BRCA testing in women with
ovarian cancer
Dr Carole Brewer
Peninsula Clinical Genetics Service
15 January 2016
Peninsula Clinical Genetics
Service
www.peninsulaclinicalgeneticsservice.co.uk/
Consultant
clinics
Genetic nurse or
counsellor clinics
Genetic mutations
• Genes that control cell growth- tumour
suppressors, oncogenes etc.
• Germline mutations (vs somatic)
• Diagnostic- mutation searching
• Predictive- testing for known family mutation
• Referrals- tend to be unaffected people
Referrals to PCGS
breast/ovary affected
breast/ovary unaffected
colon affected
colon-at risk
other
Reasons for BRCA testing
• For the benefit of family: Predictive tests
for relatives
• Management of future risks- patient and
relatives
Reasons for BRCA testing
• For the benefit of family: Predictive tests
for relatives
• Management of future risks- patient and
relatives
• Influence current management
brca 35
Ovca 63
brca 47
brca 35
Ovca 63
brca 47
BRCA1 mutation
brca 35
Ovca 63
brca 47
Predictive genetic testing
•
•
•
•
Unaffected, at-risk relatives
Usually at 50% risk
Mutation already identified in family
Usually 2 counselling appointments, 4
weeks apart, blood taken at second
• Result 4 weeks later, given in person.
brca 35
Ovca 63
brca 47
Mutation negative
Mutation positive
BRCA mutation carriers
• Ovarian cancer risks determined by
– Gene
– Family history
• BRCA1: 20-60%
• BRCA2: 10-20%
Age-related ovca risks
• BRCA1– less than 2% before 40,
– From 45, 1% per annum, rising to 2.5% at 65y
• BRCA2
– Later and lower
– <1% per annum
Age-related ovca risks
• BRCA1- low before 40, ~1% pa 40-60
–
–
–
–
0.6% by 40y
23% by 50y
30% by 60y
63% by 70y
• BRCA2-low before 50
– 0.4% by 50y
– 7.4% by 60y
– 27% by 70y
Age-related ovca risks, (compared
with breast cancer risks)
• BRCA1-breast cancer risk ~2% per annum
30’s onwards
–
–
–
–
0.6% by 40y (18%)
23% by 50y (49%)
30% by 60y (64%)
63% by 70y (70-80%)
• BRCA2– 0.4% by 50y (28%)
– 7.4% by 60y
– 27% by 70y (80%)
Ovarian cancer
Ovca
54
Familial Ovarian cancer
• How to assess risk of ovarian ca?
Ivy
Rose
Shirley
Marjorie,
70y
Pat
63y
38y
Gill
37y
42y
54y
Jo
47y
63y
42y
Breast cancer
Ovarian cancer
Ovca 63
brca 47
Manchester scoring system (Evans et al , 2004)
Cancer
Score
FBC <30
11
FBC 30-39
8
FBC 40-49
6
FBC 50-59
4
FBC >59
2
MBC <60
13
MBC>59
10
Ovca <60
13
Ovca >59
10
Pancreatic cancer
1
Prostate cancer <60
2
Prostate cancer >59
1
Manchester scoring system (Evans et al , 2004)
Cancer
Score
FBC <30
11
FBC 30-39
8
FBC 40-49
6
FBC 50-59
4
FBC >59
2
MBC <60
13
MBC>59
10
Ovca <60
13
Ovca >59
10
Pancreatic cancer
1
Prostate cancer <60
2
Prostate cancer >59
1
Manchester scoring system-revised,
taking into account histology (Evans et al )
Tumour histology and biomarkers (in
index case only)
Score
Her2+
-4
Lobular
-2
DCIS only
-1
LCIS only
-4
Grade 1 IDC
-2
Grade 2 IDC
0
Grade 3 IDC
+2
ER+
-1
ER-
+1
Grade 3, triple negative
+4
Ovary: mucinous, borderline, germ cell
(?except granulosa)
No score given
Manchester scoring system-revised,
taking into account histology (Evans et al )
Tumour histology and biomarkers (in
index case only)
Score
Her2+
-4
Lobular
-2
DCIS only
-1
LCIS only
-4
Grade 1 IDC
-2
Grade 2 IDC
0
Grade 3 IDC
+2
ER+
-1
ER-
+1
Grade 3, triple negative
+4
Ovary: mucinous, borderline, germ
cell (?except granulosa)
No score given
Manchester scoring system
• Score 15 =10% chance of finding a
mutation
• Score of 20=20% chance
Genetic factors
BRCA1/2
Other highly
penetrant genes?
Moderate family history,
modest increased risk
Genetic testing or
surgery not usually
indicated
Environmental factors
Other potential ovarian cancer susceptilibity
genes: RAD51B, RAD51C, RAD51D
• 28/3429 (0.82%) cases v 3/2000 controls (0.11%)
• Odds ratios 5.2 – 12 depending on gene
• =moderate risk, but rare
• Song et al 2015
Other potential ovarian cancer susceptilibity
genes:BRIP1, BARD1,PALB2, NBN
• BRIP: 0.9% cases, 0.09% controls.
– RR 11 EOC, 14 for HGS ovca
• BARD1, PALB2, NBN:
• No difference between cases and controls
• Ramus et al 2015
Ivy
Rose
Shirley
Marjorie,
70y
Pat
63y
38y
Gill
37y
42y
54y
Jo
47y
63y
42y
Breast cancer
Ovarian cancer
Ivy
Rose
Shirley
Marjorie,
70y
Pat
63y
38y
Gill
37y
42y
54y
Jo
47y
63y
42y
Breast cancer
Ovarian cancer
Manchester score: 57!
Ivy
Rose
Shirley
Marjorie,
70y
Pat
63y
38y
Gill
37y
42y
54y
Jo
47y
42y
BRCA1 mutation
Ovca 63
brca 47
Manchester sore: 10+6 =16
Ovca 63
brca 47
Manchester sore: 10+6 =16
~10% chance of finding a
mutation
Ovca 63
brca 47
No surviving affected relative
Ovca 63
brca 47
No surviving affected relative,
So chance of mutation 5%
(no testing)
Ovarian cancer
Ovca
54
Why is important to know?
Normal cell
Double stranded DNA
Normal cell
DS-DNA break
Double stranded DNA
Normal cell
Double stranded DNA
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
Normal cell
Double stranded DNA
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
Repaired by non-HR
system
PARP -dependent
Error prone
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
Repaired by non-HR
system
PARP -dependent
Error prone
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
Repaired by non-HR
system
PARP -dependent
Error prone
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
Repaired by non-HR
system
PARP -dependent
Error prone
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
Repaired by non-HR
system
PARP -dependent
Error prone
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
Repaired by non-HR
system
PARP -dependent
Error prone
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
With PARP
inhibition
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
With PARP
inhibition
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
BRCA-deficient cell
With PARP
inhibition
Repaired by
Homologous repair system –
HR (BRCA1, BRCA2, RAD51 etc)
Error-free
Management of BRCA-related ovarian
cancer
• Better prognosis
• Respond to platinum and non-platinum
(even if early relapse)
• Olaparib treatment/ PARPi trials
• limiting testing may be denying some
patients a useful therapeutic option?
Why not test everyone?
Why not test everyone?
• Cost
– Genetic testing
– Counselling
Why not test everyone?
• Cost
– Genetic testing #500+
– Counselling
Why not test everyone?
• Cost
– Genetic testing
– Counselling
• Interpretation of results
– (Cancer penetrance)
Why not test everyone?
• Cost
– Genetic testing
– Counselling
• Interpretation of results
– (Cancer penetrance)
– Variants of uncertain significance (VUSs)
Variants of uncertain significance
(VUSs)
• Sequence change in gene that isn’t
clearly pathogenic
Variants of uncertain significance
(VUSs)
• Sequence change in gene that isn’t
clearly pathogenic
• How common?
Variants of uncertain significance
(VUSs)
• Sequence change in gene that isn’t
clearly pathogenic
• How common?- 5-10%
Ovarian cancer
Ovca
54
Chance of
VUS =chance
of pathogenec
mutation
Ovarian cancer
Ovca
54
?
BRCA2
VUS
Variants of uncertain significance
(VUSs)
• Sequence change in gene that isn’t
clearly pathogenic
• How common?- 5-10%
• Can we use these for predictive testing?
Variants of uncertain significance
(VUSs)
• Sequence change in gene that isn’t
clearly pathogenic
• How common?- 5-10%
• Can we use these for predictive
testing?- NO!
Variants of uncertain significance
(VUSs)
• Sequence change in gene that isn’t
clearly pathogenic
• How common?- 5-10%
• Can we use these for predictive
testing?- NO!
• Will these be resolved in foreseeable
future?
Variants of uncertain significance
(VUSs)
• Sequence change in gene that isn’t
clearly pathogenic
• How common?- 5-10%
• Can we use these for predictive
testing?- NO!
• Will these be resolved in foreseeable
future? Unlikely
Ovarian cancer
Will she benefit from PARPi?
Variants of uncertain significance
(VUSs)
• Sequence change in gene that isn’t
clearly pathogenic
• How common?- 5-10%
• Can we use these for predictive
testing?- NO!
• Will these be resolved in foreseeable
future? Unlikely
• Will this woman benefit from PARPi?
Ovarian cancer
Ovca
54
How likely is a BRCA mutation?
Is there any family history?
Australian ovarian cancer study group
Alsop et al J clin oncol 2012
• n=1001: non-mucinous, unselected for
FH, any age
• Overall pick up 14% (n=141, with 83
VUS)
– 16.6% serous
– 22.6% HGS
– 8.3% >60
– 8.2% with no, or unknown FH
Australian ovarian cancer study group
Alsop et al J clin oncol 2012
• n=1001: non-mucinous, unselected for
FH, any age
• Overall pick up 14% (n=141, with 83
VUS)
– 16.6% serous
– 22.6% High Grage Serous
– 8.3% >60
– 8.2% with no, or unknown FH
Australian ovarian cancer study group
Alsop et al J clin oncol 2012
• n=1001: non-mucinous, unselected for
FH, any age
• Overall pick up 14% (n=141, with 83
VUS)
– 16.6% serous
– 22.6% HGS
– 8.3% >60
– 8.2% with no, or unknown FH
Australian ovarian cancer study group
Alsop et al J clin oncol 2012
• n=1001: non-mucinous, unselected for
FH, any age
• Overall pick up 14% (n=141, with 83
VUS-8.2%
– 16.6% serous
– 22.6% HGS
– 8.3% >60
– 8.2% with no, or unknown FH
Typical BRCA patient
•
•
•
•
•
•
Ovarian cancer
Serous
FIGO 3
Grade 3
Young (55 v 60.5)
No PH brca, but often FH
…but, compared with overall cohort
•
•
•
•
•
Fallopian tube and PPC
FIGO 3 and 4
Age: 41-50
PH: 27% brca (8% cohort overall)
FH: 53% (19% cohort overall)
BRCA mutations in unselected
ovarian cancer
• Greek cohort- 6 founder mutations
• BRCA1 mutations in 27/592 (4.6%)
sporadic cases
• 71% cases with mutation were HGS
• Stavropoulou et al 2013
Peninsula experience: BRCA testing
in HGS ovca <60
• 40 referrals since Sept 2013
• 24 offered testing
– 2 declined
– 4 results awaited
– 12 negative
– 4 positive
– 2* Variant of uncertain significance (VUS)
BRCA testing in HGS ovca <60
• of the 18 results
BRCA testing in HGS ovca <60
• of the 17 results
– 4 (23.5%) positive
BRCA testing in HGS ovca <60
• of the 18 results
– 3 (17.6%) positive
– 12 (67%) negative
BRCA testing in HGS ovca <60
• of the 18 results
– 3 (17.6%) positive
– 12 (70%) negative
– 2 (11%) uncertain
29317
54
Cancer
(nos) 40
‘womb’
1901
82
72
68
‘Endometrial’
ca 70
HGS Ovca
42y
85
63
No
cancers
86
25691
Embolism
78
Died
young
BRCA 72
neg
HGS Ovca
46y
No info
Multiple
myeloma 60
78
?brca
60s
G2 IDC
46
28019
‘spine’ cancer
79y
Lung 70
82y ?breast
cancer
PPC 50y
31889
71 heart
PPC 65y
BRCA testing threshold
• 10% chance of a pathogenic mutation
– Manchester Score 15, eg
2 ovca any age
1 ovca <60 plus brca any age
1 ovca >60 age, plus 2 brca <60,
• High grade serous ovca <60y (MS13)
Genetic testing: BRCA1/2
searching for a mutation
• Manchester scoring system used to
select families for testing. Threshold
10% chance of mutation
• Blood from affected relative
• 8 weeks
Consider
• Should we be testing more women with
ovarian cancer?
Should we be testing all women with ovarian
cancer?
• High grade serous- how many women?
• Refer to genetics?
• ways to incorporate this in to routine care
pathway?
• Future involvement of clinical genetics?
The future
1. Continue to refer all women for BRCA
testing to clinical genetics?
2. If purpose is to determine management
testing by oncology?
3. Collaborative approach?
– Testing by oncol with input from CG
Pros and cons: status quo
pros
• Patient: Detailed FH
assessment, and
thorough genetic
counselling
• Gynaeoncol: One less
thing…
• Clinical
genetics:maintains
control, gatekeeping etc
cons
• Patient and oncol:
Waiting time/delays
• CG: Workload
Pros and cons -full mainstreaming
Pros
• Pt: seamless, (fewer
delays)
• GO: control
• GC: workload, successful
maintreaming
Cons
• PT:Family issues
• GO: FUNDING, one more
thing…
• CG: loss of gatekeeping
etc
Pros and cons -collaborative approach
Pros
• Best of both worlds
• Involvement in process,
maintains control
• Successful collaborationmainstreaming
Cons
• None?
• Funding
• None
• (other than setting up)
• Cheaper overall
Peninsula clinical genetics
service
www.peninsulaclinicalgeneticsservice.co.uk/
Consultant
clinics
Genetic nurse or
counsellor clinics