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13-08-2015 | Breast cancer | Article

PARP inhibitors in the management of breast cancer: current data and future prospects

Journal: BMC Medicine

Authors: Luca Livraghi, Judy E. Garber

Publisher: BioMed Central

Abstract

Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARPs is a promising strategy for targeting cancers with defective DNA-damage repair, including BRCA1 and BRCA2 mutation-associated breast and ovarian cancers. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. We herein review the development of PARP inhibitors and the basis for the excitement surrounding these agents, their use as single agents and in combinations, as well as their toxicities, mechanisms of acquired resistance, and companion diagnostics.

Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res. 2011;17:1082–9. doi:10.1158/1078-0432.CCR-10-2560.PubMedPubMedCentral

Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012;21:134–47. doi:10.1158/1055-9965.EPI-11-0775.PubMed

Sharma P, Klemp JR, Kimler BF, Mahnken JD, Geier LJ, Khan QJ, et al. Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer Res Treat. 2014;145:707–14. doi:10.1007/s10549-014-2980-0.PubMedPubMedCentral

Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33:304–11. doi:10.1200/JCO.2014.57.1414.PubMed

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;361:123–34. doi:10.1056/NEJMoa0900212.PubMed

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;33:244–50. doi:10.1200/JCO.2014.56.2728.PubMed

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;12:852–61. doi:10.1016/S1470-2045(11)70214-5.PubMed

Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004;26:882–93. doi:10.1002/bies.20085.PubMed

De Vos M, Schreiber V, Dantzer F. The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochem Pharmacol. 2012;84:137–46. doi:10.1016/j.bcp.2012.03.018.PubMed

10.

Burkle A, Virag L. Poly(ADP-ribose): PARadigms and PARadoxes. Mol Aspects Med. 2013;34:1046–65. doi:10.1016/j.mam.2012.12.010.PubMed

11.

Caldecott KW. Single-strand break repair and genetic disease. Nat Rev Genet. 2008;9:619–31. doi:10.1038/nrg2380.PubMed

12.

Ali AA, Timinszky G, Arribas-Bosacoma R, Kozlowski M, Hassa PO, Hassler M, et al. The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks. Nat Struct Mol Biol. 2012;19:685–92. doi:10.1038/nsmb.2335.PubMedPubMedCentral

13.

Rulten SL, Fisher AE, Robert I, Zuma MC, Rouleau M, Ju L, et al. PARP-3 and APLF function together to accelerate nonhomologous end-joining. Mol Cell. 2011;41:33–45. doi:10.1016/j.molcel.2010.12.006.PubMed

14.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. doi:10.1016/j.cell.2011.02.013.PubMed

15.

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;434:913–7. doi:10.1038/nature03443.PubMed

16.

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;434:917–21. doi:10.1038/nature03445.PubMed

17.

Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011;5:387–93. doi:10.1016/j.molonc.2011.07.001.PubMed

18.

Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72:5588–99. doi:10.1158/0008-5472.CAN-12-2753.PubMedPubMedCentral

19.

Tutt AN, Lord CJ, McCabe N, Farmer H, Turner N, Martin NM, et al. Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb Symp Quant Biol. 2005;70:139–48. doi:10.1101/sqb.2005.70.012.PubMed

20.

Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4:814–9. doi:10.1038/nrc1457.PubMed

21.

Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell. 2006;9:121–32. doi:10.1016/j.ccr.2006.01.013.PubMed

22.

Sonnenblick A, de Azambuja E, Azim Jr HA, Piccart M. An update on PARP inhibitors-moving to the adjuvant setting. Nat Rev Clin Oncol. 2015;12:27–41. doi:10.1038/nrclinonc.2014.163.PubMed

23.

Balmana J, Tung NM, Isakoff SJ, Grana B, Ryan PD, Saura C, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol. 2014;25:1656–63. doi:10.1093/annonc/mdu187.PubMed

24.

Del Conte G, Sessa C, von Moos R, Vigano L, Digena T, Locatelli A, et al. Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours. Br J Cancer. 2014;111:651–9. doi:10.1038/bjc.2014.345.PubMedPubMedCentral

25.

O’Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, et al. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014;32:3840–7. doi:10.1200/JCO.2014.55.2984.PubMed

26.

Patel AG, De Lorenzo SB, Flatten KS, Poirier GG, Kaufmann SH. Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin Cancer Res. 2012;18:1655–62. doi:10.1158/1078-0432.CCR-11-2890.PubMedPubMedCentral

27.

Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res. 2006;8:R38. doi:10.1186/bcr1522.PubMedPubMedCentral

28.

McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66:8109–15. doi:10.1158/0008-5472.CAN-06-0140.PubMed

29.

Lukas J, Lukas C, Bartek J. More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nat Cell Biol. 2011;13:1161–9. doi:10.1038/ncb2344.PubMed

30.

Isakoff SJ, Overmoyer B, Tung NM, Gelman RS, Habin K, Qian J, et al. A phase II trial expansion cohort of the PARP inhibitor veliparib (ABT888) and temozolomide in BRCA1/2 associated metastatic breast cancer. Cancer Res. 2011;71:P3-16-05.

31.

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;14:882–92. doi:10.1016/S1470-2045(13)70240-7.PubMed

32.

De Bono JS, Mina LA, Gonzalez M, Curtin NJ, Wang E, Henshaw JW, et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. J Clin Oncol. 2013;31:2580.

33.

Kristeleit RS, Burris HA, LoRusso P, Patel MR, Asghar US, El-Khouly F, et al. Phase 1/2 study of oral rucaparib: final phase 1 results. J Clin Oncol. 2014;32:2573.

34.

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;376:235–44. doi:10.1016/S0140-6736(10)60892-6.PubMed

35.

Ershler WB. Capecitabine monotherapy: safe and effective treatment for metastatic breast cancer. Oncologist. 2006;11:325–35. doi:10.1634/theoncologist.11-4-325.PubMed

36.

Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, et al. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007;8:219–25. doi:10.1016/S1470-2045(07)70041-4.PubMed

37.

Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377:914–23. doi:10.1016/S0140-6736(11)60070-6.PubMed

38.

Low JA, Wedam SB, Lee JJ, Berman AW, Brufsky A, Yang SX, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol. 2005;23:2726–34. doi:10.1200/JCO.2005.10.024.PubMed

39.

Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25:3407–14. doi:10.1200/JCO.2006.09.3849.PubMed

40.

Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol. 2007;25:3399–406. doi:10.1200/JCO.2006.08.9102.PubMed

41.

Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010;28:1138–44. doi:10.1200/JCO.2009.24.2024.PubMedPubMedCentral

42.

Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91. doi:10.1056/NEJMoa1209124.PubMed

43.

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;376:245–51. doi:10.1016/S0140-6736(10)60893-8.PubMed

44.

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;366:1382–92. doi:10.1056/NEJMoa1105535.PubMed

45.

Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, et al. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer. 2013;49:2972–8. doi:10.1016/j.ejca.2013.05.020.PubMedPubMedCentral

46.

Press JZ, De Luca A, Boyd N, Young S, Troussard A, Ridge Y, et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer. 2008;8:17. doi:10.1186/1471-2407-8-17.PubMedPubMedCentral

47.

National Cancer Institute. Veliparib with or without carboplatin in treating patients with stage III or stage IV breast cancer. https://www.clinicaltrials.gov/ct2/show/NCT01149083. Accessed 15 Jun 2015.

48.

Abbvie. A study evaluating veliparib as a single agent or in combination with chemotherapy in subjects with solid tumors. https://www.clinicaltrials.gov/ct2/show/NCT02033551. Accessed 15 Jun 2015.

49.

Coleman RL, Sill MW, Bell-McGuinn K, Aghajanian C, Gray HJ, Tewari KS, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015;137:386–91. doi:10.1016/j.ygyno.2015.03.042.PubMedPubMedCentral

50.

Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13:2728–37. doi:10.1158/1078-0432.CCR-06-3039.PubMed

51.

Palma JP, Wang YC, Rodriguez LE, Montgomery D, Ellis PA, Bukofzer G, et al. ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumors. Clin Cancer Res. 2009;15:7277–90. doi:10.1158/1078-0432.CCR-09-1245.PubMed

52.

Isakoff SJ, Overmoyer B, Tung NM, Gelman RS, Giranda VL, Bernhard KM, et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin Oncol. 2010;28:1019.

53.

Rodler ET, Gralow J, Kurland BF, Griffin M, Yeh R, Thompson JA, et al. Phase I: Veliparib with cisplatin (CP) and vinorelbine (VNR) in advanced triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer. J Clin Oncol. 2014;32:2569.

54.

Somlo G, Frankel PH, Luu TH, Ma C, Arun B, Garcia A, et al. Efficacy of the combination of ABT-888 (veliparib) and carboplatin in patients with BRCA-associated breast cancer. J Clin Oncol. 2013;31:1024.

55.

Pahuja S, Beumer JH, Appleman LJ, Tawbi HA, Stoller RG, Lee JJ, et al. A phase I study of veliparib (ABT-888) in combination with weekly carboplatin and paclitaxel in advanced solid malignancies and enriched for triple-negative breast cancer (TNBC). J Clin Oncol. 2015;33:1015.

56.

Kummar S, Chen A, Ji J, Zhang Y, Reid JM, Ames M, et al. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res. 2011;71:5626–34. doi:10.1158/0008-5472.CAN-11-1227.PubMedPubMedCentral

57.

Samol J, Ranson M, Scott E, Macpherson E, Carmichael J, Thomas A, et al. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Invest New Drugs. 2012;30:1493–500. doi:10.1007/s10637-011-9682-9.PubMed

58.

Murai J, Zhang Y, Morris J, Ji J, Takeda S, Doroshow JH, et al. Rationale for poly(ADP-ribose) polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition. J Pharmacol Exp Ther. 2014;349:408–16. doi:10.1124/jpet.113.210146.PubMedPubMedCentral

59.

Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008;105:17079–84. doi:10.1073/pnas.0806092105.PubMedPubMedCentral

60.

Tesaro, Inc. A phase III trial of niraparib versus physician’s choice in Her2 negative, germline BRCA mutation-positive breast cancer patients (BRAVO). https://clinicaltrials.gov/ct2/show/NCT01905592. Accessed 15 Jun 2015.

61.

BioMarin Pharmaceutical. A study evaluating talazoparib (BMN 673), a PARP inhibitor, in advanced and/or metastatic breast cancer patients with BRCA mutation (EMBRACA Study). https://clinicaltrials.gov/ct2/show/NCT01945775. Accessed 15 Jun 2015.

62.

AstraZeneca. Assessment of the efficacy and safety of olaparib monotherapy versus physicians choice chemotherapy in the treatment of metastatic breast cancer patients with germline BRCA1/2 mutations. (OlympiAD). https://clinicaltrials.gov/ct2/show/NCT02000622. Accessed 15 Jun 2015.

63.

AbbVie. A phase 3 randomized, placebo-controlled trial of carboplatin and paclitaxel with or without veliparib (ABT-888) in HER2-negative metastatic or locally advanced unresectable BRCA-associated breast cancer. https://clinicaltrials.gov/ct2/show/NCT02163694. Accessed 15 Jun 2015.

64.

European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003726/smops/Positive/human_smop_000744.jsp&mid=WC0b01ac058001d127. Accessed 15 Jan 2015.

65.

U. S. Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427554.htm. Accessed 15 Jan 2015.

66.

Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol. 2015;16:87–97. doi:10.1016/S1470-2045(14)71135-0.PubMed

67.

Tutt A, Kaufman B, Gelber R, McFadden E, Goessl CD, Viale G, et al. OlympiA: A randomized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm). J Clin Oncol. 2015;33, TPS1109.

68.

AstraZeneca. Olaparib as adjuvant treatment in patients with germline BRCA mutated high risk HER2 negative primary breast cancer (OlympiA). https://clinicaltrials.gov/ct2/show/NCT02032823. Accessed 15 Jun 2015.

69.

Hoosier Cancer Research Network. PARP inhibition for triple negative breast cancer (ER-/PR-/HER2-) with BRCA1/2 mutations. https://clinicaltrials.gov/ct2/show/NCT01074970. Accessed 15 Jun 2015.

70.

Dwadasi S, Tong Y, Walsh T, Danso MA, Ma CX, Silverman P, et al. Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple-negative breast cancer (TNBC): Hoosier Oncology Group BRE09-146. J Clin Oncol. 2014;32:1019.

71.

Rugo HS, Olopade O, DeMichele A, van’t Veer L, Buxton M, Hylton N, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: first efficacy results from the I-SPY 2 TRIAL. Cancer Res. 2013;73:S5–02.

72.

von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15:747–56. doi:10.1016/S1470-2045(14)70160-3.

73.

Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, et al. Impact of the addition of carboplatin and/or Bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (alliance). J Clin Oncol. 2015;33:13–21. doi:10.1200/JCO.2014.57.0572.PubMed

74.

AbbVie. A study evaluating safety and efficacy of the addition of ABT-888 plus carboplatin versus the addition of carboplatin to standard chemotherapy versus standard chemotherapy in subjects with early stage triple negative breast cancer. https://clinicaltrials.gov/ct2/show/NCT02032277. Accessed 15 Jun 2015.

75.

BioMarin Pharmaceutical. Neoadjuvant bmn673 for patients with a BRCA deleterious mutation. https://www.clinicaltrials.gov/ct2/show/NCT02282345. Accessed 15 Jun 2015.

76.

To C, Kim EH, Royce DB, Williams CR, Collins RM, Risingsong R, et al. The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice. Cancer Prev Res (Phila). 2014;7:698–707. doi:10.1158/1940-6207.CAPR-14-0047.

77.

Khan OA, Gore M, Lorigan P, Stone J, Greystoke A, Burke W, et al. A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br J Cancer. 2011;104:750–5. doi:10.1038/bjc.2011.8.PubMedPubMedCentral

78.

Rajan A, Carter CA, Kelly RJ, Gutierrez M, Kummar S, Szabo E, et al. A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res. 2012;18:2344–51. doi:10.1158/1078-0432.CCR-11-2425.PubMed

79.

Dean E, Middleton MR, Pwint T, Swaisland H, Carmichael J, Goodege-Kunwar P, et al. Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Br J Cancer. 2012;106:468–74. doi:10.1038/bjc.2011.555.PubMedPubMedCentral

80.

Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68.PubMed

81.

Lowndes NF, Toh GW. DNA repair: the importance of phosphorylating histone H2AX. Curr Biol. 2005;15:R99–R102. doi:10.1016/j.cub.2005.01.029.PubMed

82.

Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, et al. GammaH2AX and cancer. Nat Rev Cancer. 2008;8:957–67. doi:10.1038/nrc2523.PubMedPubMedCentral

83.

Chiarugi A. A snapshot of chemoresistance to PARP inhibitors. Trends Pharmacol Sci. 2012;33:42–8. doi:10.1016/j.tips.2011.10.001.PubMed

84.

Bouwman P, Jonkers J. Molecular pathways: how can BRCA-mutated tumors become resistant to PARP inhibitors? Clin Cancer Res. 2014;20:540–7. doi:10.1158/1078-0432.CCR-13-0225.PubMed

85.

Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med. 2013;19:1381–8. doi:10.1038/nm.3369.PubMed

86.

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;451:1111–5. doi:10.1038/nature06548.PubMed

87.

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;69:6381–6. doi:10.1158/0008-5472.CAN-09-1178.PubMedPubMedCentral

88.

Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008;68:2581–6. doi:10.1158/0008-5472.CAN-08-0088.PubMedPubMedCentral

89.

Wurzer G, Herceg Z, Wesierska-Gadek J. Increased resistance to anticancer therapy of mouse cells lacking the poly(ADP-ribose) polymerase attributable to up-regulation of the multidrug resistance gene product P-glycoprotein. Cancer Res. 2000;60:4238–44.PubMed

90.

Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol. 2010;17:688–95. doi:10.1038/nsmb.1831.PubMedPubMedCentral

91.

Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A, et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell. 2010;141:243–54. doi:10.1016/j.cell.2010.03.012.PubMedPubMedCentral

92.

Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L, Zander SA, et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 2013;3:68–81. doi:10.1158/2159-8290.CD-12-0049.PubMed

93.

Oplustilova L, Wolanin K, Mistrik M, Korinkova G, Simkova D, Bouchal J, et al. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment. Cell Cycle. 2012;11:3837–50. doi:10.4161/cc.22026.PubMedPubMedCentral

94.

Norquist B, Wurz KA, Pennil CC, Garcia R, Gross J, Sakai W, et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29:3008–15. doi:10.1200/JCO.2010.34.2980.PubMedPubMedCentral

95.

Ang JE, Gourley C, Powell CB, High H, Shapira-Frommer R, Castonguay V, et al. Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study. Clin Cancer Res. 2013;19:5485–93. doi:10.1158/1078-0432.CCR-13-1262.PubMed

96.

AbbVie. The study evaluating efficacy and tolerability of veliparib in combination with temozolomide or in combination with carboplatin and paclitaxel versus placebo in subjects with BRCA1 and BRCA2 mutation and metastatic breast cancer. https://clinicaltrials.gov/ct2/show/NCT01506609. Accessed 15 Jun 2015.

97.

PARP inhibitor BMN-673 in treating patients with BRCA1 and BRCA2 wild-type, metastatic or recurrent, triple-negative or HER2-negative breast cancer. https://clinicaltrials.gov/ct2/show/NCT02401347. Accessed 15 Jun 2015.

98.

Johnson N, Li YC, Walton ZE, Cheng KA, Li D, Rodig SJ, et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med. 2011;17:875–82. doi:10.1038/nm.2377.PubMedPubMedCentral

99.

Timms KM, Abkevich V, Hughes E, Neff C, Reid J, Morris B, et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 2014;16:475. doi:10.1186/s13058-014-0475-x.PubMedPubMedCentral

100.

Richardson AL, Silver DP, Szallasi Z, Birkbak NJ, Wang ZC, Iglehart JD, et al. Homologous recombination deficiency (HRD) score predicts response to cisplatin neoadjuvant chemotherapy in patients with triple negative breast cancer. San Antonio Breast Cancer Symposium Proceedings. 2014;2014:P3-06-11.

101.

Telli ML, Timms K, Reid JE, Neff C, Abkevich V, Gutin A, et al. Combined homologous recombination deficiency (HRD) scores and response to neoadjuvant platinum-based chemotherapy in triple-negative and/or BRCA1/2 mutation-associated breast cancer. J Clin Oncol. 2015;33:1018.

102.

von Minckwitz G, Timms K, Untch M, Elkin EP, Fasching PA, Schneeweiss A, et al. Prediction of pathological complete response (pCR) by homologous recombination deficiency (HRD) after carboplatin-containing neoadjuvant chemotherapy in patients with TNBC: results from GeparSixto. J Clin Oncol. 2015;33:1004.

103.

Tutt A, Ellis P, Kilburn L, Gilett C, Pinder S, Abraham J, et al. TNT: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). San Antonio Breast Cancer Symposium Proceedings. 2014;2014:S3–01.

104.

Cisplatin vs paclitaxel for triple neg. https://clinicaltrials.gov/show/NCT01982448. Accessed 15 Jun 2015.

105.

Phase II study of BMN 673. https://clinicaltrials.gov/ct2/show/NCT02286687. Accessed 15 Jun 2015.

106.

Gottipati P, Vischioni B, Schultz N, Solomons J, Bryant HE, Djureinovic T, et al. Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cells. Cancer Res. 2010;70:5389–98. doi:10.1158/0008-5472.CAN-09-4716.PubMed

107.

Balmana J, Domchek SM, Tutt A, Garber JE. Stumbling blocks on the path to personalized medicine in breast cancer: the case of PARP inhibitors for BRCA1/2-associated cancers. Cancer Discov. 2011;1:29–34. doi:10.1158/2159-8274.CD-11-0048.PubMed

108.

Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014;25:32–40. doi:10.1093/annonc/mdt384.PubMed

109.

Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, et al. miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011;41:210–20. doi:10.1016/j.molcel.2010.12.005.PubMed

110.

Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1:315–22. doi:10.1002/emmm.200900041.PubMedPubMedCentral

111.

Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJ, et al. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood. 2010;116:4578–87. doi:10.1182/blood-2010-01-265769.PubMed

112.

Williamson CT, Muzik H, Turhan AG, Zamo A, O’Connor MJ, Bebb DG, et al. ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors. Mol Cancer Ther. 2010;9:347–57. doi:10.1158/1535-7163.MCT-09-0872.PubMedPubMedCentral

113.

Ha K, Fiskus W, Choi DS, Bhaskara S, Cerchietti L, Devaraj SG, et al. Histone deacetylase inhibitor treatment induces ‘BRCAness’ and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget. 2014;5:5637–50.PubMedPubMedCentral

114.

Veliparib and dinaciclib with or without carboplatin in treating patients with advanced solid tumors. https://clinicaltrials.gov/ct2/show/NCT01434316. Accessed 15 Jun 2015.

115.

De P, Sun Y, Carlson JH, Friedman LS, Leyland-Jones BR, Dey N. Doubling down on the PI3K-AKT-mTOR pathway enhances the antitumor efficacy of PARP inhibitor in triple negative breast cancer model beyond BRCA-ness. Neoplasia. 2014;16:43–72.PubMedPubMedCentral

116.

Phase I study of the oral PI3kinase inhibitor BKM120 or BYL719 and the oral PARP inhibitor olaparib in patients with recurrent triple negative breast cancer or high grade serous ovarian cancer. https://clinicaltrials.gov/ct2/show/NCT01623349. Accessed 15 Jun 2015.

117.

Liu L, Zhou W, Cheng CT, Ren X, Somlo G, Fong MY, et al. TGFbeta induces ‘BRCAness’ and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes. Mol Cancer Res. 2014;12:1597–609. doi:10.1158/1541-7786.MCR-14-0201.PubMedPubMedCentral

118.

Matulonis U, Wulf G, Barry W, Birrer M, Westin S, Spagnoletti T, et al. Phase I of oral BKM120 or BLY719 and olaparib for high-grade serous ovarian cancer or triple-negative breast cancer: Final results of the BKM120 plus olaparib cohort. Proceedings of the 106th Annual Meeting of the American Association for Cancer Research. 2015 Apr 18–22:CT324.

119.

Yamamoto N, Nokihara H, Yamada Y, Goto Y, Tanioka M, Shibata T, et al. A phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer Sci. 2012;103:504–9. doi:10.1111/j.1349-7006.2011.02179.x.PubMed

120.

Pahuja S, Beumer JH, Appleman LJ, Tawbi HA, Stoller RG, Lee JJ, et al. Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCA-wt) breast cancer patients in a phase I study of single-agent veliparib (V). J Clin Oncol. 2014;32:135.

121.

Drew Y, Ledermann JA, Jones A, Hall G, Jayson GC, Highley M, et al. Phase II trial of the poly(ADP-ribose) polymerase (PARP) inhibitor AG-014699 in BRCA-1 and -2 mutated, advanced ovarian and/or locally advanced or metastatic breast cancer. J Clin Oncol. 2011;29:3104.

122.

Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A, McCarthy NJ, et al. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res. 2013;15:R88. doi:10.1186/bcr3484.PubMedPubMedCentral

123.

Lee JM, Hays JL, Annunziata CM, Noonan AM, Minasian L, Zujewski JA, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst. 2014;106:dju089.

124.

Appleman LJ, Beumer JH, Jiang Y, Puhalla S, Lin Y, Owonikoko TK, et al. A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies. J Clin Oncol. 2012;30:3049.

125.

Tan AR, Toppmeyer D, Stein MN, Moss RA, Gounder M, Lindquist DC, et al. Phase I trial of veliparib, (ABT-888), a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with doxorubicin and cyclophosphamide in breast cancer and other solid tumors. J Clin Oncol. 2011;29:3041.

126.

Bell-McGuinn KM, Gray HJ, Fleming GF, Cristea MC, Medina DM, Xiong H, et al. Phase I study of ABT-888 in combination with carboplatin and gemcitabine in subjects with advanced solid tumors. J Clin Oncol. 2013;31:2584.

127.

Wesolowski R, Zhao M, Geyer SM, Lustberg MB, Mrozek E, Layman RM, et al. Phase I trial of the PARP inhibitor veliparib (V) in combination with carboplatin (C) in metastatic breast cancer (MBC). J Clin Oncol. 2014;32:1075.

128.

Kummar S, Ji J, Morgan R, Lenz HJ, Puhalla SL, Belani CP, et al. A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res. 2012;18:1726–34. doi:10.1158/1078-0432.CCR-11-2821.PubMedPubMedCentral

129.

Molife LR, Roxburgh P, Wilson RH, Gupta A, Middleton MR, Evans TRJ, et al. A phase I study of oral rucaparib in combination with carboplatin. J Clin Oncol. 2013;31:2586.

130.

Plummer R, Stephens P, Aissat-Daudigny L, Cambois A, Moachon G, Brown PD, et al. Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors. Cancer Chemother Pharmacol. 2014;74:257–65. doi:10.1007/s00280-014-2486-9.PubMedPubMedCentral

131.

BioMarin Pharmaceutical. A phase 2, 2-stage, 2-cohort study of talazoparib (BMN 673), in locally advanced and/or metastatic breast cancer patients with BRCA mutation (ABRAZO Study). https://clinicaltrials.gov/ct2/show/NCT02034916. Accessed 15 Jun 2015.

132.

Cancer Research UK. Rucaparib (CO-338; formally called AG-014699 or PF-0136738) in treating patients with locally advanced or metastatic breast cancer or advanced ovarian cancer. https://clinicaltrials.gov/ct2/show/NCT00664781. Accessed 15 Jun 2015.

133.

PARP inhibition for triple negative breast cancer (ER-/PR-/HER2-) with BRCA1/2 mutations. https://clinicaltrials.gov/ct2/show/NCT01074970. Accessed 15 Jun 2015.

134.

Bundred N, Gardovskis J, Jaskiewicz J, Eglitis J, Paramonov V, McCormack P, et al. Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery. Invest New Drugs. 2013;31:949–58. doi:10.1007/s10637-012-9922-7.PubMed

135.

Kummar S, Kinders R, Gutierrez ME, Rubinstein L, Parchment RE, Phillips LR, et al. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol. 2009;27:2705–11. doi:10.1200/JCO.2008.19.7681.PubMedPubMedCentral

Medicine Matters Oncology

Abstract