Downloaded 134 times
![Pembrolizumab for MSI-H or MMR-Deficient
Cancers
In May 2017, the PD-1 inhibitor pembrolizumab received
accelerated approval from FDA for:
– MSI-H or MMR-deficient CRC that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
– For ALL unresectable or metastatic MSI-H or MMR-deficient
SOLID TUMORS (pediatric and adult) that have progressed on
prior treatment and with no satisfactory alternative treatment
options
Dosage and administration (MSI-H cancers): 200 mg IV every 3
wks
Pembrolizumab [package insert]. 2017.](https://image.slidesharecdn.com/geneticsinprostatecancer-190204134738/75/Genetics-in-prostate-cancer-28-2048.jpg)
Uploaded byAlok Gupta
Genetics in prostate cancer
The document discusses the molecular and genetic understanding of castration-resistant prostate cancer (CRPC), emphasizing the role of genomic alterations and DNA repair defects. It highlights the heritability of prostate cancer, the impact of germline mutations in DNA repair genes, and the therapeutic implications of exploiting these defects for treatment, such as the use of PARP inhibitors. Additionally, it presents findings from studies on the prevalence of DNA repair alterations in prostate cancer and the efficacy of treatments targeting these genetic vulnerabilities.
More Related Content
Similar to Genetics in prostate cancer
More from Alok Gupta
Genetics in prostate cancer
- 1. Molecular and GeneticUnderstanding of CRPC Updates from Lab and Lessons for Clinic Dr Alok Gupta MD, DM, Consultant Medical Oncologist Max Super Speciality Hospital, New Delhi Ex-Asst. Professor, AIIMS, New Delhi
- 2. Outline Genomic alterationsin prostate cancer DNA damage response pathways DNA repair defects in advanced prostate cancer Therapeutic implications of DNA repair defects in advanced prostate cancer HRD - PARP inhibitors and synthetic lethality MMR defects and immune checkpoint inhibitors Conclusions
- 3. Heritability of prostatecancer (PCa) Family history is strong risk factor • Nordic twin study1 • 57% heritability for PCa • Only melanoma had higher heritability (58%) • BUT…..identifying specific genes that contribute to this risk has proven challenging • Genetic linkage studies in multi-case PCa families over 2 decades revealed few candidates e.g. HOXB13 G84E mutation present in 3.1% of familial PCa2 1Mucci et al. JAMA. 2016 Jan 5;315(1):68-76 2Ewing et al. JAMA. 2016 Jan 5;315(1):68-76
- 4. Germline DNA repairgene mutations & Prostate Cancer Higher risk of developing PCa Mutated gene Increased risk of PCa Reference BRCA2 Up to 8.6 fold Br J Cancer. 2011;105(8):1230-4 BRCA1 3.75 fold Br J Cancer. 2012;106(10):1697 ATM 2.2 fold Nat Genet. 2015;47(8):906 CHEK2 1.6 fold J Clin Oncol. 2016;34(11):1208 NBN 3.9 fold Cancer Res. 2004;64(4):1215 PALB2 ??? 0.4% of metastatic PCa N Engl J Med. 2016;375(5):443-53 MMR/Lynch 4.9 fold Genet Med. 2014;16(7):553
- 5. More aggressive PCa(vs. non-carriers) • BRCA2 • Younger onset, higher T stage, higher Gleason, more LN involvement, shorter PCa-specific survival and OS1,2 • BRCA2 or BRCA1 or ATM : • 4-fold higher risk lethal PCa, shorter OS3 • BRCA1 : • Higher recurrence rates, shorter PCa-specific survival4 1J Natl Cancer Inst. 2007;99(12):929 2J Clin Oncol. 2013;31(14):1748 3Eur Urol. 2017;71(5):740 4Clin Cancer Res. 2010;16(7):2115 Germline DNA repair gene mutations & Prostate Cancer
- 6. 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.
- 7. References in slidenotes. EZH2 ARgene expression Mutation/gain/V7 PCA3 AMACR Prostatic intraepithelial neoplasia Localized PCa Loss of 8p (NKX3.1)? Activation of β-catenin, wnt Loss of APC Castration- resistant PCa Metastatic PCa Curable Incurable Normal prostatic epithelium Epigenomic changes, including GSTP1 hypermethylation Inactivation of p53, RB1, CDK12 ETS gene family activation via fusion with TMPRSS2 or other AR-driven genes cMYC Mutations in SPOP, FOXA1, epigenetic regulators Anaplastic/ NE PCa Loss of PTEN, 13q (RB1), 5q (CHD1), 16q, 6q, 3p (FOXP1, SHQ1) Gain of 8q, 3q (PIK3CA) Tx Genomic Alterations in Prostate Cancer Progression Compromised DNA repair
- 8.
- 9. DNA Damage Response(DDR) Cellular DNA is subject to continuous damage from both environmental agents (mutagens) and endogenous sources ‒ 1000s of events/day (eg, ssDNA and dsDNA breaks, alkylation, x-linked) DDR has evolved to maintain DNA sequence and fidelity ‒ At least 6 different types of DNA repair processes exist to deal with wide variety of DNA damage Inherited defects in DDR are among the most carcinogenic of all hereditary syndromes (eg, Lynch syndrome, HBOC) Some DDR defects can be exploited for therapeutic benefit O’Connor MJ. Mol Cell. 2015;60:547-560.
- 10. DNA repair genemutations • Evolution of next-generation sequencing has allowed germline DNA repair gene mutations to be linked to PCa Single strand DNA repair pathways Double strand DNA repair pathways Mismatch repair (MMR) Homologous recombination (HR) Base excision repair Non-homologous end joining (NHEJ) Nucleotide excision repair DNA damage response (DDR)
- 11. Consequences of DNADamage If DNA damage correctly repaired, no consequences If no repair or inefficient repair due to defects in DDR genes ‒ Cell death is most common fate – unrepaired dsDNA breaks are lethal ‒ Can result in accumulation of DNA damage in the form of mutations ‒ Activation of oncogenes, inactivation of tumor suppressor genes Accumulation of DNA damage/mutations can lead to cancer formation/progression ‒ Resulting cancer cells may be more susceptible to drugs that inactivate remaining DNA repair pathways Mateo J, et al. Euro Urol. 2017;71:417-425.
- 12. DNA Repair Defectsin Prostate Cancer
- 13. DNA Repair Defectsin Localized Prostate Cancer Sequence analysis of localized, nonindolent prostate tumors with similar risk profiles (N = 477) – 200 whole-genome sequences, 277 whole-exome sequences 47/477 (9.9%) tumors had DNA repair mutations – FANCA (n = 9) – ATM (n = 8) – RAD51 (n = 7) – CDK12 (n = 6) – BRCA2 (n = 5) Fraser M, et al. Nature. 2017;541:359-364.
- 14. DNA Repair Defectsin mCRPC 34/150 (22.7%) mCRPC pts had DNA repair alterations, many of which were biallelic – 19/150 (12.7%) with loss of BRCA2 – ~ 90% were biallelic, with 8/150 (5.3%) resulting from a pathogenic germline BRCA2 mutation + a somatic event – Recurrent biallelic loss of ATM also observed, including some arising from pathogenic germline alterations – Mutation events also observed in BRCA1, CDK12, FANCA, RAD51B, and RAD51C Robinson D, et al. Cell. 2015;5:1215-1228.
- 15. Genomic Landscape ofAdvanced Prostate Cancer 23% of metastatic CRPCs harbor DNA repair alterations The frequency of DNA repair alterations increases with disease progression Robinson D et al, Cell, 2015 Robinson D, et al. Cell. 2015;161:1215-1228.
- 16. DNA Repair Defectsin mCRPC: Enrichment Analysis in Primary vs Metastatic Tumors Tumor Samples (N = 918) Primary Metastasis 583 335 CARD11 Primary DNA repair defects: 11% Metastases DNA repair defects: 21% Significance (Fisher’s qvalue) Genomic Alteration Frequency AlteredPrimarySamples(%) Altered Metastatic Samples (%) 50 10 5 30 0 0 5 10 30 50 Amplification/mutation Homdel/mutation Mutation SPOP PTEN KMT2C KMT2D MYC FOXA1 TP53 RB1 BRCA2 AR ZFHX3 CDK12 APC IDH1 RYBP/FOXP1 JAK1 SPEN IGF2R PREX2 CTNNB1 CCND1 FAT1 MGA MED12 USP28 ANKRD11 GNAS ERF CHD8 GRIN2A RNF43 USP7 ASXL1 SAMD9 Armenia J, et al. ASCO 2017. Abstract 131.
- 17. Therapeutic Implications of DNARepair Defects in Advanced Prostate Cancer
- 18. PARP Biology PARP(polyADPribose polymerase) enzymes play a key role in the repair of ssDNA breaks via BER pathway Bind 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 NAD+ Nicotinamide + pADPr Lig3XRCC1 Polß PNK PARP Ohmoto A, et al. Onco Targets Ther. 2017;10:5195-5208.
- 19. PARPi Leads toIncrease 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 XRCC1 DNA Lig III PNK 1 DNA Polβ During S-phase, replication fork is arrested at site of ssDNA breaks Degeneration into dsDNA breaks ssDNA breaks PARP inhibition
- 20. Synthetic Lethality Hypothesis FarmerH, 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
- 21. TOPARP: Trial ofOlaparib in mCRPC 30 patients 20 patientsTotal: 50 patients (49 evaluable) Eligibility: Histologically confirmed metastatic CRPC, ECOG 0-2, no previous PARPi or platinum Mateo J, et al. N Engl J Med. 2015;373:1697-1708. FIRST PART: TREATED UNSELECTED mCRPC pts Randomized study in unselected mCRPC pts Biomarker guided patient selection in next part (Part B) END OF TRIAL High response rate: ≥ 50% Responding Intermediate RR (10-50% responding) Putative biomarker identified (RR > 50%) Low antitumor activity RR < 10%
- 22. 49evaluable pts-RR 33% 16/49ptshadDNArepair defect -RR 88%
- 23. Radiologic PFS byPresence of Genomic Defects in DNA Repair Genes OS by Presence of Genomic Defects in DNA Repair Genes ProportionofPatients ProportionofPatients Mateo J, et al. N Engl J Med. 2015;373:1697-1708. 0 0.25 0.50 0.75 1.00 0 1 2 3 4 5 6 7 8 9 101112 131415 16171819 20 Mos Since Trial Entry Log-rank P < .001 Biomarker positive, median: 9.8 mos Biomarker negative, median: 2.7 mos 0 0.25 0.50 0.75 1.00 0 1 2 3 4 5 6 7 8 9 101112 131415 16171819 20 Mos Since Trial Entry Log-rank P = .05 Biomarker positive, median: 13.8 mos Biomarker negative, median: 7.5 mos TOPARP-A: PFS and OS by Presence of DNA Repair Defects All patients (N = 50) treated with olaparib 400 mg PO BID
- 24. De Felice F,et al. Drug Des Devel Ther. 2017;11:547-552. Olaparib: Ongoing Studies in Prostate Cancer Trial Study Design Eligibility Study Arms Endpoint Results TOPARP Phase II Advanced CRPC Oral olaparib ORR 33% ORR Kaufman, et al Phase II BRCA1/2-mut adv solid tumors (PC n = 8) Oral olaparib ORR PFS: 9.8 vs 2.7 mos OS: 13.8 vs 7.5 mos ORR in PC: 50% NCT01972217 Randomized phase II mCRPC Olaparib + abiraterone Safety PFS: 7.2 mo OS: 18.4 mo (ongoing study) NCT02484404 Phase I/II Adv/recurrent solid tumors Anti-PD-L1 + olaparib Safety Recommended dose (ongoing) KEYNOTE 365 Phase I/II mCRPC Anti-PD-L1 + cediranib ± olaparib Pembro + olaparib Safety AEs, ORR, OS (ongoing) NCT02893917 Randomized Phase II mCRPC Olaparib + cediranib PFS PFS, RR, OS (ongoing) NCT02324998 Phase I Int/high-risk PC Olaparib ± placebo Degree of PARPi AEs (ongoing)
- 25.
- 26. MMR Mutations inmCRPC 3/150 (2%) had MMR mutations 4/150 (2.7%) were MSI-high Patient Cases With DNA Repair Defects Reprinted from Robinson D, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. Copyright © 2015 with permission from Elsevier Inc.
- 27. PD-1 Inhibition inMMR-Deficient Cancers Le DT, et al. ASCO 2016. Abstract 103. Le DT, et al. N Engl J Med. 2015;372:2509-2520. Radiographic Response With Pembrolizumab -100 MMR-P CRC MMR-D CRC MMR-D non-CRC ChangeFromBLinthe SumofLongest Diameters(%) 20% increase (PD) 100 0 50 -50 30% decrease (PR) Biochemical Response With Pembrolizumab MMR-P CRC MMR-D CRC MMR-D non-CRC ChangeinTumor MarkerLevel(%) Days 0% (no change) 200 0 -100 0 100 200 400300 100 Pt PFS(%) PFS with Pembrolizumab Mos MMR-D (mPFS: NR) 100 50 0 0 3 6 12 15 18 21 24 27 30 MMR-P (mPFS: 2.3 mos) 9 OS(%) Mos MMR-D (mOS: NR) OS with Pembrolizumab100 50 0 0 3 6 12 15 18 21 24 27 30 MMR-P (mOS: 5.98 mos) 9
- 28. Pembrolizumab for MSI-Hor MMR-Deficient Cancers In May 2017, the PD-1 inhibitor pembrolizumab received accelerated approval from FDA for: – MSI-H or MMR-deficient CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan – For ALL unresectable or metastatic MSI-H or MMR-deficient SOLID TUMORS (pediatric and adult) that have progressed on prior treatment and with no satisfactory alternative treatment options Dosage and administration (MSI-H cancers): 200 mg IV every 3 wks Pembrolizumab [package insert]. 2017.
- 29. KEYNOTE-016: Responses toPembrolizumab 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 ChangeFrom BaselineSLD(%) Prostate Prostate (n = 1)
- 30. MMR Mutations inmCRPC 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 FractionUnstableLoci 0 500 1000 1500 0.10 0 0.30 0.20 0.50 0.40 Nonsynonymous Mutations Negative MSI Positive 149 147 148 150 32, 41, 49, 67, 93
- 31. Conclusions DNA repairmutations are common in prostate cancer, particularly mCRPC ‒ Both somatic and germline mutations can lead to DNA repair defects 20% to 30% of metastatic CRPCs harbor alterations in DNA repair genes HR DNA repair mutations sensitize to PARP inhibitors ‒ “Synthetic lethality” hypothesis in action MMR mutations are rare...but may sensitize to immune checkpoint inhibitors
- 32.