Giuseppe Fornarini, U.O. Oncologia Medica 1 Ospedale Policlinico San Martino IRCCS Genova. Trattamenti della malattia con mutazioni di BRCA e altro

Transcription

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 Germline pathogenic alterations may have both familial and therapeutic implications To whom should we offer germline genetic testing? Presented By Heather Cheng at 218 ASCO Annual Meeting

4 More recent genetic findings in advanced PC may also inform therapy Presented By Heather Cheng at 218 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. 217;71: Emmanuel S. Antonarakis, MBBCh

8 Double-Stranded (ds)dna Repair Homologous recombination Pathways DNA damage from ionizing radiation or other dsdna injury FANC genes, BRCA1/2, ATM, PALB2, RAD5, 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. 217;71: Makridakis NM, et al. Front Genet. 212;3:174. Emmanuel S. Antonarakis, MBBCh

9 Germline Mutations in Prostate Cancer: 1 in 1 Distribution of Presumed Pathogenic Germline Mutations RAD51C MSH6 1% MSH2 1% 1% MRE11A GEN1 2% 1% BRIP1 1% FAM175A PMS2 2% NBN 2% 1% ATR 2% RAD51D PALB2 4% 4% BRCA2 BRCA1 7% 44% CHEK2 12% ATM 13% Pritchard CC, et al. N Engl J Med. 216;375: % (82/692) of men with metastatic prostate cancer inherited a germline DNA repair mutation vs 4.6% of 499 men with localized disease Presumed Pathogenic Germline Mutations in Metastatic Cases (N = 692) Gene No. of Mutations % of Men BRCA ATM CHEK2* BRCA *n = 534; data censored for metastatic cases with inadequate sequencing.

10 Association Between Germline DNA- Repair Defects and Intraductal/Ductal Distribution of Pathogenic Germline Mutations CDH1 5% MSH6 5% PALB2 5% NBN 5% Histology Germline mutations in 14% (21/15) of men with recurrent/advanced prostate cancer Men with intraductal/ductal histology more likely to have germline mutations BRCA1 9% CHEK2 14% BRCA2 43% Incidence of Pathogenic Germline Mutations ATM 14% Intra/Ductal Histology No Intra/Ductal Histology P Value* 4% (1/25) 9% (11/125) P =.3 Isaacsson Velho P, et al. The Prostate. 218;[Epub ahead of print]. *Fisher s test. Emmanuel S. Antonarakis, MBBCh

11 Effect of DDR Mutation on Treatment Responses Presented By Carmel Pezaro at 218 ASCO Annual Meeting

12 Selected Trials for mcrpc with Relevance to DNA repair defects Presented By Heather Cheng at 218 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 DNA damage PARP NAD+ Nicotina mide + padpr XRCC1 Lig3 PNK Polß Ohmoto A, et al. Onco Targets Ther. 217;1: Emmanuel S. Antonarakis, MBBCh

14 PARPi Leads to Increase in dsdna 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 DNA Polβ Breaks PNK 1 PARP PARP inhibition XRCC1 ssdna breaks DNA Lig III During S-phase, replication fork is arrested at site of ssdna breaks Ohmoto A, et al. Onco Targets Ther. 217;1: Degeneration into dsdna breaks Emmanuel S. Antonarakis, MBBCh

15 Synthetic Lethality Hypothesis PARP function BRCA function PARP function BRCA function PARP function BRCA function Normal cell Normal cell Non-BRCA mutation carrier BRCA mutation carrier (1 allele lost) Cancer cell BRCA mutation carrier (both alleles lost) DNA damage PARP inhibitor DNA damage PARP inhibitor DNA damage PARP inhibitor PARP function BRCA function PARP function BRCA function PARP function BRCA function Repair, Survival Repair, Survival Repair, Survival Repair, Survival Repair, Survival Farmer H, et al. Nature. 25;434: Bryant et al. Nature. 25;434: Cell Death Emmanuel S. Antonarakis, MBBCh

16 TOPARP Presented By Carmel Pezaro at 218 ASCO Annual Meeting

17 TOPARP Results: Response Presented By Carmel Pezaro at 218 ASCO Annual Meeting

18

19 TOPARP Results Presented By Carmel Pezaro at 218 ASCO Annual Meeting

20 Single Agent Trials In Progress Presented By Carmel Pezaro at 218 ASCO Annual Meeting

21 Slide 17 Presented By Carmel Pezaro at 218 ASCO Annual Meeting

22 Combination Trials In Progress Presented By Carmel Pezaro at 218 ASCO Annual Meeting

23 Clinical Data Extrapolations Presented By Carmel Pezaro at 218 ASCO Annual Meeting

24 DNA Repair Defects and Hormonal Therapy

25 Probability of PFS Abiraterone in mcrpc With HR Deficiency 2/8 (25%) evaluable pts with mcrpc had DNA repair defects DNA Repair Defects* BRCA2 ATM BRC A1 RAD5 1B RAD51 C PALB2 FANCA 2 copy losses 1 copy loss Biallelic Copy-neutral LOH Missense Frameshi ft Nonsens e Monoallelic Not detected In-frame indel *Data shown for 25 of 8 pts with exploratory tumor sequencing. Hussain M, et al. J Clin Oncol. 217;[Epub ahead of print] PFS by DRD Status + Censored Log-rank P =.254 Median, Mos (95% CI) DRD: 14.5 ( ) WT: 8.1 ( ) Pts at Mos Risk, n DRD WT Emmanuel S. Antonarakis, MBBCh

26 PFS (%) OS (%) Abiraterone or Enzalutamide and HR 1 8 PFS by DRD Status Deficiency Any Mutation No Yes (other) Yes (ATM/BRCA1/BRCA2) 1 8 OS by DRD Status Any Mutation No Yes (Other) Yes (ATM/BRCA1/BRCA2) Mos Mos Pts at Risk, n No Pts at Risk, n No Yes (other) Yes (other) Yes (ATM/BRCA1/ Yes 3 (ATM/BRCA1/ BRCA2) BRCA2) Antonarakis ES, et al. Eur Urol In press. Emmanuel S. Antonarakis, MBBCh

27 Probability of PFS Abiraterone vs Enzalutamide and HR Randomized phase II crossover study in treatmentnaive pts with mcrpc (N = 22) BRCA2- or ATM-truncating mutations or rearrangements: Somatic (ctdna): 6/115 (5.2%) Germline (WBC): 8/22 (4.%) Monoallelic BRCA2 or ATM deletion in 21 pts No TTP differences (P =.25) Deficiency Pts at Risk, n Time to Progression by HRR Status* HR Mos Annala M, et al. Cancer Discov. 218;[Epub ahead of print]. *Abiraterone + enzalutamide arms combined. Emmanuel S. Antonarakis, MBBCh P Value PSA > 4 ng/ml LDH > ULN ALP > ULN Hemoglobin < Visceral mets ECOG PS ctdna > 2% HRR defect 5.27 <.1 HRR defect Yes No ctdna unquantifiable

28 DNA Repair Defects and Immune Checkpoint Inhibitors

29 Change From Baseline SLD (%) KEYNOTE-16: Responses to Pembrolizumab in MMR-Deficient Tumors Radiographic responses across 12 tumor types at 2 wks (N = 86) 1 Prostate Ampulla of Vater Cholangiocarcinoma Colorectal Endometrial cancer Gastroesophageal Neuroendocrine Osteosarcoma Pancreas Prostate Small Intestine Thyroid Unknown primary Prostate (n = 1) Le DT, et al. Science. 217;357: Emmanuel S. Antonarakis, MBBCh

30 Fraction Unstable Loci MMR Mutations in mcrpc 4/15 (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 #15) MSH2 and MLH1 MSI Analysis: Hypermutated vs Nonhypermutated CRPC MSI Positive 32, 41, 49, 67, 93 Negative Nonsynonymous Mutations 15 Robinson D, et al. Cell. 215;161: Emmanuel S. Antonarakis, MBBCh

31 MMR Mutations Can Cause HRD Mutations Patient Case Gene Mutation Primary MMR mutation MSH2 E89X* + LOH = MSI-high (> 1 mut/mb) Secondary DNA-repair mutations BRCA2 ERCC4 ERCC5 FANCM MSH6 *Protein truncation by stop codon (X) or frameshift (fs). E1646fs* M361fs* E474fs* V1336fs* F114fs* This patient should be treated with a PD-1 inhibitor, not a PARP inhibitor Emmanuel S. Antonarakis, MBBCh

32 MMR Defects in Prostatic Ductal Carcinoma 4/1 (4%) had MMR mutations; 3/1 (3%) had MSI and hypermutation Pt No. Ductal Component for NGS, % Est. Tumor Content From NGS, % MMR Gene Alteration HR Gene Alteration Hypermut Total Coding Muts/1.2 Mb Sequenced No CHEK2 c.11delc + LOH No MSH2 inversion No No No No No MSH6 c.19_191del + LOH No Yes MSH2-GRHL2 rearrangement + LOH No Yes No No No No No No No BRCA2 c.594delt + likely LOH No MLH1 exon UTR homozygous deletion No Yes 32 Schweizer MT, et al. Oncotarget. 216;7: Emmanuel S. Antonarakis, MBBCh

33 CD8 (cells/mm 2 ) 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% (5/142) P <.5 Guedes LB, et al. Clin Cancer Res. 217;23: Cases with MSH2 loss Controls P = without MSH2.8 loss Emmanuel S. Antonarakis, MBBCh

34 DNA Repair and Platinum Chemotherapy

35 PSA (ng/ml) PSA (ng/ml) Platinum Response in mcrpc With HR Deficiency Pt Allele BRCA2 Mutation Mutation Type 1 1 c.9196c>t; p.q366x Premature stop bp del in exon 11 Fs deletion 2 1 c.894delc; 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 mos ABI ENZ DOC CAR +DOX * Pt * Clinical Treatment Course Cheng H, et al. Eur Urol. 216;69: PSA (ng/ml) 5 ABI DOC ENZ CAR +DOC 18 mos CAR +DOC Pt mos CAR ABI CAR CAR CIS PA +DOC +DOC +ETO C * Clinical Treatment Course *Time of metastatic biopsy. Emmanuel S. Antonarakis, MBBCh

36 Cell Viability (%) Tumor Volume (mm 3 ) Platinum Response in mcrpc With FANCA Deficiency 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 (S188F) with somatic LOH also identified In preclinical studies, loss of FANCA associated with increased cisplatin sensitivity Increased Cisplatin Sensitivity With Loss of FANCA Cell Culture Model FANCA KO2.8 μm Control 2.5 μm Control KO Cisplatin IC 5 (μm) Beltran H, et al. JAMA Oncol. 215;1: IC 5 FANCA GAPDH Xenograft Model Vehicle Cisplatin Days Emmanuel S. Antonarakis, MBBCh

37 PSA Decline (%) HR Deficiency and Response to Carboplatin 8/141 (5.7%) men with mcrpc had pathogenic germline BRCA2 variants PSA Response With Carboplatin/Docetaxel by BRCA2 Carrier Status * * * Observations (n=141) *Carriers of pathogenic germline variants in other DNA repair genes (MSH2, ATM, BLM, FANCA). Pomerantz MM, et al. Cancer. 217;123: * BRCA2 carrier BRCA2 noncarrier OS With Carboplatin/Docetaxel by BRCA2 Carrier Status Probability of OS 1. Pts at Risk, n BRCA2 noncarrier BRCA2 carrier BRCA2 carrier BRCA2 noncarrier Log-rank P = Mos After Initiation of Carboplatin/Docetaxel 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!!!!!