• Non ci sono risultati.

Trattamenti della malattia con mutazioni di BRCA e altro

N/A
N/A
Protected

Academic year: 2022

Condividi "Trattamenti della malattia con mutazioni di BRCA e altro"

Copied!
39
0
0

Testo completo

(1)

Giuseppe Fornarini, U.O. Oncologia Medica 1 Ospedale Policlinico San Martino

IRCCS Genova

Trattamenti della malattia con mutazioni

di BRCA e altro…

(2)

Background

Prostate cancer is inheritable…but

Important to know the family history

A different type of genes are involved…BRCA1/2, Lynch Syndrome…others

Pts with BRCA2 mutation have 3-9x risk of PC and more lethal

Germline could be different from somatic mutation

In advanced disease clinical management does not differ

To whom should we offer germline genetic testing

and when… because

(3)

To whom should we offer germline genetic testing?

Presented By Heather Cheng at 2018 ASCO Annual Meeting

Germline pathogenic alterations may have both

familial and therapeutic implications

(4)

More recent genetic findings in advanced PC may also inform therapy

Presented By Heather Cheng at 2018 ASCO Annual Meeting

(5)
(6)

Outline

• The 6 DNA repair pathways

• Prevalence of DNA repair defects in prostate cancer

• DNA repair and therapeutic implications

– PARP inhibitors – Hormonal therapy

– Immune checkpoint inhibitors – Platinum chemotherapy

Emmanuel S. Antonarakis, MBBCh

(7)

Single-Stranded (ss)DNA Repair Pathways

• Mismatch repair

– Base errors from DNA replication and recombination – MSH2, MSH6, MLH1, PMS2

• Nucleotide excision repair

– DNA damage from UV light, polycyclic aromatic hydrocarbons – XPA-G, ERCC1-8, CSA/B, RPA, RAD23A/B

• Base excision repair

– DNA damage from alkylation, oxidation/ROS, deamination – PARP1/2/3, POLβ, MUTYH, XRCC1, MBD4, NTHL1

Mateo J, et al. Eur Urol. 2017;71:417-425.

Emmanuel S. Antonarakis, MBBCh

(8)

Double-Stranded (ds)DNA Repair Pathways

• Homologous recombination

– DNA damage from ionizing radiation or other dsDNA injury

– FANC genes, BRCA1/2, ATM, PALB2, RAD50, RAD51, NBN, GEN1, MRE11, BLM, ATR

• Nonhomologous end joining

– DNA damage from ionizing radiation or other dsDNA injury – XRCC4/5/6, LIG4, DCLRE1C, PRKDC, NHEJ1, POLL/M

• Translesion DNA synthesis

– Error-prone recovery mechanism when no DNA template

– POLH, POLI, POLK, PCNA, REV1/3 (error-prone DNA polymerases)

Mateo J, et al. Eur Urol. 2017;71:417-425. Makridakis NM, et al. Front Genet. 2012;3:174.

Emmanuel S. Antonarakis, MBBCh

(9)

• 11.8% (82/692) of men with metastatic prostate cancer

inherited a germline DNA repair mutation vs 4.6% of

499 men with localized disease

Germline Mutations in Prostate

Cancer: 1 in 10

Pritchard CC, et al. N Engl J Med. 2016;375:443- 453.

Distribution of Presumed Pathogenic Germline

Mutations

PALB2 4%

RAD51D 4%

ATR 2%

NBN 2% PMS2 2% GEN1 2% MSH2 1% MSH6 1% RAD51C

1% MRE11A 1% BRIP1 1%

FAM175A 1%

BRCA2 44%

ATM 13%

CHEK2 12%

BRCA1 7%

Gene No. of Mutations

% of Men

BRCA2 37 5.35

ATM 11 1.59

CHEK2* 10 1.87

BRCA1 6 0.87

Presumed Pathogenic Germline Mutations

in Metastatic Cases (N = 692)

*n = 534; data censored for metastatic cases with inadequate sequencing.

(10)

• Germline mutations in 14% (21/150) of men with

recurrent/advanced prostate cancer

• Men with intraductal/ductal histology more likely to have germline mutations

Association Between Germline DNA- Repair Defects and Intraductal/Ductal

Histology

Isaacsson Velho P, et al. The Prostate. 2018;[Epub ahead of print].

Intra/Ductal Histology

No

Intra/Ductal Histology

P Value*

40% (10/25) 9% (11/125) P = .003

*Fisher’s test.

Incidence of Pathogenic Germline Mutations

Distribution of Pathogenic Germline Mutations

CDH1 5%

MSH6 5%

PALB2 5%

NBN 5%

BRCA2 43%

CHEK2 14%

ATM 14%

BRCA1 9%

Emmanuel S. Antonarakis, MBBCh

(11)

Effect of DDR Mutation on Treatment Responses

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

(12)

Selected Trials for mCRPC with Relevance to DNA repair defects

Presented By Heather Cheng at 2018 ASCO Annual Meeting

(13)

PARP Biology

• A key role in the repair of ssDNA breaks via BER pathway

• Binds directly to sites of DNA damage

• Once activated, uses NAD as a substrate to add large, branched chains of poly(ADP-ribose) polymers (ie, PARylation) to itself and interaction partners

• Recruits other DNA repair enzymes to site of damage

Ohmoto A, et al. Onco Targets Ther. 2017;10:5195-5208.

DNA damage

NAD+ Nicotina

mide + pADPr

Lig3 XRCC1

Polß PNK PARP

Emmanuel S. Antonarakis, MBBCh

(14)

PARPi Leads to Increase in dsDNA Breaks

• Inhibition of PARP:

– Prevents

recruitment of DNA repair

enzymes to ssDNA breaks, or traps PARP on DNA – Leads to failure

of ssDNA repair and accumulation of ssDNA breaks – Replication fork is

arrested at

damage, produces dsDNA breaks

Ohmoto A, et al. Onco Targets Ther. 2017;10:5195-5208.

PARP

During S-phase, replication fork is arrested at site of ssDNA breaks

Degeneration into dsDNA breaks

ssDNA breaks PARP

inhibition

XRCC1

DNA Lig III PNK 1

DNA Polβ

Emmanuel S. Antonarakis, MBBCh

(15)

Synthetic Lethality Hypothesis

Farmer H, et al. Nature. 2005;434:917-921. Bryant et al. Nature. 2005;434:913-917.

Repair, Survival

Repair, Survival

Normal cell

Non-BRCA mutation carrier PARP function

BRCA function

PARP inhibitor

PARP function BRCA function

DNA damage

Repair, Survival

Repair, Survival

Normal cell

BRCA mutation carrier

(1 allele lost) PARP function BRCA function

PARP inhibitor

PARP function BRCA function

DNA damage

Repair,

Survival

Cell Death

Cancer cell

BRCA mutation carrier

(both alleles lost)

PARP function BRCA function

PARP inhibitor DNA damage

PARP function BRCA function

Emmanuel S. Antonarakis, MBBCh

(16)

TOPARP

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

(17)

TOPARP Results: Response

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

(18)
(19)

TOPARP Results

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

(20)

Single Agent Trials In Progress

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

(21)

Slide 17

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

(22)

Combination Trials In Progress

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

(23)

Clinical Data Extrapolations

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

(24)

DNA Repair Defects and

Hormonal Therapy

(25)

Abiraterone in mCRPC With HR Deficiency

• 20/80 (25%) evaluable pts with mCRPC had DNA repair defects

Hussain M, et al. J Clin Oncol. 2017;[Epub ahead of print].

PFS by DRD Status DNA Repair Defects*

BRCA2 ATM BRC RAD5A1 RAD511B PALB2 C

FANCA

Frameshi ft

Nonsens e

Not detected In-frame indel Copy-neutral

LOH Missense

+ Censored

Log-rank P = .0254 Median, Mos (95%

CI)

DRD: 14.5 (11.0- 19.5)

WT: 8.1 (5.5-11.0)

Probability of PFS

Mos

0.2

0.4 0.6 0.8 1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

20 19 13 6 4 3 2 1 20

43 34 20 10 5 3 0 60

DRD WT Pts at Risk, n

*Data shown for 25 of 80 pts with exploratory tumor sequencing.

Biallelic Monoallelic

2 copy losses 1 copy loss

Emmanuel S. Antonarakis, MBBCh

(26)

Abiraterone or Enzalutamide and HR Deficiency

PFS by DRD Status

Antonarakis ES, et al. Eur Urol. 2018. In press.

PFS (%)

0 6 12 18 24

20 40 60 80 100

0

Any Mutation No

Yes (other)

Yes (ATM/BRCA1/BRCA2)

Mos

Yes (other) Yes (ATM/BRCA1/

BRCA2) Pts at Risk, n

150 102 60 38 18

13 9 6 4 3

9 8 6 4 3

No

OS by DRD Status

Any Mutation No

Yes (Other)

Yes (ATM/BRCA1/BRCA2)

OS (%)

20 40 60 80 100

0

0 6 12 18 24 30 36 42 48

Mos

Yes (other) Yes (ATM/BRCA1/

BRCA2) Pts at Risk, n

No 150 145 128 75 75 52 35 22 11

13 13 13 9 8 6 5 3 0

9 9 8 7 6 4 4 4 0

Emmanuel S. Antonarakis, MBBCh

(27)

Abiraterone vs Enzalutamide and HR Deficiency

• Randomized phase II

crossover study in treatment- naive pts with mCRPC (N = 202)

• BRCA2- or ATM-truncating

mutations or rearrangements:

– Somatic (ctDNA): 6/115 (5.2%)

– Germline (WBC): 8/202 (4.0%)

• Monoallelic BRCA2 or ATM deletion in 21 pts

– No TTP differences (P = .205)

Annala M, et al. Cancer Discov. 2018;[Epub ahead of print].

Time to Progression by HRR Status*

*Abiraterone + enzalutamide arms combined.

8 2

6 6

4 1

2 9

1 4

5 3 1 1

0 5

6 2

3 3

1 7

8 5 2 0 1

4

2 0 0 0 0 0 0 Pts at

Risk, n

Probability of PFS

0 4 8 1 2

1 6

2 0

2 4

2 8 0.

2 0 0.

6 0

. 4 1.

0 0

. 8

Mos

HR P Value PSA > 40 ng/mL 1.50 .032

LDH > ULN 1.87 .008 ALP > ULN 1.16 .496 Hemoglobin < 130 1.45 .055 Visceral mets 2.27 .004 ECOG PS 2 1.26 .327 ctDNA > 2% 1.44 .086 HRR defect 5.27 < .001

HRR defect Yes No

ctDNA unquantifiable

Emmanuel S. Antonarakis, MBBCh

(28)

DNA Repair Defects and

Immune Checkpoint Inhibitors

(29)

KEYNOTE-016: Responses to

Pembrolizumab in MMR-Deficient Tumors

• Radiographic responses across 12 tumor types at 20 wks (N = 86)

Le DT, et al. Science. 2017;357:409-413.

Ampulla of Vater Cholangiocarcinoma Colorectal

Endometrial cancer Gastroesophageal Neuroendocrine Osteosarcoma Pancreas

Prostate

Small Intestine Thyroid

Unknown primary

100 50 0 -50 -100 Change F rom Ba se li ne SL D (% )

Prostate

Prostate (n = 1)

Emmanuel S. Antonarakis, MBBCh

(30)

MMR Mutations in mCRPC

• 4/150 (2.7%) mCRPC pts were MSI-high, 3 of

whom had MMR mutations (2%)

– 13 mut/Mb (Pt #149) – MSH2

– 21 mut/Mb (Pt #147) – no MMR mutation

– 23 mut/Mb (Pt #148) – MSH2

– 25 mut/Mb (Pt #150) – MSH2 and MLH1

Robinson D, et al. Cell. 2015;161:1215- 1228.

MSI Analysis:

Hypermutated vs Nonhypermutated CRPC

Fraction Unstable Loci

0 50

0

100 0

150 0 0.1

0 0 0.3

0 0.2

0 0.5

0 0.4

0

Nonsynonymous Mutations

Negative MSI Positive

149

147

148 150

32, 41, 49, 67, 93

Emmanuel S. Antonarakis, MBBCh

(31)

MMR Mutations Can Cause HRD Mutations

• This patient should be treated with a PD-1 inhibitor, not a PARP inhibitor

Patient Case Gene Mutation

Primary MMR mutation  MSH2 E809X* + LOH = MSI-high (> 100

mut/Mb) Secondary DNA-repair

mutations

 BRCA2

 ERCC4

 ERCC5

 FANCM

 MSH6

 E1646fs*

 M361fs*

 E474fs*

 V1336fs*

 F1104fs*

*Protein truncation by stop codon (X) or frameshift (fs).

Emmanuel S. Antonarakis, MBBCh

(32)

MMR Defects in Prostatic Ductal Carcinoma

• 4/10 (40%) had MMR mutations; 3/10 (30%) had MSI and hypermutation

Schweizer MT, et al. Oncotarget.

2016;7:82504-82510.

Pt No.

Ductal Component

for NGS, %

Est. Tumor Content From NGS, %

MMR Gene Alteration HR Gene Alteration Hyper- mut

Total Coding Muts/1.2 Mb Sequenced

1 71 30 No CHEK2 c.1100delC + LOH No 4

2 45 40 MSH2 inversion No No 4

3 65 60 No No No 4

4 30

60 MSH6 c.1900_1901del + LOH No Yes 29

5 97 50 MSH2-GRHL2 rearrangement +

LOH No Yes 34

6 99 50 No No No 5

7 25 0 -- -- -- --

8 31 70 No No No 5

9 35

10 No BRCA2 c.594delT + likely LOH No 3

10 -- 60 MLH1 exon 19+ 3’UTR

homozygous deletion No Yes 32

Emmanuel S. Antonarakis, MBBCh

(33)

MMR Defects and Gleason Grade

• 1.2% (14/1176) of primary adenocarcinomas and NEPC had MSH2 protein loss by IHC

• Pathology and MSH2 loss

– Primary Gleason pattern 5 enriched for MSH2 loss: 8%

(7/91)

– MSH2 loss in pts with any other Gleason score: < 1%

(5/1042) – P < .05

Guedes LB, et al. Clin Cancer Res.

2017;23:6863-6874.

Cases with MSH2 loss

Controls without MSH2 loss P =

.008

CD 8 (ce ll s/m m

2

)

1200 1000 800 600 400 200 0

Emmanuel S. Antonarakis, MBBCh

(34)

DNA Repair and

Platinum Chemotherapy

(35)

Platinum Response in mCRPC With HR Deficiency

Cheng H, et al. Eur Urol. 2016;69:992- 995.

Clinical Treatment Course Clinical Treatment Course

Pt Allele BRCA2 Mutation Mutation Type

1 1 c.9196C>T; p.Q3066X Premature stop 2 127 bp del in exon 11 Fs deletion 2 1 c.8904delC; p.V2969Cfs *7 Fs deletion 2 c.2611delT; p.S871Qfs *3 Fs deletion

3 1 Homozygous copy loss Copy loss

2 Homozygous copy loss Copy loss

Pt 2

PSA (ng/mL)

7 0 6 0 5 0 4 0 3 0 2 0 1 0 0

2012 2013 2014 2015

5 mos

ABI ENZ DOC CAR

+DOX

Pt 1

PSA (ng/mL)

50 40 0 300 0 2 0 100 0 0

2012 2013 2014

18 mos

ABI ENZ

DOC CAR

+DOC CAR

+DOC CIS

+ETO

30 mos

ABI CAR PA

C CAR

+DOC

Pt 3

PSA (ng/mL)

1 2 1 0 8 6 4 2 0

2011 2012 2013 2014

CAR +DOC

*

*

Time of metastatic biopsy.

*

*

Emmanuel S. Antonarakis, MBBCh

(36)

• Near-CR to cisplatin/docetaxel in a pt with metastatic NEPC, lasting 12 mos – Genome of metastatic tumor found to be highly altered; germline FANCA

mutation (S1088F) with somatic LOH also identified

– In preclinical studies, loss of FANCA associated with increased cisplatin sensitivity

0.01 10

Platinum Response in mCRPC With FANCA Deficiency

Beltran H, et al. JAMA Oncol. 2015;1:466-474.

Increased Cisplatin Sensitivity With Loss of FANCA

Xenograft Model Cell Culture

Model 130 110 90 70 50 30 10 Cell Viability (%) 0

0.1 1.0 100 Cisplatin IC50 (μM)

FANCA KO2 Control

IC50 0.8 μM 2.5 μM

Control KO2

FANCA GAPDH

800 600 400 200 0 1000

Tumor Volume (mm3 )

0 4 8 11 14 Days

Vehicle Cisplatin

Emmanuel S. Antonarakis, MBBCh

(37)

HR Deficiency and Response to Carboplatin

• 8/141 (5.7%) men with mCRPC had pathogenic germline BRCA2 variants

Pomerantz MM, et al. Cancer. 2017;123:3532-3539.

OS With

Carboplatin/Docetaxel by BRCA2 Carrier Status PSA Response With

Carboplatin/Docetaxel by BRCA2 Carrier Status

*Carriers of pathogenic germline variants in other DNA repair genes (MSH2, ATM, BLM, FANCA).

Observations (n=141)

BRCA2 carrier BRCA2 noncarrier Log-rank P = .03

Mos After Initiation of Carboplatin/Docetaxel

Probability of OS1.00

0.75 0.50 0.25 0

0 12 24 36 48 60 72 84 96

Pts at Risk, n BRCA2 noncarrier BRCA2 carrier

133 51 14 6 5 3 2 1 1 8 5 3 3 2 2 0 0 0 BRCA2 carrier

BRCA2 noncarrier

*

*

* *

PSA Decline (%)

0 25 50 75 100

Emmanuel S. Antonarakis, MBBCh

(38)

Conclusions

• Not all DNA repair lesions are created equal

• Somatic (and germline) DNA repair mutations are common in prostate cancer, particularly mCRPC

• HRD mutations may sensitize to PARP inhibitors, platinum agents

• MMR mutations may sensitize to immune checkpoint inhibitors

• The role of germline vs somatic, and single- vs double-copy inactivation, remains unclear

Emmanuel S. Antonarakis, MBBCh

(39)

Grazie!!!!!

Riferimenti

Documenti correlati

Purpose: To quantitatively visualize retinal vascular flow in patients with diabetic retinopathy using Optical Coherence Tomography Angiography and a novel perfusion density

Presented By Jeffrey Weber at 2018 ASCO Annual Meeting.. Subgroup Analysis of RFS: Disease Stage III and IV. Presented By Jeffrey Weber at 2018 ASCO Annual Meeting.. Keynote

Presented By Martine Piccart-Gebhart at 2018 ASCO Annual Meeting.6. In favour of

Presented By Hedy Kindler at 2019 ASCO Annual Meeting... Come spiegare PFS

Presented By Claire Falandry at 2019 ASCO Annual Meeting... EWOC-1

Presented By Jeffrey Weber at 2018 ASCO Annual Meeting... Subgroup Analysis of RFS: Disease Stage III

Presented By Lowell Schnipper at 2014 ASCO Annual Meeting... Il

Presented By Gilberto Lopes at 2018 ASCO Annual Meeting..