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BRCA testing in women with ovarian cancer PowerPoint Presentation

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Description : Check out this medical presentation on Familial Pancreatic Cancer, which is titled "BRCA testing in women with ovarian cancer", to know about BRCA testing and its benefits in managing the future risks-patient and relatives.

Tags : Familial Pancreatic Cancer, BRCA testing, women, ovarian cancer

Published on : May 18, 2021 | Views : 2200 | Downloads : 0

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Slide 1-

BRCA testing in women with ovarian cancer Dr Carole Brewer Peninsula Clinical Genetics Service
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Consultant clinics Genetic nurse or counsellor clinics Peninsula Clinical Genetics Service www.peninsulaclinicalgeneticsservice.co.uk/
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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
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Referrals to PCGS
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Reasons for BRCA testing For the benefit of family: Predictive tests for relatives Management of future risks- patient and relatives
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Reasons for BRCA testing For the benefit of family: Predictive tests for relatives Management of future risks- patient and relatives Influence current management
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Ovca 63 brca 47 brca 35
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Ovca 63 brca 47 brca 35 BRCA1 mutation
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Ovca 63 brca 47 brca 35
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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.
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Ovca 63 brca 47 brca 35 Mutation positive Mutation negative
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BRCA mutation carriers Ovarian cancer risks determined by Gene Family history BRCA1: 20-60% BRCA2: 10-20%
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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
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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
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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%)
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Ovarian cancer Ovca 54
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Familial Ovarian cancer How to assess risk of ovarian ca?
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47y 38y 63y Breast cancer Ovarian cancer 37y 42y 54y Gill Jo Marjorie, 70y Pat Shirley Rose Ivy 42y 63y
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Ovca 63 brca 47
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Manchester scoring system (Evans et al , 2004)
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Manchester scoring system (Evans et al , 2004)
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Manchester scoring system-revised, taking into account histology (Evans et al )
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Manchester scoring system-revised, taking into account histology (Evans et al )
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Score 15 =10% chance of finding a mutation Score of 20=20% chance Manchester scoring system
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Genetic factors BRCA1/2 Other highly penetrant genes? Environmental factors Moderate family history, modest increased risk Genetic testing or surgery not usually indicated
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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
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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
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47y 38y 63y Breast cancer Ovarian cancer 37y 42y 54y Gill Jo Marjorie, 70y Pat Shirley Rose Ivy 42y 63y
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47y 38y 63y Breast cancer Ovarian cancer 37y 42y 54y Gill Jo Marjorie, 70y Pat Shirley Rose Ivy 42y 63y Manchester score: 57!
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47y 38y 63y 37y 42y 54y Gill Jo Marjorie, 70y Pat Shirley Rose Ivy 42y BRCA1 mutation
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Ovca 63 Manchester sore: 10+6 =16 brca 47
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Ovca 63 Manchester sore: 10+6 =16 ~10% chance of finding a mutation brca 47
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Ovca 63 No surviving affected relative brca 47
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Ovca 63 No surviving affected relative, So chance of mutation 5% (no testing) brca 47
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Ovarian cancer Ovca 54 Why is important to know?
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Double stranded DNA Normal cell
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Double stranded DNA DS-DNA break Normal cell
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free Double stranded DNA Normal cell
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free Double stranded DNA Normal cell
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free Repaired by non-HR system PARP -dependent Error prone BRCA-deficient cell
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free Repaired by non-HR system PARP -dependent Error prone BRCA-deficient cell
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free Repaired by non-HR system PARP -dependent Error prone BRCA-deficient cell
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free Repaired by non-HR system PARP -dependent Error prone BRCA-deficient cell
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell Repaired by non-HR system PARP -dependent Error prone
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell Repaired by non-HR system PARP -dependent Error prone
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell With PARP inhibition
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell With PARP inhibition
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Repaired by Homologous repair system –HR (BRCA1, BRCA2, RAD51 etc) Error-free BRCA-deficient cell With PARP inhibition
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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?
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Why not test everyone?
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Why not test everyone? Cost Genetic testing Counselling
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Why not test everyone? Cost Genetic testing #500+ Counselling
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Why not test everyone? Cost Genetic testing Counselling Interpretation of results (Cancer penetrance)
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Why not test everyone? Cost Genetic testing Counselling Interpretation of results (Cancer penetrance) Variants of uncertain significance (VUSs)
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Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic
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Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?
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Variants of uncertain significance (VUSs) Sequence change in gene that isn’t clearly pathogenic How common?- 5-10%
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Ovarian cancer Ovca 54 Chance of VUS =chance of pathogenec mutation
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Ovarian cancer Ovca 54 BRCA2 VUS ?
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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?
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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!
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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?
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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
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Ovarian cancer Will she benefit from PARPi?
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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?
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Ovarian cancer Ovca 54 How likely is a BRCA mutation? Is there any family history?
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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
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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
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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
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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
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Typical BRCA patient Ovarian cancer Serous FIGO 3 Grade 3 Young (55 v 60.5) No PH brca, but often FH
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…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)
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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
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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)
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BRCA testing in HGS ovca <60 of the 18 results
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BRCA testing in HGS ovca <60 of the 17 results 4 (23.5%) positive
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BRCA testing in HGS ovca <60 of the 18 results 3 (17.6%) positive 12 (67%) negative
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BRCA testing in HGS ovca <60 of the 18 results 3 (17.6%) positive 12 (70%) negative 2 (11%) uncertain
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29317 HGS Ovca 42y Cancer (nos) 40 ‘Endometrial’ ca 70 72 68 63 85 82 ‘womb’ 1901 54
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HGS Ovca 46y Died young 72 Multiple myeloma 60 78 No cancers 86 No info Embolism 78 25691 G2 IDC 46 ?brca 60s BRCA neg
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28019 PPC 50y ‘spine’ cancer 79y Lung 70 82y ?breast cancer
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31889 PPC 65y 71 heart
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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)
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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
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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?
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The future Continue to refer all women for BRCA testing to clinical genetics? If purpose is to determine management testing by oncology? Collaborative approach? Testing by oncol with input from CG
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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
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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
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Pros and cons -collaborative approach Pros Best of both worlds Involvement in process, maintains control Successful collaboration- mainstreaming Cons None? Funding None (other than setting up) Cheaper overall
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Consultant clinics Genetic nurse or counsellor clinics Peninsula clinical genetics service www.peninsulaclinicalgeneticsservice.co.uk/
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