223. PubMed

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Kroenke CH, Sweeney C, Kwan ML, Quesenberry CP, Weltzien EK, Habel LA, Castillo A, Bernard PS, Factor RE, Kushi LH, Caan BJ. Race and breast cancer survival by intrinsic subtype based on PAM50 gene expression. Breast Cancer Res Treat. 2014; 144(3): 689-99. PubMed

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Educational Videos

Last Update: January 2019

Breast Cancer

Key Points

American Society of Clinical Oncology 2016 Prognostic Marker Recommendations

Diagnosis

Indications for Testing

Histology

Prognosis

Screening

Indications for testing in individuals with any of the following

Hereditary gene mutations

Monitoring

Pharmacogenetics

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology^®

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	Breast Cancer. ARUP Consult^©. Retrieved February 15, 2019, from: https://arupconsult.com/content/breast-cancer

Breast Cancer

Key Points

American Society of Clinical Oncology 2016 Prognostic Marker Recommendations

Diagnosis

Indications for Testing

Histology

Prognosis

Screening

Indications for testing in individuals with any of the following

Hereditary gene mutations

Monitoring

Pharmacogenetics

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult

References from the ARUP Institute for Clinical and Experimental Pathology^®