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25-05-2017 | PARP inhibitors | Article

PARP Inhibitors in Prostate Cancer

Journal: Current Treatment Options in Oncology

Authors: Praveen Ramakrishnan Geethakumari, MD, Matthew J. Schiewer, PhD, Karen E. Knudsen, PhD, Wm. Kevin Kelly, DO

Abstract

The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve “synthetic lethality” in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded “breakthrough designation” to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential “BRCAness” of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. doi:10.3322/caac.21332.CrossRefPubMed

Knudsen KE, Penning TM. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab. 2010;21(5):315–24. doi:10.1016/j.tem.2010.01.002.CrossRefPubMedPubMedCentral

Knudsen KE, Scher HI. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res. 2009;15(15):4792–8. doi:10.1158/1078-0432.CCR-08-2660.CrossRefPubMedPubMedCentral

Geethakumari PR, Cookson MS, Kelly WK. Prostate cancer clinical trials working group. The evolving biology of castration-resistant prostate cancer: review of recommendations from the prostate cancer clinical trials working group 3. Oncology (Williston Park). 2016;30(2):187–95. 99

Khemlina G, Ikeda S, Kurzrock R. Molecular landscape of prostate cancer: implications for current clinical trials. Cancer Treat Rev. 2015;41(9):761–6. doi:10.1016/j.ctrv.2015.07.001.CrossRefPubMed

Spratt DE, Zumsteg ZS, Feng FY, Tomlins SA. Translational and clinical implications of the genetic landscape of prostate cancer. Nat Rev Clin Oncol. 2016;13(10):597–610. doi:10.1038/nrclinonc.2016.76.CrossRefPubMedPubMedCentral

•• Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–28. doi:10.1016/j.cell.2015.05.001. Multi-institutional study exploring the genomic landscape of mCRPC and showing that up to 90% patients harbor clinically actionable molecular aberrations.CrossRefPubMedPubMedCentral

• Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443–53. doi:10.1056/NEJMoa1603144. Multi-center study showing that the incidence of germline mutations in genes mediating DNA repair in mCRPC (11.8%) is significantly higher than the incidence in localized prostate cancer (4.6%)CrossRefPubMedPubMedCentral

Kraus WL. PARPs and ADP-ribosylation: 50 years … and counting. Mol Cell. 2015;58(6):902–10. doi:10.1016/j.molcel.2015.06.006.CrossRefPubMedPubMedCentral

10.

Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7. doi:10.1038/nature03443.CrossRefPubMed

11.

Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21. doi:10.1038/nature03445.CrossRefPubMed

12.

Brown JS, Kaye SB, Yap TA. PARP inhibitors: the race is on. Br J Cancer. 2016;114(7):713–5. doi:10.1038/bjc.2016.67.CrossRefPubMedPubMedCentral

13.

Helleday T. PARP inhibitor receives FDA breakthrough therapy designation in castration resistant prostate cancer: beyond germline BRCA mutations. Ann Oncol. 2016;27(5):755–7. doi:10.1093/annonc/mdw048.CrossRefPubMed

14.

Benjamin RC, Gill DM. ADP-ribosylation in mammalian cell ghosts. Dependence of poly(ADP-ribose) synthesis on strand breakage in DNA. J Biol Chem. 1980;255(21):10493–501.PubMed

15.

Durkacz BW, Omidiji O, Gray DA, Shall S. (ADP-ribose)n participates in DNA excision repair. Nature. 1980;283(5747):593–6.CrossRefPubMed

16.

Juarez-Salinas H, Sims JL, Jacobson MK. Poly(ADP-ribose) levels in carcinogen-treated cells. Nature. 1979;282(5740):740–1.CrossRefPubMed

17.

El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW. A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res. 2003;31(19):5526–33.CrossRefPubMedPubMedCentral

18.

Gagne JP, Isabelle M, Lo KS, Bourassa S, Hendzel MJ, Dawson VL, et al. Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes. Nucleic Acids Res. 2008;36(22):6959–76. doi:10.1093/nar/gkn771.CrossRefPubMedPubMedCentral

19.

Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, Swanson SK, et al. Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. Proc Natl Acad Sci U S A. 2009;106(33):13770–4. doi:10.1073/pnas.0906920106.CrossRefPubMedPubMedCentral

20.

Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol. 1998;18(6):3563–71.CrossRefPubMedPubMedCentral

21.

Timinszky G, Till S, Hassa PO, Hothorn M, Kustatscher G, Nijmeijer B, et al. A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nat Struct Mol Biol. 2009;16(9):923–9. doi:10.1038/nsmb.1664.CrossRefPubMed

22.

Ceccaldi R, Rondinelli B, D’Andrea AD. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 2015; doi:10.1016/j.tcb.2015.07.009.PubMedPubMedCentral

23.

Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med. 2015;66:129–43. doi:10.1146/annurev-med-081313-121208.CrossRefPubMed

24.

Schiewer MJ, Knudsen KE. Transcriptional roles of PARP1 in cancer. Mol Cancer Res. 2014;12(8):1069–80. doi:10.1158/1541-7786.MCR-13-0672.CrossRefPubMedPubMedCentral

25.

Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, et al. Poly(ADP-ribose) polymerase inhibition: “targeted” therapy for triple-negative breast cancer. Clin Cancer Res. 2010;16(19):4702–10. doi:10.1158/1078-0432.CCR-10-0939.CrossRefPubMedPubMedCentral

26.

Dedes KJ, Wilkerson PM, Wetterskog D, Weigelt B, Ashworth A, Reis-Filho JS. Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. Cell Cycle. 2011;10(8):1192–9.CrossRefPubMedPubMedCentral

27.

Kim MY, Zhang T, Kraus WL. Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal. Genes Dev. 2005;19(17):1951–67. doi:10.1101/gad.1331805.CrossRefPubMed

28.

Lord CJ, Ashworth A. Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol. 2008;8(4):363–9. doi:10.1016/j.coph.2008.06.016.CrossRefPubMed

29.

Penning TD. Small-molecule PARP modulators—current status and future therapeutic potential. Current opinion in drug discovery & development. 2010;13(5):577–86.

30.

Yap TA, Sandhu SK, Carden CP, de Bono JS. Poly(ADP-ribose) polymerase (PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin. 2011;61(1):31–49. doi:10.3322/caac.20095.CrossRefPubMed

31.

Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. BioEssays. 2004;26(8):882–93. doi:10.1002/bies.20085.CrossRefPubMed

32.

D’Amours D, Desnoyers S, D’Silva I, Poirier GG. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. The Biochemical journal. 1999;342(Pt 2):249–68.CrossRefPubMedPubMedCentral

33.

Krishnakumar R, Gamble MJ, Frizzell KM, Berrocal JG, Kininis M, Kraus WL. Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science. 2008;319(5864):819–21. doi:10.1126/science.1149250.CrossRefPubMed

34.

Krishnakumar R, Kraus WL. PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. Mol Cell. 2010;39(5):736–49. doi:10.1016/j.molcel.2010.08.014.CrossRefPubMedPubMedCentral

35.

Krishnakumar R, Kraus WL. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell. 2010;39(1):8–24. doi:10.1016/j.molcel.2010.06.017.CrossRefPubMedPubMedCentral

36.

Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10(4):293–301. doi:10.1038/nrc2812.CrossRefPubMedPubMedCentral

37.

Kraus WL. Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Curr Opin Cell Biol. 2008;20(3):294–302. doi:10.1016/j.ceb.2008.03.006.CrossRefPubMedPubMedCentral

38.

Kraus WL, Lis JT. PARP goes transcription. Cell. 2003;113(6):677–83.CrossRefPubMed

39.

Tulin A, Chinenov Y, Spradling A. Regulation of chromatin structure and gene activity by poly(ADP-ribose) polymerases. Curr Top Dev Biol. 2003;56:55–83.CrossRefPubMed

40.

Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011;19(5):664–78. doi:10.1016/j.ccr.2011.04.010.CrossRefPubMedPubMedCentral

41.

Tomlins SA, Alshalalfa M, Davicioni E, Erho N, Yousefi K, Zhao S, et al. Characterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypes. Eur Urol. 2015;68(4):555–67. doi:10.1016/j.eururo.2015.04.033.CrossRefPubMedPubMedCentral

42.

Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310(5748):644–8. doi:10.1126/science.1117679.CrossRefPubMed

43.

Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14(9):882–92. doi:10.1016/S1470-2045(13)70240-7.CrossRefPubMed

44.

•• Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697–708. doi:10.1056/NEJMoa1506859. The Phase 2 TOPARP-A trial showed significant response rate of 88% in patients with mCRPC harboring mutations in DNA repair genes to PARPi with olaparib and improvement in PFS and OS in the biomarker-positive groupCrossRefPubMedPubMedCentral

45.

Han S, Brenner JC, Sabolch A, Jackson W, Speers C, Wilder-Romans K, et al. Targeted radiosensitization of ETS fusion-positive prostate cancer through PARP1 inhibition. Neoplasia. 2013;15(10):1207–17.CrossRefPubMedPubMedCentral

46.

Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134–49. doi:10.1158/2159-8290.CD-12-0120.CrossRefPubMedPubMedCentral

47.

Pu H, Horbinski C, Hensley PJ, Matuszak EA, Atkinson T, Kyprianou N. PARP-1 regulates epithelial-mesenchymal transition (EMT) in prostate tumorigenesis. Carcinogenesis. 2014;35(11):2592–601. doi:10.1093/carcin/bgu183.CrossRefPubMedPubMedCentral

48.

Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34. doi:10.1056/NEJMoa0900212.CrossRefPubMed

49.

Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51. doi:10.1016/S0140-6736(10)60893-8.CrossRefPubMed

50.

Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–44. doi:10.1016/S0140-6736(10)60892-6.CrossRefPubMed

51.

Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–61. doi:10.1016/S1470-2045(11)70214-5.CrossRefPubMed

52.

Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50. doi:10.1200/JCO.2014.56.2728.CrossRefPubMed

53.

Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382–92. doi:10.1056/NEJMoa1105535.CrossRefPubMed

54.

Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852–61. doi:10.1016/S1470-2045(14)70228-1.CrossRefPubMed

55.

Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75–87. doi:10.1016/S1470-2045(16)30559-9.CrossRefPubMed

56.

Benafif S, Hall M. An update on PARP inhibitors for the treatment of cancer. Onco Targets Ther. 2015;8:519–28. doi:10.2147/OTT.S30793.PubMedPubMedCentral

57.

Jones P, Wilcoxen K, Rowley M, Toniatti C. Niraparib: a poly(ADP-ribose) polymerase (PARP) inhibitor for the treatment of tumors with defective homologous recombination. J Med Chem. 2015;58(8):3302–14. doi:10.1021/jm5018237.CrossRefPubMed

58.

Zhang J. Poly (ADP-ribose) polymerase inhibitor: an evolving paradigm in the treatment of prostate cancer. Asian J Androl. 2014;16(3):401–6. doi:10.4103/1008-682X.123684.CrossRefPubMedPubMedCentral

59.

Ito S, Murphy CG, Doubrovina E, Jasin M, Moynahan ME. PARP inhibitors in clinical use induce genomic instability in normal human cells. PLoS One. 2016;11(7):e0159341. doi:10.1371/journal.pone.0159341.CrossRefPubMedPubMedCentral

60.

Drean A, Lord CJ, Ashworth A. PARP inhibitor combination therapy. Crit Rev Oncol Hematol. 2016;108:73–85. doi:10.1016/j.critrevonc.2016.10.010.CrossRefPubMed

61.

Hussain M, Carducci MA, Slovin S, Cetnar J, Qian J, McKeegan EM, et al. Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Investig New Drugs. 2014;32(5):904–12. doi:10.1007/s10637-014-0099-0.CrossRef

62.

VanderWeele DJ, Paner GP, Fleming GF, Szmulewitz RZ. Sustained complete response to cytotoxic therapy and the PARP inhibitor veliparib in metastatic castration-resistant prostate cancer—a case report. Front Oncol. 2015;5:169. doi:10.3389/fonc.2015.00169.CrossRefPubMedPubMedCentral

63.

Palmbos PL, Hussain MH. Targeting PARP in prostate cancer: novelty, pitfalls, and promise. Oncology (Williston Park). 2016;30(5):377–85.

64.

Hussain M DS, Twardowski P, et al. 2016. Co-targeting androgen receptor (AR) and DNA repair: a randomized ETS gene fusion-stratified trial of abiraterone+ prednisone (Abi)+/− the PARP-1 inhibitor veliparib for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) (NCI9012)—a University of Chicago phase II consortium trial. J Clin Oncol.; 34 (suppl; abstr 5010).

65.

Corcoran NM, Clarkson MJ, Stuchbery R, Hovens CM. Molecular pathways: targeting DNA repair pathway defects enriched in metastasis. Clin Cancer Res. 2016;22(13):3132–7. doi:10.1158/1078-0432.CCR-15-1050.CrossRefPubMed

66.

Chao OS, Goodman Jr OB. Synergistic loss of prostate cancer cell viability by coinhibition of HDAC and PARP. Mol Cancer Res. 2014;12(12):1755–66. doi:10.1158/1541-7786.MCR-14-0173.CrossRefPubMed

67.

Baldwin POA, Thong J, et al. Nanoformulations of PARP inhibitors olaparib and talazoparib for targeted cancer therapy. Cancer Res. 2016;76(14 Supplement):4335. doi:10.1158/1538-7445.AM2016-4335.CrossRef

68.

Belz JON, Baldwin P, et al. Sustained release of PARP inhibitor talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer. Cancer Res. 2016;76(14 Supplement):3900. doi:10.1158/1538-7445.AM2016-3900.CrossRef

69.

Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res. 2016;22(15):3764–73. doi:10.1158/1078-0432.CCR-15-2477.CrossRefPubMed

70.

Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16(2):110–20. doi:10.1038/nrc.2015.21.CrossRefPubMed

71.

Mateo J, Boysen G, Barbieri CE, Bryant HE, Castro E, Nelson PS, et al. DNA repair in prostate cancer: biology and clinical implications. Eur Urol. 2016; doi:10.1016/j.eururo.2016.08.037.

72.

Modena A, Iacovelli R, Scarpa A, Brunelli M, Ciccarese C, Fantinel E, et al. Investigating BRCA mutations: a breakthrough in precision medicine of castration-resistant prostate cancer. Target Oncol. 2016; doi:10.1007/s11523-016-0450-9.

73.

Ganguly B, Dolfi SC, Rodriguez-Rodriguez L, Ganesan S, Hirshfield KM. Role of biomarkers in the development of PARP inhibitors. Biomark Cancer. 2016;8(Suppl 1):15–25. doi:10.4137/BIC.S36679.CrossRefPubMedPubMedCentral

74.

Rafii S GC, Ang JE, Kumar R, et al.. (2015) What clinical factors influence advanced BRCA1/2 mutant ovarian cancer patient (BMOC pt) outcomes to poly(ADP-ribose) polymerase inhibitor (PARPi) treatment? J Clin Oncol; 33(suppl; abstr 5546).

75.

Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008;451(7182):1111–5. doi:10.1038/nature06548.CrossRefPubMed

76.

Sakai W, Swisher EM, Jacquemont C, Chandramohan KV, Couch FJ, Langdon SP, et al. Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 2009;69(16):6381–6. doi:10.1158/0008-5472.CAN-09-1178.CrossRefPubMedPubMedCentral

77.

Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008;451(7182):1116–20. doi:10.1038/nature06633.CrossRefPubMedPubMedCentral

78.

O’Sullivan Coyne G, Chen A, Kummar S. Delivering on the promise: poly ADP ribose polymerase inhibition as targeted anticancer therapy. Curr Opin Oncol. 2015;27(6):475–81. doi:10.1097/CCO.0000000000000238.CrossRefPubMed

79.

Lord CJ, Tutt AN, Ashworth A. Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors. Annu Rev Med. 2015;66:455–70. doi:10.1146/annurev-med-050913-022545.CrossRefPubMed

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Medicine Matters Oncology

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