Download Hereditary Breast Cancer Testing

Hereditary Breast Cancer Testing
clinician guide
Ambry’s test offerings are designed to provide flexible,
comprehensive options tailored to your patients’
personal and family histories.
New Solutions for Hereditary Breast Cancer
Identifying and understanding the genetic contribution to breast cancer allows for
individualized disease management, and provides insight into personal and familial
risks for cancer. For the portion of breast cancer that is due to inherited causes (up to
10%), modified treatment, surveillance, and risk-reducing options may be
appropriate.
total hereditary breast cancer
BRCAplus and BreastNext
BRCA1 and BRCA2
We Offer Several Testing Options for Hereditary Breast Cancer:
1. Comprehensive BRCA1/2 sequencing and deletion/duplication (i.e. large
rearrangement) analyses
2. BRCAplus: a next generation sequencing (NGS) panel of 6 breast cancer
susceptibility genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, TP53)
3. BRCAplus-Expanded: a NGS panel of 8 breast cancer susceptibility genes (ATM,
BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, TP53)
4. BreastNext: an NGS panel of 17 breast cancer susceptibility genes
(ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NBN, NF1, PALB2,
PTEN, RAD50, RAD51C, RAD51D, TP53)
BRCA1 and BRCA2
Mutations in these two highly penetrant genes increase the risk for cancers
of the breast, ovaries, pancreas, and prostate.
brca1/2 lifetime cancer risks (%)
45-87
General Population
BRCA1/2 Mutation Carrier
11-40
15-20
12
Breast
Cancer
5-10
2
0.1
Ovarian
Cancer
Male Breast
Cancer
14
increased
1.5
Prostate
Cancer
Pancreatic
Cancer
BRCA1/2 mutation carriers often develop cancer at younger than typical ages and have an
increased risk for second primary tumors.
Target Populations for BRCA1/2 Testing
BRCA1/2 genetic testing is indicated for individuals with a personal and/or
family history of any of the following:
1. Early-onset breast cancer
(diagnosed < 45 years of age)
2. Triple negative (ER-/PR-/HER2/
neu-) breast cancer diagnosed
< 60 years of age
3. Ovarian, fallopian tube, or primary
peritoneal cancer at any age
4. Bilateral or multiple primary
breast cancers
5. Male breast cancer at any age
6. Ashkenazi Jewish descent with
breast cancer at any age
7. 3 or more cases of breast, ovarian,
pancreatic, and/or high-grade
prostate cancer at any age
8. Known BRCA1 or BRCA2 mutation
in the family
brca1 and brca2
Hereditary breast and ovarian cancer (HBOC) is a cancer predisposition
syndrome most commonly caused by germline (inherited) mutations in
BRCA1 and BRCA2.
brca1 and brca2
Recommendations for Patients with a BRCA1/2 Mutation
WOMEN
Breast Cancer
Management
• Breast awareness starting at 18
• Clinical breast exam every 6-12 months and breast MRI annually,
starting at age 25
• Annual breast MRI and mammogram at age 30-75
• Optional risk-reducing mastectomy
• Discuss chemoprevention options
Ovarian Cancer
Management
• Risk-reducing bilateral salpingo oophorectomy between age
35-40, or after completion of childbearing
• Consider transvaginal ultrasound and CA-125 every 6 months,
beginning at age 30 or 5-10 years before earliest ovarian cancer
in family
• Discuss chemoprevention options
MEN
Breast Cancer
Management
• Breast self-exam training and education, starting at age 35
• Clinical breast exam every 6-12 months, starting at age 35
• Consider mammogram at age 40; annual mammogram if indicated
based on baseline study findings
Prostate
Cancer
Management
• Consider prostate screening starting at age 40 with digital rectal
exam and PSA
Recommendations for Patients with No Mutation Detected
For those with a personal history of breast cancer, stage appropriate care
and follow-up are recommended.
For those with a family history of breast cancer (no personal history):
• Clinical breast exam every 6-12 months
• Annual breast imaging beginning at age 35, or 5-10 years earlier than
youngest breast cancer in family
• For women with a lifetime breast cancer risk of greater than 20%,
annual imaging with mammogram and breast MRI may be indicated
If there is a known BRCA1/2 mutation in the family and your patient has
negative genetic testing, general breast screening is most likely appropriate.
If there are other types of cancers in the family, other screening and
prevention options may be appropriate, specific to cancers in the family.
BRCAplus/BRCAplus-Expanded
BRCAplus is a multi-gene test that analyzes 6 breast cancer susceptibility
genes, all with medical management guidelines (listed in blue).
BRCAplus-Expanded includes 8 high-risk and moderate-risk breast cancer
susceptibility genes, all with medical management guidelines (listed in blue
and black, respectively).
ASSOCIATED
CANCER(S)
SYNDROME/ADDITIONAL
CHARACTERISTICS
BRCA1, BRCA2*
Breast, ovarian,
pancreatic, prostate,
male breast
Hereditary breast and ovarian cancer (HBOC)
- Fallopian tube and primary peritoneal
cancers
- Triple negative (ER-, PR-, HER2/neu-) breast
cancers common with BRCA1 mutations
- Founder mutations are known for many
populations (e.g. Ashkenazi Jewish,
Portuguese, Icelandic, Danish, and more)
Fanconi anemia (BRCA2 only)*
CDH1
Breast, gastric,
colorectal
Hereditary diffuse gastric cancer
- Diffuse gastric cancer
- Lobular breast cancer
- Signet ring carcinoma
PALB2*
Breast, ovarian,
Fanconi anemia*
pancreatic, male breast
PTEN
Breast, thyroid,
uterine, colorectal,
kidney
PTEN hamartoma tumor syndrome (PHTS)
Cowden syndrome (CS)
- Cutaneous lesions (trichilemmomas,
acral keratosis, papillomatous papules)
- Macrocephaly and other clinical findings
- Lhermitte-Duclos disease
- GI hamartomas or ganglioneuromas
TP53
Breast, sarcoma,
brain, adrenocortical,
leukemia,
gastrointestinal,
genitourinary
Li-Fraumeni syndrome (LFS)
- Childhood onset cancers
- Increased radiation sensitivity
- Risk for multiple primary tumors
ATM*
Breast, pancreatic
Ataxia-telangiectasia
- Risk for lymphoma and leukemia in
homozygous mutations carriers
CHEK2
Breast, colorectal
* Biallelic mutations in these genes are associated with respective syndromes described
under Additional Characteristics.
brcaplus/brcaplus-expanded
GENE
lifetime breast cancer risks by brcaplus-expanded gene (%)
General
Population
BRCAplus-Expanded Gene Mutation
12
2-4 fold
ATM
45-87
BRCA1, BRCA2
39-52
CDH1
CHEK2
PALB2
brcaplus/brcaplus-expanded
PTEN
TP53
2 fold
33-58
up to 50
significantly
increased*
* Breast cancer is the most common cancer in women with TP53 mutations. Although
the breast cancer risk with a TP53 mutation is significantly elevated above the general
population, the specific risk is not well defined.
Benefits of Testing
Knowing your patient has an increased cancer susceptibility can aid in
medical management. For example:
1. Increased breast screening for ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2,
PTEN, and TP53 mutation carriers:
• Clinical breast exams more frequently
• Breast imaging with mammogram and breast MRI
• Initiate screening at a younger age
2. Discuss option of risk-reducing bilateral mastectomy with BRCA1, BRCA2,
CDH1, PALB2, PTEN, and TP53 gene mutation carriers
3. Avoid radiation treatment, if possible, for TP53 mutation carriers
4. Targeted surveillance and prevention options specific to the gene mutation
and syndrome identified
5. Identify at-risk family members with targeted genetic testing for identified
familial mutation, and develop an individualized cancer screening and
prevention program
6. Assist couples in reproductive decision making (e.g. advise mutation
carriers about assisted reproduction options including pre-implantation
genetic diagnosis)
BreastNext
BreastNext is a multi-gene panel including 17 breast cancer susceptibility
genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH,
NF1, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, and TP53.
lifetime breast cancer risks by breastnext gene (%)
ATM
BARD1
BreastNext Gene Mutation
2-4 fold
increased*
BRCA1,
BRCA2
BRIP1
45-87
increased*
CDH1
CHEK2
MRE11A,
RAD50, NBN
MUTYH
NF1
39-52
2 fold
increased*
increased*
3-5 fold
33-58
PALB2
up to 50
PTEN
RAD51C
RAD51D
TP53
increased*
increased*
significantly
increased**
**Breast cancer risk associated with a BARD1, BRIP1, MRE11A, MUTYH, NBN, RAD50,
RAD51C, or RAD51D mutation is elevated above the general population but is not well
defined.
breastnext
**Breast cancer risk associated with a TP53 mutation is significantly elevated above the
general population but is not well defined.
BreastNext Genes, Associated Cancers, and Characteristics
BRCAplus is a multi-gene test that analyzes 6 breast cancer susceptibility
genes, all with medical management guidelines (listed in blue).
breastnext
BreastNext includes 17 high-risk and moderate-risk breast cancer
susceptibility genes (in blue and black, respectively).
GENE
ASSOCIATED
CANCER(S)
SYNDROME/ADDITIONAL
CHARACTERISTICS
BRCA1, BRCA2*
Breast, ovarian,
pancreatic, prostate,
male breast
Hereditary breast ovarian cancer (HBOC)
- Fallopian tube and primary peritoneal
cancers
- Triple negative (ER-, PR-, HER2/neu-) breast
cancers associated with BRCA1 mutations
- Founder mutations are known for many
populations (e.g. Ashkenazi Jewish,
Portuguese, Icelandic, Danish, and more)
Fanconi anemia (BRCA2 only)*
CDH1
Breast, gastric,
colorectal
Hereditary diffuse gastric cancer
- Diffuse gastric cancer
- Lobular breast cancer
- Signet ring carcinoma
PALB2*
Breast, ovarian,
pancreatic, male
breast
Fanconi anemia*
PTEN
Breast, thyroid,
uterine, colorectal,
kidney
PTEN hamartoma tumor syndrome (PHTS)
Cowden syndrome (CS)
- Cutaneous lesions (trichilemmomas,
acral keratosis, papillomatous papules)
- Macrocephaly and other clinical findings
- Lhermitte-Duclos disease
- GI hamartomas or ganglioneuromas
TP53
Breast, sarcoma,
brain, adrenocortical,
leukemia,
gastrointestinal,
genitourinary
Li-Fraumeni syndrome (LFS)
- Childhood-onset cancers
- Increased radiation sensitivity
- Risk for multiple primary tumors
ATM*
Breast, pancreatic
Ataxia-telangiectasia
- Risk for lymphoma and leukemia in
homozygous mutations carriers
BARD1
Breast, ovarian
BRIP1*
Breast, ovarian
Fanconi anemia*
* Biallelic mutations in these genes are associated with respective syndromes described
under Additional Characteristics.
Continued: BreastNext Genes, Associated Cancers,
and Characteristics
GENE
ASSOCIATED
CANCER(S)
SYNDROME/ADDITIONAL
CHARACTERISTICS
CHEK2
Breast, colorectal
MRE11A*
Breast, possibly
ovarian
Ataxia-telangiectasia-like disorder*
MUTYH*
Breast, colorectal
MUTYH-associated polyposis (MAP)*
- Tens to hundreds of GI polyps
NBN*
Breast
Possibly ovarian
Nijmegen breakage syndrome*
NF1
Breast, optic glioma,
CNS, GIST, PGL/PCC
Neurofibromatosis type 1 (NF1)
- Hyperpigmented skin lesions
- Neurofibromas
- Lisch nodules
- Many additional characteristics
RAD50*
Breast, possibly
ovarian
Nijmegen breakage syndrome-like disorder*
RAD51C*
Breast, ovarian
Fanconi Anemia*
RAD51D
Breast, ovarian
* Biallelic mutations in these genes are associated with respective syndromes described
under Additional Characteristics.
CNS: central nervous system
GIST: gastrointestinal stromal tumor
PGL/PCC: paragangliomas/pheochromocytomas
Target Population for Multi-Gene Breast Cancer Panels
BRCAplus or BreastNext may be informative for individuals with a personal
and/or family history of any of the following:
1. Early-onset breast cancer
(diagnosed < 45 years of age)
2. Bilateral or multiple primary
breast cancers
5. 3 or more cases of breast cancer*
6. 3 or more cases of breast, ovarian,
and/or pancreatic cancer*
3. Male breast cancer at any age
7. 3 or more cases of breast, uterine,
and/or thyroid cancer*
4. Breast and ovarian cancer in the
same woman
8. Multiple close family members
with breast and other cancers*
* On the same side of the family
Genetic Test Results Explained
A patient undergoing genetic testing will receive one of three possible
results: positive, negative, or inconclusive (i.e. variant of unknown
significance or VUS).
RESULTS
EXPLANATION
Positive
•
•
•
•
Negative
• No clinically significant genetic changes identified in any of the
genes tested
• Cancer risk is based on personal and family history
• Cancer screening and prevention recommendations based on family
history
• Genetic testing may or may not be indicated for family members
A mutation was found in one of the genes tested
Increased risk for cancer specific to the gene mutation
Cancer screening and prevention recommendations specific to gene
Testing at-risk relatives for specific mutation will be indicated
Inconclusive • A genetic change was identified, but current knowledge cannot
predict if the change is disease-causing or benign
• Cancer risk is based on personal and family history
• Cancer screening and prevention recommendations based on family
history
• Family studies may be indicated
VUS Rates and Family Studies Program
Variants of unknown significance (VUS) are more common in multi-gene panels
because they analyze multiple genes simultaneously. As information is
accumulated, updated VUS rates will be made readily available. The possibility of
inconclusive results warrants careful discussion in pre- and post-test counseling
sessions, particularly for multi-gene panels. Detailed interpretation of any VUS
identified is included in the test report.
We are committed to careful analysis and timely reclassification of VUS. If a VUS is
identified, complimentary testing of informative relatives may be offered through
our Family Studies Program. Familial tracking (segregation studies) can assist in
clarifying the nature of a VUS. When enough evidence has been accumulated to
reclassify the VUS as either disease-causing or benign, you will be automatically
notified.
We have invested heavily in both research and clinical collaborations to ensure the
quality and accuracy of our variant analyses and interpretations.
For more information, please visit:
www.ambrygen.com/variantclassification
Specimen Requirements
Blood: Collect 6-10cc blood in purple top EDTA tube (preferred) or yellow top citric
acetate tube. Storage: 2-8°C and do not freeze. Shipment: Room temperature for
two-day delivery. For transfusion patients: Wait at least two weeks after a packed
cell or platelet transfusion and at least four weeks after a whole blood transfusion
prior to blood draw.
Blood Spot: Blood spots are not accepted.
Saliva: Fill 1 tube with saliva up to black line (1cc of saliva) in Oragene Self Collection
container. After tube is closed 1cc of buffer will mix with saliva for a total volume of
2cc. Store at room temperature in sterile bag. Shipment: Room temperature for
two-day delivery.
DNA: 20 μg of DNA in TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 200 μl at
~100 ng/μl. Please provide DNA OD 260-280 ratio (preferred 1.7-1.9) and send
agarose picture with high mw genomic DNA, if available. Store at -20°C. Ship
frozen on dry ice (preferred) or ice.
Ambry Expertise
support
Board-certified genetic counselors, laboratory directors, and medical directors are
readily available to assist with test selection, case reviews, and result interpretation.
insurance
Ambry is contracted with the majority of commercial insurances and Medicare. All
out-of-network patients are treated as in-network to minimize out-of-pocket costs.
Medicaid coverage varies by state and preverification is recommended.
patient protection plan
Ambry’s billing policy is to preverify insurance coverage (with or without patient
sample) for genetic testing. We will contact the patient after their sample is received,
if their out-of-pocket cost is estimated to exceed $100. We are committed to working
with you and your patients to make the genetic testing process as simple and
cost-effective as possible, and our Billing Department is available to answer any
questions your patient may have. Our Billing Department can be reached by phone
at +1-949-900-5795 or [email protected].
progeny’s family history questionnaire (fhq)
With Progeny’s FHQ, patients can complete their family health history at their own
pace. Pedigrees are automatically generated and managed along with all submitted
data. With no re-entry of data, referral and clinical decisions can be made
immediately. Template FHQs are available for use in your clinic at no cost, or custom
questionnaires can be designed for you. Visit progenygenetics.com/clinical/trial for
more.
about ambry genetics
Ambry Genetics is a privately-held healthcare company with the most comprehensive
suite of genetic testing solutions for inherited and non-inherited diseases. Since 1999,
Ambry has tested approximately half a million patient samples benefiting 90% of all
U.S. patients covered by public and private insurers. Ambry is dedicated to scientific
collaboration by offering its rapidly growing database of anonymized genomic data
(variant frequencies) free to the global medical research community to fulfill the
promise of the human genome to cure or manage all human disease. Ambry is
dedicated to the belief that human health should not be patented or owned, and
genomic data should be freely shared so we can try to understand all human disease.
To order your complimentary sample submission kits, please contact:
Ambry Genetics
15 Argonaut
Aliso Viejo, CA 92656 USA
+1 866-262-7943
[email protected]
For more details about these tests, visit ambrygen.com
References used to develop clinical content are available at ambrygen.com
15 Argonaut, Aliso Viejo, CA 92656 USA
Toll Free +1 866 262 7943
Fax +1 949 900 5501
50339.1462_v5
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