implicaciones terapÉuticas de las mutaciones brca · 17.2% prca patients carry a germline mutation...
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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
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
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
DNA damage and RepairDNA damage and Repair
Hoeijmakers, Nature, 2001
Genomic InstabilityMutations
HALLMARKS OF CANCERHALLMARKS OF CANCER
Hanahan &Weinberg, 2000, CellHanahan & Weinberg, 2011, Cell
Figure 6
Hanahan & Weinberg, 2011, Cell
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
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
ATM ATR BAP1 BARD1 BRCA1
BRCA2 BRIP1 CHEK2 FAM175A GEN1
MLH1 MRE11A MSH2 MSH6 NBN
PALB2 PMS2 RAD51C RAD51D XRCC2
Pritchard, NEJM, 2016
Prevalence of germline mutations in DNA repair genes
3%
12%
Metastatic PrCa Early PrCa
5%3%
General Population
Pritchard, NEJM, 2016
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
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)
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
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
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
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
gBRCA2 mutations are an independent prognostic factor for MFS and CSS
Castro et al, JCO, 2013
Carriers n=14Non-carriers
n=140
Leongarmonlert, BJC, 2012
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
Different genes may have different impact
Mixing tigers and cats?
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
150 mCRPC23% mutations in DNA repair genes12% defects in BRCA28% germline mutations
Robinson, Cell, 2015
• 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
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
Castro Eur Urol, 2015
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
Mateo et al, NEJM, 2015
DNA repair defects and platine-based chemotherapy
21 Germline and/or somatic BRCA2, PALB2, ATM
Cheng, Eur Urol, 2016Kumar, Nat Medicine, 2016
Slide 1
Presented By Maha Hussain at 2017 ASCO Annual Meeting
Study Design
Presented By Maha Hussain at 2017 ASCO Annual Meeting
Progression Free Survival & Overall Survival
Presented By Maha Hussain at 2017 ASCO Annual Meeting
Slide 9
Presented By Maha Hussain at 2017 ASCO Annual Meeting
Depth of PSA Decline by DRD status
Presented By Maha Hussain at 2017 ASCO Annual Meeting
PFS by DRD Status: Overall & By Arm
Presented By Maha Hussain at 2017 ASCO Annual Meeting
Slide 15
Presented By Maha Hussain at 2017 ASCO Annual Meeting
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
Genomic Landscape at Baseline
Presented By Kim Chi at 2017 ASCO Annual Meeting
Genomic Correlates with TTP
Presented By Kim Chi at 2017 ASCO Annual Meeting
BRCA2/ATM
Presented By Kim Chi at 2017 ASCO Annual Meeting
Genomic Landscape at Baseline
Presented By Kim Chi at 2017 ASCO Annual Meeting
ctDNA Fraction
Presented By Kim Chi at 2017 ASCO Annual Meeting
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
• 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
Plataforma PR CU EPlataforma PR CU E
Titulo diapositivaTitulo diapositiva
PROREPAIR sites
426 pts enrolled from 38 sitesEnrollment period
February 2013 -April 2016
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
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
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
Rational for Co-Targeting AR Signaling and PARP
Presented By Maha Hussain at 2017 ASCO Annual Meeting