implicaciones terapÉuticas de las mutaciones brca · 17.2% prca patients carry a germline mutation...
TRANSCRIPT
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IMPLICACIONES TERAPÉUTICAS DE LAS MUTACIONES BRCA.
¿Debemos testar la vía de BRCA en nuestros pacientes?
Elena CastroUnidad Cáncer de Próstata
Centro Nacional de Investigaciones Oncológicas
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SummarySummary
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
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SummarySummary
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
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DNA damage and RepairDNA damage and Repair
Hoeijmakers, Nature, 2001
Genomic InstabilityMutations
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HALLMARKS OF CANCERHALLMARKS OF CANCER
Hanahan &Weinberg, 2000, CellHanahan & Weinberg, 2011, Cell
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Figure 6
Hanahan & Weinberg, 2011, Cell
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SummarySummary
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
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Gene Panels
• Similar price and time than only BRCA1 and BRCA2– Terapeutical implications– Prognostic implications– Relatives( BROCA panel, UW Onco-Plex, custom panels,…)
• Unknown clinical and therapeutical implications of some genes• Ethical implications
• More testing ------ More VUS• Ethical implications
• Centres with experpertise in somatic and germline mutations• Germline• Somatic + germline
• Similar price and time than only BRCA1 and BRCA2– Terapeutical implications– Prognostic implications– Relatives( BROCA panel, UW Onco-Plex, custom panels,…)
• Unknown clinical and therapeutical implications of some genes• Ethical implications
• More testing ------ More VUS• Ethical implications
• Centres with experpertise in somatic and germline mutations• Germline• Somatic + germline
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ATM ATR BAP1 BARD1 BRCA1
BRCA2 BRIP1 CHEK2 FAM175A GEN1
MLH1 MRE11A MSH2 MSH6 NBN
PALB2 PMS2 RAD51C RAD51D XRCC2
Pritchard, NEJM, 2016
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Prevalence of germline mutations in DNA repair genes
3%
12%
Metastatic PrCa Early PrCa
5%3%
General Population
Pritchard, NEJM, 2016
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32
2 2 2 1 1 1 1 1 1
10 CHEK2(12%)
6 BRCA1 ( 7%)
RAD51DATR
GEN1NBN
PMS2FAM175A
RAD51C
MSH6MSH2
BRP1
MRE11A
37 BRCA2(45%)
Gene N=692 %
ATM 11 1.59
ATR 2 0.29
BAP1 0 0
BARD1 0 0
BRCA1 6 0.87
BRCA2 37 5.3
BRIP1 1 0.14
CHEK2 10 1.44
FAM175A 1 0.14
Pritchard et al, NEJM, 2016
11 ATM(13%)
10 CHEK2(12%)
37 BRCA2(45%)
GEN1 2 0.29
MLH1 0 0
MRE11A 1 0.14
MSH2 1 0.14
MSH6 1 0.14
NBN 2 0.29
PALB2 3 0.43
PMS2 2 0.29
RAD51C 1 0.14
RAD51D 3 0.43
XRCC2 0 0
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gDNA repair mutationscannot be suspectedbased on clinical parametersor family history
Similar age at diagnosis (p=0.90)
No association with ethnic background(p=0.84)
Carriers vs Non-Carriers
Pritchard CC et al. N Engl J Med 2016
Similar family history of PrCa (p=1.0)
No association with ethnic background(p=0.84)
71% vs 50% had a FDR afected with cancerother than PrCa (p=0,001)
Trend to Gleason ≥8 (p=0.04, CI95% 1-3.5)
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37% of mutation carriers did not qualify for testing based on available guidelines
17.2% PrCa patients carry a germline mutation65% in other genes diferent from BRCA2
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BRCApro:- 48% of families had >10% probability of BRCA2 and would had been tested- 21% would have been tested if the PrCa case were the probandp=1.9x10-4
Manchester Score- 42% of families had >10% probability of BRCA2 and would had been tested- 21% would have been tested if the PrCa case were the probandp=0.011
Oliva L, manuscript in preparation
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Prevalence of BRCA mutations in different ovarian cancer populations
Israel26% overall32% serous
Greece10% overall (BRCA1)60% serous (BRCA1)
Florida (USA)14-16% overall
Canada12-13% overall33-36%serous
Norway23% overall
Sweden8% overall8% serous Denmark
6% overall5% serousNederlands
6% overall11% serous
Australia14% overall17% serous
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gBRCA mutations areassociated with
Gleason ≥8Nodal involvementMetastasis
No association withPSA levelsage at diagnosis
gBRCA mutations areassociated with
Gleason ≥8Nodal involvementMetastasis
No association withPSA levelsage at diagnosis
Castro et al, JCO, 2013
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gBRCA2 mutations are an independent prognostic factor for MFS and CSS
Castro et al, JCO, 2013
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Carriers n=14Non-carriers
n=140
Leongarmonlert, BJC, 2012
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NBS1 (NBN) 657del5 CHEK2 1100delC, IVS2+1G, del5395, I157T
5y-CSS 49% vs 72% p=0.008 5y-CSS 71% vs 72% p=0.95
Cybulski C, BJC, 2013
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Different genes may have different impact
Mixing tigers and cats?
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SummarySummary
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
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150 mCRPC23% mutations in DNA repair genes12% defects in BRCA28% germline mutations
Robinson, Cell, 2015
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• 228/936 (24%) unique samples had at least one mutation in a DNA repair gene• The highes rates of DNA repair mutations were found in visceral metastases including brain, pelvisand liver, which were significangly higher that either prostate tissue (20%) and bone sites (19%)(p<0.01)• The most commonly mutated genes in the DNA repair pathways are: BRCA2 (11.4%), ATM (5.8%,)MSH6 (2.5%), MSH2 (2.1%), ATR (1.6%), MLH1 (1.3%) and BRCA1 (1.2%)
ASCO GU 2017
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SummarySummary
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
• DNA repair and genomic instability as a Hallmark of Cancer
• Germline mutations
• Somatic mutations
• Treatment implications
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Castro Eur Urol, 2015
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Castro et al, Ann Oncol, 2016Taylor, Nat Comm, 2017
• High burden chromosomal aberrations• CNA in normal prostate tissue• Some aberrations may not be random• Hypermetilation paterns similar to metastatic sporadic
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Mateo et al, NEJM, 2015
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DNA repair defects and platine-based chemotherapy
21 Germline and/or somatic BRCA2, PALB2, ATM
Cheng, Eur Urol, 2016Kumar, Nat Medicine, 2016
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Slide 1
Presented By Maha Hussain at 2017 ASCO Annual Meeting
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Study Design
Presented By Maha Hussain at 2017 ASCO Annual Meeting
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Progression Free Survival & Overall Survival
Presented By Maha Hussain at 2017 ASCO Annual Meeting
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Slide 9
Presented By Maha Hussain at 2017 ASCO Annual Meeting
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Depth of PSA Decline by DRD status
Presented By Maha Hussain at 2017 ASCO Annual Meeting
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PFS by DRD Status: Overall & By Arm
Presented By Maha Hussain at 2017 ASCO Annual Meeting
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Slide 15
Presented By Maha Hussain at 2017 ASCO Annual Meeting
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A randomized phase II cross-over study of abiraterone + prednisone vs enzalutamide for patients with metastatic, castration-resistant prostate cancer
Presented By Kim Chi at 2017 ASCO Annual Meeting
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Genomic Landscape at Baseline
Presented By Kim Chi at 2017 ASCO Annual Meeting
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Genomic Correlates with TTP
Presented By Kim Chi at 2017 ASCO Annual Meeting
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BRCA2/ATM
Presented By Kim Chi at 2017 ASCO Annual Meeting
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Genomic Landscape at Baseline
Presented By Kim Chi at 2017 ASCO Annual Meeting
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ctDNA Fraction
Presented By Kim Chi at 2017 ASCO Annual Meeting
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PROSTAC: Docetaxel
A
PROSTAC: Cabazitaxel
B
C
PROCURE network studiesPROCURE network studies
2T 3T 4T1T 4T
2014
1T 2T 3T 4T 1T 2T 3T 4T 1T 2T
2015 2016 2017
2T 3T1T 4T
2013
PROREPAIR Study
PROSTAC: Cabazitaxel
PROSABI: Acetato de abiraterona
C
PRORADIUM: Radium-223E
PROSENZA: EnzalutamidaF
Plataforma PR CU EPlataforma PR CU E
D
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• Primary aim: impact of BRCA1, BRCA2, ATM, PALB2 germline mutations on CSS frommCRPC
• Secondary aims: impact of DRD in response to abiraterone, enzalutamide, docetaxel, cabazi,radium-223
• Sample size: 408 Pts (171 deaths)• Mutations prevalence of 5%• Estimated median CSS 30 months• HR Carriers/Non-carriers 3.33• alpha of 0.05 and a power of 0.80
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Plataforma PR CU EPlataforma PR CU E
Titulo diapositivaTitulo diapositiva
PROREPAIR sites
426 pts enrolled from 38 sitesEnrollment period
February 2013 -April 2016
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Gene N=426 %
ATM 8 1.9%
BRCA1 4 0.9%
BRCA2 13 3.0%
CHEK2 4 0.9%
MRE11A 2 0.5%
MSH2 2 0.5%
MSH6 1 0.2%
TOTAL 34 8%
Gene N=692 %
ATM 11 1.59
ATR 2 0.29
BAP1 0 0
BARD1 0 0
BRCA1 6 0.87
BRCA2 37 5.3
BRIP1 1 0.14
CHEK2 10 1.44
FAM175A 1 0.14
GEN1 2 0.29
MLH1 0 0
MRE11A 1 0.14
MSH2 1 0.14
MSH6 1 0.14
NBN 2 0.29
PALB2 3 0.43
PMS2 2 0.29
RAD51C 1 0.14
RAD51D 3 0.43
XRCC2 0 0
- No BRCA1/BRCA2 Ashkenazi founder mutations
- No CHEK2 1100 del
- Preliminary analyses suggest no CSS differencesbetween carriers and non carriers
- Similar responses to currently available therapies
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CONCLUSIONSCONCLUSIONS• DNA repair defects are a common event in prostate cancer
• 12%-8% germline• ≈20% somatic- Specific PrCa genes panels
•Not all DDR are created equal• Defects in different genes may have different impacts• Bialellic defect ≠ monoallelic defect
• BRCA2, BRCA1 and possible ATM germline mutations are associated to shortersurvival from diagnosis of PrCa• Their response to currently available survival-prolonging therapies may be similarto that of non-carriers
• The impact of somatic mutations in outcomes remains unknown
• Test at time of diagnosis or when considering PARPi or Platins• Re-test for the occurrence of secondary alterations
• DNA repair defects are a common event in prostate cancer• 12%-8% germline• ≈20% somatic- Specific PrCa genes panels
•Not all DDR are created equal• Defects in different genes may have different impacts• Bialellic defect ≠ monoallelic defect
• BRCA2, BRCA1 and possible ATM germline mutations are associated to shortersurvival from diagnosis of PrCa• Their response to currently available survival-prolonging therapies may be similarto that of non-carriers
• The impact of somatic mutations in outcomes remains unknown
• Test at time of diagnosis or when considering PARPi or Platins• Re-test for the occurrence of secondary alterations
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CNIO Prostate Cancer Lab TeamDavid Olmos MD PhD, Group leaderElena Castro MD PhD, Senior investigatorNuria Romero MD PhD, Post-doc Rio HortegaMaría I. Pacheco PhD, Sr Scientific officerPaz Nombela BSc, PhD studentYlenia Cendon, PhD StudentLorena Magraner, PhDFernando López campos MD, VisitingTeresa Garcés del Rey,Ana G-Pecharroman, Visiting
Clinical Research ProgrammeAntonio López BSc PhD, Clinical Trials UnitBerta Nasarre Pharm, Clinical Trials Unit
Not currently at CNIOMercedes Alonso PhD, Until Jan 2015Floortje Van der Poll, Until May 2015
AcknowledgmentsAcknowledgments
PR CU EPR CU E
CNIO Prostate Cancer Lab TeamDavid Olmos MD PhD, Group leaderElena Castro MD PhD, Senior investigatorNuria Romero MD PhD, Post-doc Rio HortegaMaría I. Pacheco PhD, Sr Scientific officerPaz Nombela BSc, PhD studentYlenia Cendon, PhD StudentLorena Magraner, PhDFernando López campos MD, VisitingTeresa Garcés del Rey,Ana G-Pecharroman, Visiting
Clinical Research ProgrammeAntonio López BSc PhD, Clinical Trials UnitBerta Nasarre Pharm, Clinical Trials Unit
Not currently at CNIOMercedes Alonso PhD, Until Jan 2015Floortje Van der Poll, Until May 2015
INGEMM - IDIPazPablo Lapunzina MD PhD, directorElena Vallespin, Geneticist
PROCURE Network coordinationDavid Olmos MD, PhD CNIOElena Castro MD PhD, CNIONuria Romero MD PhD, CNIOAna Medina MD PhD, C.O. GaliciaRafael Morales MD, VHIOEnrique Glez-Billabeitia MD PhD, HUMMDavid Lorente MD, H. La FeJavier Puente MD PhD, HC San CarlosMaribel Saez MD, IBIMAAlvaro Montesa MD, IBIMAJosep M. Piulats MD PhD, ICO L’Hospitalet
CNIO-IBIMA GU Clinical TrialsDavid Olmos MD PhD, coordinatorCarolina Navas PhD, Post-docGala Grau, Research NurseLeticia Rivera, Data CoordinatorEmilio Alba MD PhD, Co-directorMaribel Saez MD, investigatorAlvaro Montesa MD, Investigator
CNIO-CIOCC Prostate CancerElena Castro MD PhD, CoordinatorNuria Romero MD PhD, InvestigatorJeanette Valero MD PhD, RT OncologistLorena Sánchez, Data coordinator
CNIO Translational bioinfomaticsFatima Al-Sharour PhD, Group leaderElena Piñeiro, Technician
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Rational for Co-Targeting AR Signaling and PARP
Presented By Maha Hussain at 2017 ASCO Annual Meeting