Download BreastNext: A 17-Gene Hereditary Breast Cancer Test

BreastNext: A 17-Gene Hereditary Breast Cancer Test
white paper november 2014
key point
logistics
BreastNext is a multi-gene test that analyzes 17 breast cancer susceptibility genes:
ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NF1, NBN, PALB2,
PTEN, RAD50, RAD51C, RAD51D, and TP53. Many patients undergoing BRCA1 and BRCA2
testing for a history of breast cancer have no mutation identified. Multi-gene testing
increases the likelihood of identifying an explanatory gene mutation that may clarify the
patient’s future cancer risk(s) and target medical management.
•Blood or saliva samples accepted
(6-10cc blood; 2 Oragene saliva kits)
• Insurance verification is performed
either before or after a sample is sent
to the lab, per the clinician’s request.
Patient notified prior to test initiation
if out-of-pocket cost is expected to be
greater than $100
•Ambry is contracted with the majority
of health plans, Medicaid plans, and
Medicare
• AmbryPort 2.0 provides an easy way
to order testing and receive reports
through a HIPAA compliant, secure
online portal
• 2-4 week TAT
potential indications for breastnext testing
•Early-onset breast cancer (diagnosed ≤ 45, particularly if diagnosed ≤ 35)
•Bilateral or multiple primary breast cancers
• Male breast cancer at any age
• Breast and ovarian cancer in the same woman
• Three or more cases* of breast, ovarian, and/or pancreatic cancer
•Multiple close family members* with breast and other cancers
* on the same side of the family
technology
• Next generation sequencing (NGS) with Sanger confirmation of all reported
alterations, including variants of unknown significance (VUS)
• Custom targeted microarray (aCGH) for detection of deletions/duplications
penetrance vs. prevalence of brcaplus and breastnext genes
penetrance vs. prevalence of brcaplus and breastnext genes
fanconi anemia/brca1/2 pathway
DNA Double-Strand Break
dna doublestrand break
BRCAplus
mre11
rad50
nbn
atm
tp53
Cell Cycle
Checkpoint
and/or
Cell Death
*
chek2
bard1
brca1
brip1
palb2
brca2
pten
rad51
xrcc3
rad51c
rad51d
* Low penetrance SNP’s have been identified in these breast cancer susceptibility genes which do not
influence clinical management and are thus not included in Ambry’s test.
rad51b
xrcc2
dna repair
DNA Repair
breastnext experience as of october 2014
Mutation Identification In Over 7000 Recent BreastNext Tests
BreastNext Mutation Distribution for Over 500 non-BRCA1/2
Positive Cases *
RAD51D RAD51C
CDH1 MUTYH biallelic
MRE11A PTEN
NBN
Negative
MUTYH Carrier
BARD1
BRIP1
VUS
Positive
68.32%
TP53
RAD50
CHEK2
NF1*
1.73%
PALB2
21.52%
ATM
8.43%
Many patients undergoing BreastNext previously underwent BRCA1 and
BRCA2 genetic testing. As 5-10% of patients are identified to have a mutation
on BRCA1 and BRCA2 testing, it is expected that the overall detection rate of
BreastNext would be 13-18% in BRCA1/2-naive patients.
rationale for considering breastnext
•Higher probability of detecting an explanatory gene mutation
than single gene testing
•Concurrent testing reduces the likelihood of patients being lost
to follow-up
•Many patients have personal and family histories that are
suggestive of mutations in multiple BreastNext genes
* Interesting Finding: 40% of NF1 mutations identified through multi-gene
panels were in patients who did not meet clinical criteria1
Summerour et al (2014, October) NF1 Mutations Detected on Multi-Gene Cancer
Panel Testing in Probands with Atypical Phenotypes, Poster presented at the 33rd
annual meeting of the National Society of Genetic Counselors, New Orleans, LA
1
CANCER IN FAMILY
POTENTIALLY CAUSATIVE GENES
Breast & Pancreatic
BRCA1, BRCA2, PALB2, ATM
Breast & Colon
TP53, CHEK2, PTEN
Breast & Ovarian
RCA1, BRCA2, BARD1, BRIP1, RAD51C,
B
RAD51D, TP53
case example
Relevant History
40
80
50
90
94
Pancreas
87
95
borderline
ovarian
tumor - 70
65
Lung
•Patient was diagnosed with breast cancer at 58
•There is a family history of multiple cancers including
pancreatic, ovarian, and breast
•Clinician ordered BreastNext given the history being
suggestive of multiple gene mutations including BRCA1,
BRCA2, PALB2, and ATM
Result
• PALB2 pathogenic mutation identified
Cancer Risks With a PALB2 Mutation
2
55
Esoph
68
Breast - 58
Bilateral
Mastectomy
70
75
Melanoma - 44
64
60
Pancreas - 60
71
Breast - 59
•Risk of breast cancer is 35% by age 70 (ranging from 33-58%
depending on family history)2
•Elevated risk for pancreatic cancer
•Possibly elevated risk for ovarian cancer
Implications
33
•Patient already had bilateral mastectomy
•Pancreatic cancer screening can be offered
•Other cancer risks (such as ovarian) may be increased
•Family members may have genetic testing for the familial
mutation to better assess their cancer risk(s)
2
50339.1465_v3
15 Argonaut, Aliso Viejo, CA 92656
Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506
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