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