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DNA Repair Defects for Therapy in Ovarian Cancer: The BRCA1/2 and PARP Inhibitor Story

  • Controversies in Gynecological Cancers
  • Published:
Indian Journal of Gynecologic Oncology Aims and scope Submit manuscript

Abstract

Ovarian cancer has the highest mortality rate among all gynecologic cancers. The standard treatment for over 40 years has been surgery and chemotherapy; however, over the last decade, targeted therapies are increasingly proven effective. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are molecules that competitively block one of the DNA repair pathways by binding to PARP, and thus push the repair process to the homologous recombination pathway. In patients with a BRCA1/2 mutation, this pathway is deficient and ultimately leads to apoptosis. Patients who harbor a BRCA1/2 mutation are at higher risk of developing certain cancers such as breast and ovarian, rendering prophylactic strategies attractive in this subset of patients. PARPi have been found to be beneficial in this group of patients; recently, various international regulatory agencies have approved this class of agents as maintenance therapy or as monotherapy in the relapsed setting. Contemporary trials are ongoing in the relapsed as well as first-line setting, monotherapy and maintenance therapy or even in combination with other agents. This review focuses on the mechanisms involved in DNA repair pertinent to BRCA1/2 mutation and PAPR inhibitor therapy, the prophylactic and therapeutic advances in this field, and the opportunities available.

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References

  1. Online Analysis. [cited 2017 Apr 27]. http://globocan.iarc.fr/Pages/online.aspx.

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.

    Article  PubMed  Google Scholar 

  3. SEER Cancer Statistics Review. Previous version—SEER cancer statistics; 1975–2007. [cited 2017 May 3]. https://seer.cancer.gov/archive/csr/1975_2007/.

  4. Meric-Bernstam F, Farhangfar C, Mendelsohn J, Mills GB. Building a personalized medicine infrastructure at a major cancer center. J Clin Oncol. 2013;31(15):1849–57.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411(6835):366–74.

    Article  CAS  PubMed  Google Scholar 

  6. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15.

    Article  Google Scholar 

  7. Farmer H, McCabe N, Lord CJ, Tutt ANJ, 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.

    Article  CAS  PubMed  Google Scholar 

  8. Prevalence and penetrance of. BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer. 2000;83(10):1301–8.

    Article  Google Scholar 

  9. Whittemore AS, Gong G, John EM, McGuire V, Li FP, Ostrow KL, et al. Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev. 2004;13(12):2078–83.

    CAS  PubMed  Google Scholar 

  10. King M-C, Marks JH, Mandell JB, New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643–6.

    Article  CAS  PubMed  Google Scholar 

  11. Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. 1998 Sep 4 [Updated 2016 Dec 15]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews(®). Seattle: University of Washington; 1993 [cited 2017 Apr 8]. http://www.ncbi.nlm.nih.gov/books/NBK1247/.

  12. Kim H, Choi DH. Distribution of BRCA1 and BRCA2 Mutations in Asian Patients with Breast Cancer. J Breast Cancer. 2013;16(4):357–65.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Guo F, Hirth JM, Lin Y-L, Richardson G, Levine L, Berenson AB, et al. Use of BRCA mutation test in the US, 2004–2014. Am J Prev Med. 2017;52:702–9.

    Article  PubMed  Google Scholar 

  14. Desai S, Jena AB. Do celebrity endorsements matter? Observational study of BRCA gene testing and mastectomy rates after Angelina Jolie’s New York Times editorial. BMJ. 2016;14(355):i6357.

    Article  Google Scholar 

  15. Li X, You R, Wang X, Liu C, Xu Z, Zhou J, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: a meta-analysis and systematic review. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(15):3971–81.

    Article  CAS  Google Scholar 

  16. Karakasis K, Burnier JV, Bowering V, Oza AM, Lheureux S. Ovarian cancer and BRCA1/2 testing: opportunities to improve clinical care and disease prevention. Front Oncol. 2016; 6 [cited 2017 May 6]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862980/.

  17. Przybycin CG, Kurman RJ, Ronnett BM, Shih I-M, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010;34(10):1407–16.

    Article  PubMed  Google Scholar 

  18. Erickson BK, Conner MG, Landen CN. The role of the fallopian tube in the origin of ovarian cancer. Am J Obstet Gynecol. 2013;209(5):409–14.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Committee on Gynecologic Practice. Committee opinion no. 620: salpingectomy for ovarian cancer prevention. Obstet Gynecol. 2015;125(1):279–81.

    Article  Google Scholar 

  20. Tschernichovsky R, Goodman A. Risk-reducing strategies for ovarian cancer in BRCA mutation carriers: a balancing act. Oncologist. 2017;22(4):450–9.

    Article  CAS  PubMed  Google Scholar 

  21. King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251–6.

    Article  CAS  PubMed  Google Scholar 

  22. Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet Lond Engl. 2000;356(9245):1876–81.

    Article  CAS  Google Scholar 

  23. Amé J-C, Spenlehauer C, de Murcia G. The PARP superfamily. BioEssays News Rev Mol Cell Dev Biol. 2004;26(8):882–93.

    Article  Google Scholar 

  24. O’Sullivan Coyne G, Chen AP, Meehan R, Doroshow JH. PARP inhibitors in reproductive system cancers: current use and developments. Drugs. 2017;77(2):113–30.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011;5(4):387–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16(2):110–20.

    Article  CAS  PubMed  Google Scholar 

  27. Turner N, Tutt A, Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer. 2004;4(10):814–9.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512–9.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. Mateo J, Friedlander M, Sessa C, Leunen K, Nicum S, Gourley C, et al. Administration of continuous/intermittent olaparib in ovarian cancer patients with a germline BRCA1/2 mutation to determine an optimal dosing schedule for the tablet formulation. Eur J Cancer. 2013;49:S161–S161

    Google Scholar 

  32. Ricks TK, Chiu H-J, Ison G, Kim G, McKee AE, Kluetz P, et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol. 2015;5 [cited 2017 May 7]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604313/.

  33. Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RHJ, Sonke GS, et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol. 2015;16(1):87–97.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–84.

    Article  CAS  PubMed  Google Scholar 

  37. SGO 48th Annual Meeting on Women’s Cancer®. [cited 2017 May 7]. https://sgo.confex.com/sgo/2017/meetingapp.cgi/Paper/8718.

  38. Shen Y, Aoyagi-Scharber M, Wang B. Trapping poly(ADP-Ribose) polymerase. J Pharmacol Exp Ther. 2015;353(3):446–57.

    Article  CAS  PubMed  Google Scholar 

  39. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154–64.

    Article  CAS  PubMed  Google Scholar 

  40. Rucaparib_RKristeleit_ESMO2016.pdf. [cited 2017 May 7]. http://clovisoncology.com/files/Rucaparib_RKristeleit_ESMO2016.pdf.

  41. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2017;0(0) [cited 2017 Sep 20]. http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)32440-6/abstract.

  42. Montoni A, Robu M, Pouliot É, Shah GM. Resistance to PARP-inhibitors in cancer therapy. Front Pharmacol. 2013;27:4.

    Google Scholar 

  43. Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AOH, Zander SAL, 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 USA. 2008;105(44):17079–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kondrashova O, Nguyen M, Shield-Artin K, Tinker AV, Teng NNH, Harrell MI, et al. Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov. 2017;7(9):984–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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(1):68–81.

    Article  CAS  PubMed  Google Scholar 

  46. Liu X, Han EK, Anderson M, Shi Y, Semizarov D, Wang G, et al. Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways. MCR. 2009;7(10):1686–92.

    Article  CAS  PubMed  Google Scholar 

  47. Alotaibi M, Sharma K, Saleh T, Povirk LF, Hendrickson EA, Gewirtz DA. Radiosensitization by PARP inhibition in DNA repair proficient and deficient tumor cells: proliferative recovery in senescent cells. Radiat Res. 2016;185(3):229–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu JF, Barry WT, Birrer M, Lee J-M, Buckanovich RJ, Fleming GF, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014;15(11):1207–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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(20):3837–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  52. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(3):244–50.

    Article  CAS  Google Scholar 

  53. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol. 2012;30(4):372–9.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Gynecology and Drug Development Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada

    Sunu Lazar Cyriac

  2. Director, Clinical Cancer Research Unit and Bras Drug Development Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada

    Amit M. Oza

  3. The Princess Margaret Drug Development Program, Princess Margaret Cancer Centre, Toronto, ON, Canada

    Katherine Karakasis

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  1. Sunu Lazar Cyriac
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  2. Amit M. Oza
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  3. Katherine Karakasis
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Correspondence to Amit M. Oza.

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Cyriac, S.L., Oza, A.M. & Karakasis, K. DNA Repair Defects for Therapy in Ovarian Cancer: The BRCA1/2 and PARP Inhibitor Story. Indian J Gynecol Oncolog 15 (Suppl 1), 65–75 (2017). https://doi.org/10.1007/s40944-017-0155-8

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