Susan M Domchek MD Basser Professor of Oncology University of Pennsylvania Sex Age Family history Depends on specific of family history Depends on whether there is a k nown genetic susceptibility ID: 589275
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Slide1
Genetic testing for breast cancer
Susan M. Domchek, MDBasser Professor of OncologyUniversity of Pennsylvania Slide2
Sex
AgeFamily historyDepends on specific of family historyDepends on whether there is a known genetic
susceptibility
Reproductive historyEarly first periodLate last periodPostmenopausal estrogen useLate first childNo breast feedingETOHObesityLack of exercise
Risk Factors for Breast CancerSlide3
Germline – the genes you are born with
Can be passed on to relativesDoes not mean that disease will happenIncreased risk of diseaseThere 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
Germline vs Somatic GeneticsSlide4
Allele Frequency
Relative Risk12
5
≥10Common VariantsRare variants (moderate)Rare variants (high)
Genetics :Cancer Risk Variants
Single nucleotide polymorphisms
CHEK2, ATM, NBN
BRCA1, BRCA2, TP53Slide5
Adapted from Couch,
Nathanson, & Offit, Science 2014Hereditary breast cancerSlide6
Risk Assessment
Disease PreventionTherapeutics
Germline genetic testing as a paradigm
for individualized care
BRCA1/2
as the prototypeSlide7
Increased
risk of other cancers:Male breast cancer
BRCA2>BRCA1
Pancreatic cancer BRCA2Prostate cancer BRCA2Melanoma BRCA2Breast cancer: 50%-70%
Second primary breast cancer: 40
%-50%
Ovarian cancer:
15-55%
BRCA1>BRCA2
BRCA1/2
-associated cancers: lifetime riskSlide8
Breast cancer
<45 Ovarian cancer cases (particularly high grade serous)Male Breast CancerBreast and ovarian cancer in a single lineage2 or more women with breast cancer <50Ashkenazi Jewish with breast or ovarian cancer
Breast cancer
< 60 and triple negativeBilateral breast cancer <60Pay attention to pancreatic cancer and high grade prostate cancerAshkenazi Jewish individuals?All women at age 30? Many issues related to population screeningWho should be considered for testing?Slide9Slide10
Estimates of breast cancer risk in
BRCA1
carriers:
Significant variability in penetranceSlide11
Kuchenbaecker
et al in press 2016
Genetic modifiers: CIMBA
BRCA1 carriers
Polygenic risk scores (PRS) using BC susceptibility SNPs identified through population-based GWAS15,252 BRCA1
8,211 BRCA2Slide12
No Prior Breast Cancer
Total
BRCA1
BRCA2Total Participants1,370869501HR (95% CI)0.54 (0.37-0.79)
0.63 (0.41-0.96)
0.36 (0.16-0.82)
Domchek et al,
JAMA
2010
Breast cancer prior
Total
BRCA1
BRCA2
Total Participants
1060
684
376
HR (95%
CI)
0.14 (0.04-0.59
)
0.1
5 (0.04-0.63
)
No cancer
events
Risk Reducing
Salpingo-Oophorectomy
and the risk of breast cancer
RRSO and the risk of ovarian cancer
PROSE ConsortiumSlide13
All eligible women
AllBRCA1BRCA2
Total Participants
2,4821587895HR (95% CI)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
RRSO and all-cause mortalitySlide14
Olaparib
Veliparib Rucaparib
Niraparib BMN-673 Tutt et al, Lancet 2010Audeh et al, Lancet 2010Gelmon et al, Lancet Oncology 2011
Treatment of BRCA1/2
-associated cancers:Platinum and PARP inhibitors
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
BRCA1/2-
associated breast and ovarian cancer Slide15Slide16
Tutt
et al, Lancet 2010Tumor shrinkage Slide17
Approval is for germline BRCA1 and BRCA2 associated ovarian cancer after treatment with
>3 lines of therapyThe FDA did not approve maintenance therapyEMA did approve maintenanceSlide18
Multiple tumor types
Cisplatin
-
resistant ovarian cancer Breast cancer with >3 lines of therapy in metastatic setting Pancreatic and prostate cancerKaufman et al, JCO 2015Domchek et al, Gyn Onc 2016Slide19
Ovarian
(n=193)Breast(n=62)Pancreas(n=23)Prostate(n=8)Other(n=12)
All
(n=298)BRCA status, n (%) BRCA1 mutation BRCA2 mutation Both 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)
Kaufman et al
JCO
, 2015Slide20
Data from the
gyn onc paperPlatinum resistance and PARP treatment
Platinum
sensitivity status(N= with measurable disease)Confirmed respondersnORR, %
(95% CI)
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
2016Slide21
Genetic testing has become complicated….
Single nucleotide polymorphism panelsSlide22
Not comprehensive sequencing of genes – such as BRCA1/2Not a stand alone for those with a strong family historySome change in reclassification
(change in how you consider someone from a risk perspective)
Calibration: How closely the predicted probabilities agree with the actual outcomeClinical utility (or actionability?)Will more women take tamoxifen?How should this impact screening in the era of changing screening recommendations?Ongoing studies
Key PointsSlide23
In the US - this
has become very complicated….Slide24
Gene
Myriad MyRisk
Ambry Cancer Next
InvitaeGeneDxUwash
BROCA
Fulgent*
# of genes
25
28
28
30
50
110
APC
x
x
x
x
x
x
ATM
x
x
x
x
x
x
BMPR1A
x
x
x
x
x
x
BRCA1
x
x
x
x
x
x
BRCA2
x
x
x
x
x
x
BRIP1
x
x
x
x
x
x
CDH1
x
x
x
x
x
x
CDK4
x
x
x
x
x
x
CDKN2A
x
x
x
x
x
x
CHEK2
x
x
x
x
x
x
EPCAM
x
x
x
x
x
x
MLH1
x
x
x
x
x
x
MSH2
x
x
x
x
x
x
MSH6
x
x
x
x
x
x
MUTYH
x
x
x
x
x
x
NBN
x
x
x
x
x
x
PALB2
x
x
x
x
x
x
PMS2
x
x
x
x
x
x
PTEN
x
x
x
xxxRAD51CxxxxxxSMAD4xxxxxxSTK11xxxxxxTP53xxxxxx
GeneMyriad MyRisk Ambry Cancer NextInvitaeGeneDxUwash BROCAFulgent*BARD1xxxxxRAD51DxxxxxMRE11AxxxRAD50xxxNF1xxVHLRenal/PGLxxxxMEN1xxxRETPGLxxxPTCH1xxPALLDxXRCC2xxxCHEK1xxAXIN2xxFANCCxxATRxxBAP1xxGALNT12xxHOXB13xxPOLD1xxPRSS1xxRAD51AxxSDHBRenal/PGLxxSDHCRenal/PGLxxSDHDRenal/PGLxxAKT1xCTNNA1xFAM175AxGEN1xGREM1xPIK3CAxPOLExPPM1DxTP53BP1x
*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
Gene
Ambry
Renal or PGL
Fulgent*
FH
x
x
FLCN
x
x
MAX
x
x
MET
x
x
MITF
x
x
SDHA
x
x
SDHAF2
x
x
TMEM127
x
x
TSC1
x
x
TSC2
x
xSlide25
Assess patient
Test for most likely gene(s)Disclose result and reassessTest for most likely gene(s)
Revolution of genetic testingSlide26
Assess patient
Send multigene panelDisclose result and reassess
New approach?Slide27
More cost effective
(for the testing) to do multigene rather than serial testingPatients (and providers!) can get testing fatigueThe same cancer can be seen with different genes mutationsOvarian cancer in both BRCA1/2
and Lynch
Uterine cancer in Lynch and CowdenBreast in Li-Fraumeni and BRCA1/2Isn’t more better?Why do this?Slide28
High penetrance and moderate penetrance genes are on one panel
Implications for counselingKeeping track of it allDon’t we recognize clinical syndromes?(And if we don’t – what does it mean?)Variants of uncertain significanceClinical utility: order tests you will act on
At least
actionabilityDomchek et al, JCO 2013Potential IssuesSlide29
Maxwell et al GIM, 2014
BRCA1/2 negative patients with BC <40N=278Patients with Class 4 VUS & Class 5 MutationsN=31 (11%)Class 3 VUS(s) onlyN=49 (18%)
MUTYH
HeterozygotesN=6 (2.2%)*Bin A GenesTP53, PTEN, STK11, CDH1, CDKN2A, MLH1, MSH2, MSH6, PMS2, MUTYH (AR)Risk established for breast or other cancersGuidelines available*Clinically actionable*N=7 (2.5%)Bin B GenesATM, BARD1, BRIP1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD50, RAD51CRisk established for breast and some other cancersLess clear actionabilityN=24 (8.6%)
No Class 3-5 VariantsN=192 (69%)
TP53N=4
MSH2
N=1
CDKN2A
N=1
ATM
&
CHEK2
N=18
Other genes
N=6
White
Non-white
6%
31%
63%
13%
13%
74%
Class 4/5 Mutation
Class 3 VUS
No Class 3-5 Variants
MUTYH
N=1
What will we find?Slide30
What do we do? ACCE Framework
ParameterDefinitionAnalytic validityHow well test measures property or characteristic it is intended to measureClinical validity
Accuracy of the test in diagnosing
or predicting risk for the health condition (sensitivity, specificity, PPV, NPV)Clinical UtilityEvidence of improved measurable clinical outcomesUsefulness and added value to patient management ELSIEthical, legal and social implicationsSlide31
What is actionable?
Something that potentially could be acted uponIt does not mean that it is acted uponIt does not mean that such action benefits a patientActionability = clinical utility Critically important that all this be studiedSlide32
Summary of Clinical Validity
GeneBreastOvary
Other
ATMYN?PancreasCHEK2YN?ColonPALB2YN?PancreasNBN
Y
(657del5)N
BRIP1
N
Y
RAD51C/D
N
Y
RAD51B
N
?
BARD1
N
N
MRE11A/RAD50
N
N
Easton et al, NEJM 2015Slide33
Risk assessment
Value of the true negativeRisk of breast and as well as risk of second primary cancerRisk of other cancers (Ovarian cancer risk for BRCA1/2 was a major reason for rapid uptake of testing)
Clinical utilitySlide34
Screening and prevention
Need to understand risks and benefitsWhat 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 utilitySlide35
Therapeutics
Prognosis: may impact administration of adjuvant therapyDrug development/selectionWill tumors with mutations in these other genes be sensitive to specific types of drugs?
Clinical utilitySlide36
Genetic testing can be very useful to patients and their family members
Both the prevent and to treat cancerGenetic testing is continuously evolvingBRCA1 and BRCA2 mutations are the most commonly found and we have reasonable data on how to manageNew 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 mutationsIn the face of rising prophylactic mastectomies, we need to emphasize to patients how mutations in these genes are different from those in BRCA1/2Conclusions