Clinical Pharmacokinetics

, Volume 57, Issue 4, pp 427–437 | Cite as

PARP Inhibitors in the Treatment of Triple-Negative Breast Cancer

  • Jill J. J. Geenen
  • Sabine C. Linn
  • Jos H. Beijnen
  • Jan H. M. SchellensEmail author
Review Article


Breast cancer is a heterogeneous disease, manifesting in a broad differentiation in phenotypes and morphologic profiles, resulting in variable clinical behavior. Between 10 and 20% of all breast cancers are triple negative. Triple-negative breast cancer (TNBC) lacks the expression of human epidermal growth factor receptor 2 (HER2) and hormone receptors; therefore, to date, chemotherapy remains the backbone of treatment. TNBC tends to be aggressive and has a high histological grade, resulting in a poor 5-year prognosis. It has a high prevalence of BRCA1 mutations and an increased Ki-67 expression. This subtype usually responds well to taxanes and/or platinum compounds and poly (ADP-ribose) polymerase (PARP) inhibitors. Studies with PARP inhibitors have demonstrated promising results in the treatment of BRCA-mutated breast and ovarian cancer, and PARP inhibitors have been studied as monotherapy and in combination with cytotoxic therapy or radiotherapy. PARP inhibitor efficacy on poly (ADP-ribose) polymer (PAR) formation in vivo can be quantified by pharmacodynamic assays that measure PAR activity in peripheral blood mononuclear cells (PBMC). Biomarkers such as TP53, ATM, PALB2 and RAD51C might be prognostic or predictive indicators for treatment response, and could also provide targets for novel treatment strategies. In summary, this review provides an overview of the treatment options for basal-like TNBC, including PARP inhibitors, and focuses on the pharmacotherapeutic options in these patients.


Compliance with Ethical Standards


No funding was provided for the preparation of this article.

Conflicts of Interest

Jill J. J. Geenen, Jan H. M. Schellens and Jos H. Beijnen declare no conflicts of interest. Sabine C. Linn received a research grant and study drug (olaparib) for the REVIVAL study (NCT02810743), and is a member of the advisory board for olaparib in breast cancer (paid to institution), Dr. Linn also has a patent (means and methods for molecular classification of BRCA-like breast and/or ovarian cancer).


  1. 1.
    World Health Organization. Breast cancer, global health estimates. Geneva: World Health Organization; 2013.Google Scholar
  2. 2.
    Liu M, Li Z, Yang J, Jiang Y, Chen Z, Ali Z, et al. Cell-specific biomarkers and targeted biopharmaceuticals for breast cancer treatment. Cell Prolif. 2016;49(4):409–20.CrossRefPubMedGoogle Scholar
  3. 3.
    Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105–17.PubMedGoogle Scholar
  4. 4.
    Tang Y, Wang Y, Kiani MF, Wang B. Classification, treatment strategy, and associated drug resistance in breast cancer. Clin Breast Cancer. 2016;16(5):335–43.CrossRefPubMedGoogle Scholar
  5. 5.
    Jia LY, Shanmugam MK, Sethi G, Bishayee A. Potential role of targeted therapies in the treatment of triple-negative breast cancer. Anticancer Drugs. 2016;27(3):147–55.CrossRefPubMedGoogle Scholar
  6. 6.
    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig. 2011;121(7):2750–67.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8):1275–81.CrossRefPubMedGoogle Scholar
  8. 8.
    Lips EH, Mulder L, Hannemann J, Laddach N, Vrancken Peeters MT, van de Vijver MJ, et al. Indicators of homologous recombination deficiency in breast cancer and association with response to neoadjuvant chemotherapy. Ann Oncol. 2011;22(4):870–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Helleday T. Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis. 2010;31(6):955–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Bunting SF, Callen E, Kozak ML, Kim JM, Wong N, Lopez-Contreras AJ, et al. BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol Cell. 2012;46(2):125–35.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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(6):688–95.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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(22):3008–15.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med. 2013;19(11):1381–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Kennedy RD, Quinn JE, Mullan PB, Johnston PG, Harkin DP. The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst. 2004;96(22):1659–68.CrossRefPubMedGoogle Scholar
  15. 15.
    Rottenberg S, Nygren AO, Pajic M, van Leeuwen FW, van der Heijden I, van de Wetering K, et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci USA. 2007;104(29):12117–22.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    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 USA. 2008;105(44):17079–84.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Evers B, Helleday T, Jonkers J. Targeting homologous recombination repair defects in cancer. Trends Pharmacol Sci. 2010;31(8):372–80.CrossRefPubMedGoogle Scholar
  18. 18.
    Lewin R, Sulkes A, Shochat T, Tsoref D, Rizel S, Liebermann N, et al. Oncotype-DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations. Breast Cancer Res Treat. 2016;157(3):511–6.CrossRefPubMedGoogle Scholar
  19. 19.
    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(3):707–14.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Murphy CG, Moynahan ME. BRCA gene structure and function in tumor suppression: a repair-centric perspective. Cancer J. 2010;16(1):39–47.CrossRefPubMedGoogle Scholar
  21. 21.
    Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4(10):814–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Andreopoulou E, Schweber SJ, Sparano JA, McDaid HM. Therapies for triple negative breast cancer. Expert Opin Pharmacother. 2015;16(7):983–98.CrossRefPubMedGoogle Scholar
  23. 23.
    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(1):13–21.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    Byrski T, Dent R, Blecharz P, Foszczynska-Kloda M, Gronwald J, Huzarski T, et al. Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res. 2012;14(4):R110.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28(3):375–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Bal A, Verma S, Joshi K, Singla A, Thakur R, Arora S, et al. BRCA1-methylated sporadic breast cancers are BRCA-like in showing a basal phenotype and absence of ER expression. Virchows Arch. 2012;461(3):305–12.CrossRefPubMedGoogle Scholar
  28. 28.
    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(4):R38.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wei M, Grushko TA, Dignam J, Hagos F, Nanda R, Sveen L, et al. BRCA1 promoter methylation in sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy. Cancer Res. 2005;65(23):10692–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Lips EH, Mulder L, Oonk A, van der Kolk LE, Hogervorst FB, Imholz AL, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer. 2013;108(10):2172–7.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Metzger-Filho O, Tutt A, de Azambuja E, Saini KS, Viale G, Loi S, et al. Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol. 2012;30(15):1879–87.CrossRefPubMedGoogle Scholar
  32. 32.
    Lu W, Wang X, Lin H, Lindor NM, Couch FJ. Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer. 2012;11(3):381–5.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Gilardini Montani MS, Prodosmo A, Stagni V, Merli D, Monteonofrio L, Gatti V, et al. ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition. J Exp Clin Cancer Res. 2013;32:95.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lehmann BD, Pietenpol JA, Tan AR. Triple-negative breast cancer: molecular subtypes and new targets for therapy. In: American Society of Clinical Oncology educational book/ASCO American Society of Clinical Oncology meeting. 2015. p. e31–9.Google Scholar
  36. 36.
    Chakravarthy AB, Kelley MC, McLaren B, Truica CI, Billheimer D, Mayer IA, et al. Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer. Clin Cancer Res. 2006;12(5):1570–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Bauer JA, Chakravarthy AB, Rosenbluth JM, Mi D, Seeley EH, De Matos Granja-Ingram N, et al. Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation. Clin Cancer Res. 2010;16(2):681–90.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087–106.CrossRefPubMedGoogle Scholar
  39. 39.
    Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res. 2013;19(19):5533–40.CrossRefPubMedGoogle Scholar
  40. 40.
    Holstege H, Horlings HM, Velds A, Langerod A, Borresen-Dale AL, van de Vijver MJ, et al. BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations. BMC Cancer. 2010;10:654.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene. 2007;26(14):2126–32.CrossRefPubMedGoogle Scholar
  42. 42.
    Hill SJ, Clark AP, Silver DP, Livingston DM. BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol. 2014;34(20):3828–42.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Turner NC, Reis-Filho JS. Basal-like breast cancer and the BRCA1 phenotype. Oncogene. 2006;25(43):5846–53.CrossRefPubMedGoogle Scholar
  44. 44.
    Joosse SA, van Beers EH, Tielen IH, Horlings H, Peterse JL, Hoogerbrugge N, et al. Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH. Breast Cancer Res Treat. 2009;116(3):479–89.CrossRefPubMedGoogle Scholar
  45. 45.
    Waddell N, Arnold J, Cocciardi S, da Silva L, Marsh A, Riley J, et al. Subtypes of familial breast tumours revealed by expression and copy number profiling. Breast Cancer Res Treat. 2010;123(3):661–77.CrossRefPubMedGoogle Scholar
  46. 46.
    Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H, Ingvarsson S, Karhu R, et al. Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res. 1997;57(7):1222–7.PubMedGoogle Scholar
  47. 47.
    Jonsson G, Naylor TL, Vallon-Christersson J, Staaf J, Huang J, Ward MR, et al. Distinct genomic profiles in hereditary breast tumors identified by array-based comparative genomic hybridization. Cancer Res. 2005;65(17):7612–21.CrossRefPubMedGoogle Scholar
  48. 48.
    Vollebergh MA, Lips EH, Nederlof PM, Wessels LF, Schmidt MK, van Beers EH, et al. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann Oncol. 2011;22(7):1561–70.CrossRefPubMedGoogle Scholar
  49. 49.
    Vollebergh MA, Lips EH, Nederlof PM, Wessels LF, Wesseling J, Vd Vijver MJ, et al. Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy. Breast Cancer Res. 2014;16(3):R47.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    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.CrossRefPubMedGoogle Scholar
  51. 51.
    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.CrossRefPubMedGoogle Scholar
  52. 52.
    Clarkson-Jones J PC, Sarda S, et al. Human biotransformation of olaparib (AZD2281) an oral poly(ADP-ribose) polymerase (PARP) inhibitor [abstract no. 417]. In: 22nd EORTC-NCI-AACR symposium on molecular targets and cancer therapeutics. 2010.Google Scholar
  53. 53.
    Ang JE C-JJ, Swaisland H, et al. A mass balance study to investigate the metabolism, excreation and pharmacokinetics of [14]-olaparib (AZD2281) in patients with advanced solid tumours refractory to standard treatments [abstract no. 405]. In: 22nd EORTC-NCI-AACR symposium on molecular targets and cancer therapeutics. 2010.Google Scholar
  54. 54.
    Dirix L, Swaisland H, Verheul HM, Rottey S, Leunen K, Jerusalem G, et al. Effect of itraconazole and rifampin on the pharmacokinetics of olaparib in patients with advanced solid tumors: results of two phase I open-label studies. Clin Ther. 2016;38(10):2286–99.CrossRefPubMedGoogle Scholar
  55. 55.
    Lee JM, Peer CJ, Yu M, Amable L, Gordon N, Annunziata CM, et al. Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in women’s cancer. Clin Cancer Res. 2017;23(6):1397–406.CrossRefPubMedGoogle Scholar
  56. 56.
    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.CrossRefPubMedGoogle Scholar
  57. 57.
    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.CrossRefPubMedGoogle Scholar
  58. 58.
    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.CrossRefPubMedGoogle Scholar
  59. 59.
    Plummer R, Swaisland H, Leunen K, van Herpen CM, Jerusalem G, De Greve J, et al. Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. Cancer Chemother Pharmacol. 2015;76(4):723–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33. doi: 10.1056/NEJMoa1706450.CrossRefPubMedGoogle Scholar
  61. 61.
    Rugo HS, Olopade OI, DeMichele A, Yau C, van ‘t Veer LJ, Buxton MB, et al. Adaptive randomization of veliparib–carboplatin treatment in breast cancer. N Engl J Med. 2016;375(1):23–34.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Mizugaki H, Yamamoto N, Nokihara H, Fujiwara Y, Horinouchi H, Kanda S, et al. A phase 1 study evaluating the pharmacokinetics and preliminary efficacy of veliparib (ABT-888) in combination with carboplatin/paclitaxel in Japanese subjects with non-small cell lung cancer (NSCLC). Cancer Chemother Pharmacol. 2015;76(5):1063–72.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Nuthalapati S, Munasinghe W, Giranda V, Xiong H. Clinical pharmacokinetics and mass balance of veliparib in combination with temozolomide in subjects with nonhematologic malignancies. Clin Pharmacokinet. 2017. doi: 10.1007/s40262-017-0547-z.
  64. 64.
    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(3):386–91.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Jones P, Altamura S, Boueres J, Ferrigno F, Fonsi M, Giomini C, et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009;52(22):7170–85.CrossRefPubMedGoogle Scholar
  66. 66.
    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.CrossRefPubMedGoogle Scholar
  67. 67.
    van Andel L, Zhang Z, Lu S, Kansra V, Agarwal S, Hughes L, et al. Human mass balance study and metabolite profiling of 14C-niraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer. Investig New Drugs. 2017. doi: 10.1007/s10637-017-0451-2.Google Scholar
  68. 68.
    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(1):87–97.CrossRefPubMedGoogle Scholar
  69. 69.
    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(4):651–9.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    van der Noll R, Marchetti S, Steeghs N, Beijnen JH, Mergui-Roelvink MW, Harms E, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer. 2015;113(3):396–402.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Do K, Doroshow JH, Kummar S. Wee1 kinase as a target for cancer therapy. Cell Cycle. 2013;12(19):3159–64.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Leijen S, Beijnen JH, Schellens JH. Abrogation of the G2 checkpoint by inhibition of Wee-1 kinase results in sensitization of p53-deficient tumor cells to DNA-damaging agents. Curr Clin Pharmacol. 2010;5(3):186–91.CrossRefPubMedGoogle Scholar
  73. 73.
    Leijen S, van Geel RM, Pavlick AC, Tibes R, Rosen L, Razak AR, et al. Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J Clin Oncol. 2016;34(36):4371–80.CrossRefPubMedGoogle Scholar
  74. 74.
    Leijen S, van Geel RMJM, Sonke GS, de Jong D, Rosenberg EH, Marchetti S, et al. Phase II study of WEE1 inhibitor AZD1775 plus carboplatin in patients with TP53-mutated ovarian cancer refractory or resistant to first-line therapy within 3 months. J Clin Oncol. 2016;34(36):4354–61.CrossRefPubMedGoogle Scholar
  75. 75.
    Karnak D, Engelke CG, Parsels LA, Kausar T, Wei D, Robertson JR, et al. Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer. Clin Cancer Res. 2014;20(19):5085–96.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Kinders RJ, Hollingshead M, Khin S, Rubinstein L, Tomaszewski JE, Doroshow JH, et al. Preclinical modeling of a phase 0 clinical trial: qualification of a pharmacodynamic assay of poly (ADP-ribose) polymerase in tumor biopsies of mouse xenografts. Clin Cancer Res. 2008;14(21):6877–85.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    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. Investig New Drugs. 2013;31(4):949–58.CrossRefGoogle Scholar
  78. 78.
    Ji J, Kinders RJ, Zhang Y, Rubinstein L, Kummar S, Parchment RE, et al. Modeling pharmacodynamic response to the poly(ADP-ribose) polymerase inhibitor ABT-888 in human peripheral blood mononuclear cells. PLoS One. 2011;6(10):e26152.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    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(16):2705–11.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    de Haan R, Pluim D, van Triest B, van den Heuvel M, Peulen H, van Berlo D, George J, Verheij M, Schellens JHM, Vens C. Development and validation of a sensitive pharmacodynamic method for individualized treatment with PARP inhibitors. Radiother Oncol. 2016. (in press).Google Scholar
  81. 81.
    Mostafa NM, Chiu YL, Rosen LS, Bessudo A, Kovacs X, Giranda VL. A phase 1 study to evaluate effect of food on veliparib pharmacokinetics and relative bioavailability in subjects with solid tumors. Cancer Chemother Pharmacol. 2014;74(3):583–91.CrossRefPubMedGoogle Scholar
  82. 82.
    Sonnenblick A, de Azambuja E, Azim HA Jr, Piccart M. An update on PARP-inhibitors: moving to the adjuvant setting. Nat Rev Clin Oncol. 2015;12:27–41.CrossRefPubMedGoogle Scholar
  83. 83.
    Wiegand R, Wu J, Sha X, LoRusso P, Li J. Simultaneous determination of ABT-888, a poly (ADPribose) polymerase inhibitor, and its metabolite in human plasma by liquid chromatography/tandem mass spectometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878:333–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Jill J. J. Geenen
    • 1
    • 2
  • Sabine C. Linn
    • 3
    • 4
    • 5
  • Jos H. Beijnen
    • 1
    • 2
    • 6
    • 7
  • Jan H. M. Schellens
    • 1
    • 2
    • 4
    • 6
    • 7
    Email author
  1. 1.Department of Clinical PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Division of PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Department of Molecular PathologyAntoni van Leeuwenhoek Hospital, Netherlands Cancer InstituteAmsterdamThe Netherlands
  4. 4.Division of Medical OncologyNetherlands Cancer InstituteAmsterdamThe Netherlands
  5. 5.Department of PathologyUtrecht University Medical CenterUtrechtThe Netherlands
  6. 6.Department of PharmacyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  7. 7.Utrecht Institute for Pharmaceutical Sciences (UIPS)Utrecht UniversityUtrechtThe Netherlands

Personalised recommendations