Download Genetic testing for breast cancer

Genetic testing for breast cancer
Susan M. Domchek, MD
Basser Professor of Oncology
University of Pennsylvania
Risk Factors for Breast Cancer
•
Sex
•
Age
•
Family history
•
–
Depends on specific of family history
–
Depends on whether there is a known genetic susceptibility
Reproductive history
–
Early first period
–
Late last period
–
Postmenopausal estrogen use
–
Late first child
–
No breast feeding
•
ETOH
•
Obesity
•
Lack of exercise
Germline vs Somatic Genetics
•
•
Germline – the genes you are born with
–
Can be passed on to relatives
–
Does not mean that disease will happen
–
Increased risk of disease
–
There is no one “breast cancer gene”
Somatic – changes in tumors that are acquired over
time
–
Can not pass on to relatives
–
Can be tested as part of decision making for therapy for cancer
Genetics :Cancer Risk Variants
Single
nucleotide
polymorphisms
Allele Frequency
Common
Variants
CHEK2, ATM, NBN
BRCA1, BRCA2, TP53
Rare variants (moderate)
1
2
Rare variants (high)
5
Relative Risk
≥10
Hereditary breast cancer
Predicted
SNP , 14%
Known
SNPs, 14%
Unknown,
50%
Moderate
penetrance ,
4%
Other high
penetrance,
3%
BRCA1/2,
15%
Adapted from Couch, Nathanson, & Offit, Science 2014
Germline genetic testing as a paradigm
for individualized care
•
Risk Assessment
•
Disease Prevention
•
Therapeutics
BRCA1/2 as the prototype
BRCA1/2-associated cancers: lifetime risk
Breast cancer: 50%-70%
Second primary breast cancer: 40%-50%
Ovarian cancer: 15-55% BRCA1>BRCA2
Increased risk of other cancers:
Male breast cancer
BRCA2>BRCA1
Pancreatic cancer
BRCA2
Prostate cancer
BRCA2
Melanoma
BRCA2
Who should be considered for testing?
• Breast cancer <45
•
•
•
•
•
•
•
•
Ovarian cancer cases (particularly high grade serous)
Male Breast Cancer
Breast and ovarian cancer in a single lineage
2 or more women with breast cancer <50
Ashkenazi Jewish with breast or ovarian cancer
Breast cancer < 60 and triple negative
Bilateral breast cancer <60
Pay attention to pancreatic cancer and high grade prostate
cancer
• Ashkenazi Jewish individuals?
• All women at age 30? Many issues related to population
screening
% Affected with Breast Cancer
Estimates of breast cancer risk in BRCA1 carriers:
Significant variability in penetrance
Easton, 1995
all mutations
linkage families
100%
90%
80%
Penn Clinic
Brose et al JNCI 2002
70%
Streuwing, 1997
185delAG, 5382insC
60%
50%
Hopper, 1999
consecutive breast ca
cases
40%
30%
Fodor, 1998
185delAG,
5382insC
consecutive breast
ca cases
20%
10%
0%
30
40
50
60
AgeAge
70
80
85
5%, 95%
10%, 90%
Average
0.6
0.8
Polygenic risk
scores (PRS) using
BC susceptibility
SNPs identified
through
population-based
GWAS
0.4
15,252 BRCA1
0.2
8,211 BRCA2
0.0
Breast cancer risk
BRCA1 carriers
1.0
Genetic modifiers: CIMBA
30
40
50
60
Age
70
80
Kuchenbaecker et al in press 2016
Risk Reducing Salpingo-Oophorectomy and the
risk of breast cancer
No Prior Breast Cancer
Total Participants
HR (95% CI)
Total
BRCA1
BRCA2
1,370
869
501
0.54 (0.37-0.79)
0.63 (0.41-0.96)
0.36 (0.16-0.82)
RRSO and the risk of ovarian cancer
Breast cancer prior
Total Participants
HR (95% CI)
PROSE Consortium
Total
BRCA1
BRCA2
1060
684
376
0.14 (0.04-0.59)
0.15 (0.04-0.63)
No cancer events
Domchek et al, JAMA 2010
RRSO and all-cause mortality
All eligible women
Total Participants
HR (95% CI)
All
BRCA1
BRCA2
2,482
1587
895
0.40 (0.26-0.61)
0.38 (0.24-0.62)
0.52 (0.22-1.23)
Domchek et al, JAMA 2010
Domchek et al, JAMA 2010
Treatment of BRCA1/2-associated cancers:
Platinum and PARP inhibitors
•
•
•
•
•
Olaparib
Veliparib
Rucaparib
Niraparib
BMN-673
Poly ADP ribose polymerase (PARP)
plays a role in the repair of single strand
breaks through base excision repair
Significant responses observed in
patients with germline BRCA1/2associated breast and ovarian cancer
Tutt et al, Lancet 2010
Audeh et al, Lancet 2010
Gelmon et al, Lancet Oncology 2011
Tumor shrinkage
Tutt et al, Lancet 2010
Approval is for germline BRCA1 and BRCA2 associated
ovarian cancer after treatment with >3 lines of therapy
The FDA did not approve maintenance therapy
EMA did approve maintenance
Multiple tumor types
Cisplatin-resistant ovarian cancer
Breast cancer with >3 lines of therapy in metastatic setting
Pancreatic and prostate cancer
Kaufman et al, JCO 2015
Domchek et al, Gyn Onc 2016
Ovarian
(n=193)
Breast
(n=62)
Pancreas
(n=23)
Prostate
(n=8)
Other
(n=12)
All
(n=298)
148 (76.7)
44 (22.8)
1 (0.5)
37 (59.7)
25 (40.3)
0
5 (21.7)
17 (73.9)
1 (4.3)
1 (12.5)
7 (87.5)
0
7 (58.3)
5 (41.7)
0
198 (66.4)
98 (32.9)
2 (0.7)
Median (SD) prior
regimens for
advanced disease
4.3 (2.2)
4.6 (2.0)
2.0 (1.6)
2.0 (1.0)
2.2 (1.3)
4.0 (2.2)
Tumor response rate
60 (31.1)
8 (12.9)
5 (21.7)
4 (50)
1 (8.3)
78 (26.2)
Complete response
6 (3.1)
0
1 (4.3)
0
0
7 (2.3)
Partial response
54 (28)
8 (12.9)
4 (17)
4 (50)
1 (8.3)
71 (23.8)
Stable (>8wks)
Stable disease
Unconfirmed PR
78 (40)
64 (33)
12 (6)
29 (47)
22 (36)
7 (11)
8 (35)
5 (22)
3 (13)
2 (25)
2 (25)
0
7 (58)
6 (50)
1 (8.3)
124 (42)
99 (33)
25 (9)
BRCA status, n (%)
BRCA1 mutation
BRCA2 mutation
Both
Kaufman et al JCO, 2015
Platinum resistance and PARP treatment
Platinum sensitivity
status
(N= with measurable
disease)
Confirmed
responders
n
ORR,
%
(95% CI)
• Data from the gyn onc paper
Median DoR,
months
(95% CI)
Total (N = 137)
46
34 (26–42)
7.9 (5.6–9.6)
Platinum sensitive
(N = 39)
18
46 (30–63)
8.2 (5.6–13.5)
Platinum resistant
(N = 81)
24
30 (20–41)
8.0 (4.8–14.8)
Platinum refractory
(N = 14)
2
14 (2–43)
6.4 (5.4–7.4)
Platinum status
unknown (N = 3)
2
67 (9–99)
6.3 (4.7–7.9)
Domchek et al, Gyn Onc 2016
Genetic testing has become complicated….
Single nucleotide polymorphism panels
Key Points
• Not comprehensive sequencing of genes – such as BRCA1/2
• Not a stand alone for those with a strong family history
• Some change in reclassification (change in how you
consider someone from a risk perspective)
• Calibration: How closely the predicted probabilities agree
with the actual outcome
• Clinical utility (or actionability?)
– Will more women take tamoxifen?
– How should this impact screening in the era of changing screening
recommendations?
• Ongoing studies
In the US - this has become very complicated….
Ambry
Myriad
Uwash Fulgent
Cancer Invitae GeneDx
MyRisk
BROCA
*
Next
# of genes
25
28
28
30
50
110
Gene
APC
ATM
BMPR1A
BRCA1
BRCA2
BRIP1
CDH1
CDK4
CDKN2A
CHEK2
EPCAM
MLH1
MSH2
MSH6
MUTYH
NBN
PALB2
PMS2
PTEN
RAD51C
SMAD4
STK11
TP53
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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x
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x
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x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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x
x
x
x
x
x
x
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x
x
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x
x
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x
x
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x
x
x
x
x
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x
x
x
x
x
x
x
x
x
x
x
x
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x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Gene
BARD1
RAD51D
MRE11A
RAD50
NF1
VHL
MEN1
RET
PTCH1
PALLD
XRCC2
CHEK1
AXIN2
FANCC
ATR
BAP1
GALNT12
HOXB13
POLD1
PRSS1
RAD51A
SDHB
SDHC
SDHD
AKT1
CTNNA1
FAM175A
GEN1
GREM1
PIK3CA
POLE
PPM1D
TP53BP1
Ambry
Myriad
Uwash Fulgent
Cancer Invitae GeneDx
MyRisk
BROCA
*
Next
x
x
x
x
x
x
x
Renal/PGL
PGL
Renal/PGL
Renal/PGL
Renal/PGL
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Gene
FH
FLCN
MAX
MET
MITF
SDHA
SDHAF2
TMEM127
TSC1
TSC2
Ambry
Fulgent
Renal or
*
PGL
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
*Rest of genes on Fulgent:
BLM, BUB1B, CTNNB1,
CYLD, DDB2, DICER1, EGFR,
EGLN1, ERCC2, ERCC3,
ERCC4, ERCC5, EXO1, EXT1,
EXT2, FANCA, FANCB,
FANCD2, FANCE, FANCF,
FANCG, FANCI, FANCL,
FANCM, GPC3, HRAS,
KIF1B, KIT, MC1R, MPL,
MSH3, NF2, PDGFRA,
PICALM, PMS1, PRKAR1A,
PRKDC, PTPN11, RB1,
RBBP8, RBM15, RECQL4,
ROBO2, SBDS, SLX4,
SMARCB1, SUFU, TERT,
TSHR, TYR, WRN ,WT1,
XPA, XPC, XRCC3
Revolution of genetic testing
Assess
patient
Test for
most likely
gene(s)
Test for
most likely
gene(s)
Disclose
result and
reassess
New approach?
Assess
patient
Send
multigene
panel
Disclose
result and
reassess
Why do this?
• More cost effective (for the testing) to do multigene
rather than serial testing
• Patients (and providers!) can get testing fatigue
• The same cancer can be seen with different genes
mutations
– Ovarian cancer in both BRCA1/2 and Lynch
– Uterine cancer in Lynch and Cowden
– Breast in Li-Fraumeni and BRCA1/2
• Isn’t more better?
Potential Issues
• High penetrance and moderate penetrance genes
are on one panel
– Implications for counseling
– Keeping track of it all
– Don’t we recognize clinical syndromes?
• (And if we don’t – what does it mean?)
• Variants of uncertain significance
• Clinical utility: order tests you will act on
– At least actionability
Domchek et al, JCO 2013
What will we find?
BRCA1/2 negative patients with BC <40
N=278
Patients with Class 4 VUS
& Class 5 Mutations
N=31 (11%)
Bin A Genes
TP53, PTEN, STK11, CDH1,
CDKN2A, MLH1, MSH2,
MSH6, PMS2, MUTYH (AR)
Risk established for breast
or other cancers
Guidelines available
*Clinically actionable*
N=7 (2.5%)
TP53
N=4
MSH2
N=1
CDKN2A
N=1
MUTYH
N=1
Class 3 VUS(s)
only
N=49 (18%)
Bin B Genes
ATM, BARD1, BRIP1, CHEK2,
FAM175A, MRE11A, NBN,
PALB2, RAD50, RAD51C
Risk established for breast
and some other cancers
Less clear actionability
N=24 (8.6%)
ATM & CHEK2
N=18
Other genes
N=6
MUTYH
Heterozygotes
N=6 (2.2%)*
No Class 3-5
Variants
N=192 (69%)
6%
13%
13%
74%
White
31%
63%
Non-white
Class 4/5 Mutation
Class 3 VUS
No Class 3-5 Variants
Maxwell et al GIM, 2014
What do we do? ACCE Framework
Parameter
Definition
Analytic
validity
How well test measures property or
characteristic it is intended to measure
Clinical
validity
Accuracy of the test in diagnosing or
predicting risk for the health condition
(sensitivity, specificity, PPV, NPV)
Clinical Utility
• Evidence of improved measurable clinical
outcomes
• Usefulness and added value to patient
management
ELSI
• Ethical, legal and social implications
What is actionable?
• Something that potentially could be acted upon
• It does not mean that it is acted upon
• It does not mean that such action benefits a patient
• Actionability = clinical utility
• Critically important that all this be studied
Summary of Clinical Validity
Gene
Breast
Ovary
Other
ATM
Y
N
?Pancreas
CHEK2
Y
N
?Colon
PALB2
Y
N
?Pancreas
NBN
Y (657del5)
N
BRIP1
N
Y
RAD51C/D
N
Y
RAD51B
N
?
BARD1
N
N
MRE11A/RAD50
N
N
Easton et al, NEJM 2015
Clinical utility
• Risk assessment
– Value of the true negative
– Risk of breast and as well as risk of second primary
cancer
– Risk of other cancers (Ovarian cancer risk for
BRCA1/2 was a major reason for rapid uptake of
testing)
Clinical utility
• Screening and prevention
–
–
–
–
–
Need to understand risks and benefits
What age to start screening?
What screening?
What age to have preventative surgery?
What to do with “unexpected” high penetrance mutation
• When we find things we don’t expect, what should we do?
Clinical utility
• Therapeutics
– Prognosis: may impact administration of adjuvant
therapy
– Drug development/selection
– Will tumors with mutations in these other genes be
sensitive to specific types of drugs?
Conclusions
• Genetic testing can be very useful to patients and their family members
– Both the prevent and to treat cancer
• Genetic testing is continuously evolving
• BRCA1 and BRCA2 mutations are the most commonly found and we
have reasonable data on how to manage
• New genetics tests are often less clear in terms of how to change
patients care – and improve patient outcome
• Variants of unknown significance should NOT be managed as
mutations
• In the face of rising prophylactic mastectomies, we need to emphasize
to patients how mutations in these genes are different from those in
BRCA1/2