Download Hereditary Breast Cancer Testing

Hereditary
Breast Cancer
Testing
Diagnostic
New solutions for hereditary breast cancer.
Identifying and understanding the genetic contribution to
breast cancer allows for individualized disease management
and provides insight to personal and familial risks for cancer.
For the 10% of breast cancer that is due to inherited causes,
modified treatment, surveillance and risk-reducing options
may be appropriate.
Ambry Genetics offers several testing options that
include BRCA1/2:
- Comprehensive BRCA1/2 sequencing and deletion/
duplication (i.e. large rearrangement) analyses
- BRCAplus: a next generation sequencing (NGS) panel
of the six clinically-actionable breast cancer genes
(BRCA1, BRCA2, CDH1, PTEN, STK11, TP53)
- BreastNext: an NGS panel of 18 breast cancer
susceptibility genes
(ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH,
NBN, NF1, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53)
Ambry’s test offerings are designed to provide flexible,
comprehensive options tailored to your patients’ personal
and family histories.
Hereditary breast-ovarian cancer (HBOC) syndrome is a cancer
predisposition syndrome caused by germline BRCA1/2 mutations.
Mutations in these two highly penetrant genes increase the risk for
cancers of the breast, ovaries, fallopian tubes, pancreas and prostate.
brca1/2 lifetime cancer risk (%)
45-87
General Population
BRCA Positive
11-40
15-20
12
2
Breast Cancer
Ovarian Cancer
5-10
14
0.1
Male Breast
Cancer
Prostate Cancer
BRCA1/2 mutation carriers often develop cancer at younger than typical ages and have an
increased risk for second primary tumors.
Target population for BRCA1/2
BRCA1/2 genetic testing is recommended 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 breast cancer
(diagnosed < 60 years of age)
5. Male breast cancer at any age
6. Ashkenazi Jewish descent
with breast cancer at any age
3. Ovarian, fallopian tube or
primary peritoneal cancer at
any age
7. Clustering of three or more
cases of breast, ovarian,
pancreatic and/or high-grade
prostate cancer at any age
4. Bilateral or multiple primary
breast cancers
8. Known BRCA1 or BRCA2
mutation in the family
BRCA1 & BRCA 2
BRCA1 & BRCA2
BRCA1 & BRCA 2
Recommendations for patients with a BRCA1/2 mutation
Breast Cancer Management
Ovarian Cancer Management
1. Breast awareness starting at 18
1. Risk-reducing bilateral salpingo
oophorectomy between age
35-40 or after completion of
childbearing
2. Clinical breast exam every
6-12 months starting at age 25
women
3. Annual mammogram and
breast MRI starting at age 25
4. Optional risk-reducing
mastectomy
2. Consider transvaginal
ultrasound and CA-125 every 6
months beginning at age 30 or
5-10 years before the earliest
ovarian cancer in the family.
5. Discuss chemoprevention
options
3. Discuss chemoprevention
options
Breast Cancer Management
1. Breast self-exam training and
education starting at age 35
men
2. Clinical breast exam every
6-12 months starting at age 35
Prostate Cancer Management
1. Consider prostate screening
starting at age 40 with digital
rectal exam and PSA
3. Consider mammogram at age 40;
annual mammogram if indicated
based on baseline study findings
Recommendations for patients with no mutation detected
For patients with a personal history of breast cancer, follow stage
appropriate care and follow-up.
For patients 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
the youngest breast cancer in the 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 BRCA mutation in the family and your patient tests
negative, 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 is a multi-gene panel including comprehensive analyses
of the six clinically-actionable breast cancer susceptibility genes
(BRCA1, BRCA2, PTEN, TP53, STK11, CDH1). Recommendations
are available for all six BRCAplus genes, which provide treatment,
surveillance and prevention option for mutation carriers.
Gene
Cancer(s)
Additional Characteristics
BRCA1
Breast
BRCA2
Ovaries
Hereditary Breast-Ovarian
Cancer syndrome (HBOC)
- Fallopian and primary peritoneal cancers
- Triple Negative (ER-, PR-, HER2/neu-) breast
cancers common with BRCA1 mutations
- Founder mutations are known for many
populations (ex: Ashkenazi Jewish,
Portuguese, Icelandic, Danish, and more)
Pancreas
Prostate
Male Breast
PTEN
Breast
Endometrium
Colorectum
Kidney
TP53
Breast
Sarcoma
Brain
Adrenocortical
Li-Fraumeni syndrome (LFS)
- Soft tissue and osteosarcomas
- Colorectal and many other cancers
- Childhood onset cancers
- Increased radiation sensitivity
- Risk for multiple primary tumors
Leukemias
STK11
Breast
Ovaries
Colorectum
Duodenum
Peutz-Jeghers syndrome (PJS)
- Childhood onset mucocutaneous
pigmentation and GI hamartomas
- Risk for additional cancers
- Can see cervical and gonadal tumors
Pancreas
CDH1
Breast
Gastric
Colorectum
Hereditary Diffuse Gastric Cancer
- Diffuse gastric cancer
- Lobular breast cancer
- Signet ring carcinoma
BRCAplus
Thyroid
PTEN Hamartoma Tumor syndrome (PHTS)
Cowden syndrome (CS)
- Mucocutaneous lesions (trichilemmomas,
acral keratosis, papillomatous papules)
- Macrocephaly
- Adult Lhermitte-Duclos disease
- GI hamartomas or ganglioneuromas
- Benign breast, thyroid, and uterus lesions
- Nonmedullary thyroid cancer
BRCAplus gene specific lifetime breast cancer risks
General
Population
BRCAplus Genes
12%
45-87%
BRCA1, BRCA2
PTEN
up to 50%
up to
93%*
TP53
STK11
CDH1
up to 45%
39-52%
*Breast cancer is the most common cancer in women with TP53 mutations. Although the breast
cancer risk associated with a TP53 mutation is significantly elevated above the general
population, the specific risk is not well defined. Combined lifetime cancer risk is shown.
BRCAplus
Benefits of testing
Knowing your patient has an increased cancer susceptibility can aid in
medical management. For example:
1. High-risk breast screening for
BRCA1, BRCA2, PTEN, TP53,
CDH1 and STK11 mutation
carriers:
- Clinical breast exams more
frequently
- Breast imaging with
mammogram & breast MRI
- Initiate screening at a
younger age
2. Discuss the option of riskreducing bilateral mastectomy
with patients who have a
BRCA1, BRCA2, PTEN or a TP53
mutation
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 family mutation
and devise an individualized
cancer screening and
prevention program
6. Assist couples in reproductive
decision making (e.g. advise
BRCA1, BRCA2, PTEN or TP53
mutation carriers about
assisted reproduction options
including pre-implantation
genetic diagnosis)
BreastNext
BreastNext is a multi-gene panel including comprehensive analyses
of 18 breast cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2,
BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NF1, NBN, PALB2, PTEN, RAD50,
RAD51C, RAD51D, STK11 and TP53).
BRCAplus includes six clinically actionable breast cancer
susceptibility genes with clear management guidelines.
BreastNext includes high-risk and intermediate-risk breast cancer
genes represented in pink and blue.
High-risk genes - BRCA1, BRCA2, PTEN, TP53, STK11, CDH1 - confer up
to a 40-87% lifetime breast cancer risk.
BreastNext
* Low penetrance SNPs have been identified in these breast cancer susceptibility
genes. These low penetrance genes do not influence clinical management and are
thus not included in Ambry’s panels.
BreastNext genes, associated cancers and other
characteristics
Gene
Cancer(s)
Additional Characteristics
BRCA1
Breast
BRCA2
Ovaries
Hereditary Breast-Ovarian
Cancer syndrome (HBOC)
- Fallopian and primary peritoneal cancers
- Triple Negative (ER-, PR-, HER2/neu-) breast
cancers common with BRCA1 mutations
- Founder mutations are known for many
populations (ex: Ashkenazi Jewish,
Portuguese, Icelandic, Danish, and more)
Pancreas
Prostate
Male Breast
PTEN
Breast
Thyroid
Endometrium
Colorectum
Kidney
TP53
Breast
Sarcoma
Brain
Adrenocortical
PTEN Hamartoma Tumor syndrome (PHTS)
Cowden syndrome (CS)
- Mucocutaneous lesions (trichilemmomas,
acral keratosis, papillomatous papules)
- Macrocephaly
- Adult Lhermitte-Duclos disease
- GI hamartomas or ganglioneuromas
- Benign breast, thyroid, and uterus lesions
- Nonmedullary thyroid cancer
Li-Fraumeni syndrome (LFS)
- Soft tissue and osteosarcomas
- Colorectal and many other cancers
- Childhood onset cancers
- Increased radiation sensitivity
- Risk for multiple primary tumors
Leukemias
STK11
Breast
Ovaries
Colorectum
Duodenum
Peutz-Jeghers syndrome (PJS)
- Childhood onset mucocutaneous
pigmentation and GI hamartomas
- Risk for additional cancers
- Can see cervical and gonadal tumors
Pancreas
BreastNext
CDH1
Breast
Gastric
Colorectum
BARD1
Breast
Possibly Ovaries
Hereditary Diffuse Gastric Cancer
- Diffuse gastric cancer
- Lobular breast cancer
- Signet ring carcinoma
Continued: BreastNext genes, associated cancers & other
associated findings.
Gene
Cancer(s)
Additional Characteristics
CHEK2
Breast
- Brain tumors have been reported
Prostate
Colorectum
Thyroid
Kidney
NF1
Breast
RAD51D
Breast
Neurofibromatosis Type 1
Ovaries
ATM*
Breast
Pancreas
BRIP1*
Breast
Ataxia-Telangiectasia
- Risk for lymphoma and leukemia in
homozygous mutations carriers
Fanconi Anemia*
Possibly Ovaries
MRE11A*
Breast
Ataxia-telangiectasia-like disorder*
Possibly Ovaries
MUTYH*
Breast
Colorectum
NBN*
Breast
MUTYH-associated polyposis (MAP)*
- 10-100’s colorectal polyps
- Can see gastric, ovarian, endometrial
and liver cancer
Nijmegen breakage syndrome*
Possibly Ovaries
PALB2*
Breast
Fanconi Anemia*
Pancreas
RAD50*
Breast
Nijmegen breakage syndrome-like disorder*
Possibly Ovaries
RAD51C*
Breast
Fanconi Anemia*
Ovaries
* Biallelic mutations in these genes are associated with respective syndromes described
under Additional Characteristics column.
Target population for panel genetic testing
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
3. Male breast cancer at any age
4. Breast and ovarian cancer in
the same woman
5. Family with three or more
cases of breast cancer
(on the same side of the family)
6. Clustering of three or more
cases of breast, ovarian,
&/or pancreatic cancer
(on the same side of the family)
7. Clustering of three or more
cases of breast, uterine,
&/or thyroid cancer
(on the same side of the family)
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 [VUS]).
positive
negative
inconclusive
A gene mutation was
found in one of the
genes tested
No clinically-significant
genetic changes
identified in any of the
genes tested
A genetic change was
identified but current
knowledge cannot
predict if the change is
disease-causing or
benign
Increased risk for
cancer specific to the
gene mutation
Cancer screening
and prevention
recomendations
specific to gene
Testing at-risk
relatives for specific
alteration will be
recommended
Cancer risk is based on
personal and family
history
Cancer screening
and prevention
recomendations based
on family history
Genetic testing may or
may not indicated for
family members
Cancer risk is based on
personal and family
history
Cancer screening
and prevention
recomendations based
on family history
Family research studies
may be indicated
VUS rates and family studies program
Our BRCA1/2 VUS rate is approximately 4% and BRCAplus
VUS rate is approximately 6-7%. VUSs are more common in
the BreastNext panel because this panel analyzes 18 genes
simultaneously. As data 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 the BreastNext panel samples. Detailed
interpretation of the variant is included in the test report.
Ambry Genetics is committed to careful analysis and timely
reclassification of VUSs. If a VUS is identified, complimentary
testing of informative relatives may be offered through Ambry’s
family studies program. Familial tracking can assist in clarifying
the nature of a VUS. When enough data has been accumulated to
reclassify the VUS as either disease-causing or benign, clinicans
will be automatically notified.
Ambry has 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
draw blood.
Blood Spot: Blood spots are not accepted.
Saliva: Accepted for all BRCA1/2 related tests. Fill 1 tube with saliva up to black
line (1cc of saliva) in Oragene Self Collection container (BreastNext requires 2
tubes). After tube is closed 1cc of buffer will mix with saliva for a total volume of
2cc. Store at room temperature in sterile bag. Ship 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
Genetic counselors
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 pre-verification is
recommended.
max out of pocket
If patient out-of-pocket financial
responsibility is potentially
greater than $100, Ambry will
contact the patient for verbal
approval prior to initiating the
test. We remain committed to
working with you and your
patients to make the genetic
testing process as simple and
cost effective as possible.
about ambry genetics
In 13 years of offering genetic
testing services, we’ve performed
hundreds of thousands of genetic
tests and identified more than
45,000 mutations in greater than
500 different genes.
Ambry Genetics offers a full
menu of diagnostic solutions
and is the world wide leader in
hereditary cancer testing. Our
comprehensive menu of over 40
individual cancer genes is the
largest available in the US.
To order your free sample
submission kits, please contact:
(866) 262 7943
[email protected]
15 Argonaut
Aliso Viejo, CA 92656
For more details about these
tests, visit ambrygen.com
D1013-09-166-MKG-00