Skip to main content

Advertisement

SpringerLink
Log in

Investigating BRCA Mutations: A Breakthrough in Precision Medicine of Castration-Resistant Prostate Cancer

  • Review Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Despite the development of novel effective therapeutic strategies, metastatic castration-resistant prostate cancer (mCRPC) remains a disease with a lethal course and a high biological and molecular heterogeneity. To date, germline mutations in the BRCA gene represent one of the main risk factors for developing prostate cancer, with a strong association with aggressive phenotype and poor clinical outcomes. A better understanding of the genomic landscape of prostate cancer has strengthened the idea that “synthetic lethality” of this disease might be useful in cancer-drug discovery, focusing on agents such as platinum compounds and poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi). In this review, we summarize the main data available on BRCA mutations and discuss the clinical implications of these genomic aberrations in the management of prostate cancer, stressing the need to identify prognostic and predictive biomarkers and to deeply understand the mechanisms of treatment resistance, in order to maximize personalized medicine protocols and therefore clinical benefit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. doi:10.1002/ijc.29210.

    Article  CAS  PubMed  Google Scholar 

  2. Galsky MD, Vogelzang NJ. Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol. 2010;21(11):2135–44. doi:10.1093/annonc/mdq050.

    Article  CAS  PubMed  Google Scholar 

  3. Eisenberger MA, Walsh PC. Early androgen deprivation for prostate cancer? N Engl J Med. 1999;341(24):1837–8. doi:10.1056/NEJM199912093412409.

    Article  CAS  PubMed  Google Scholar 

  4. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–12. doi:10.1056/NEJMoa040720.

    Article  CAS  PubMed  Google Scholar 

  5. Petrylak DP, Tangen CM, Hussain MH, Lara Jr PN, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513–20. doi:10.1056/NEJMoa041318.

    Article  CAS  PubMed  Google Scholar 

  6. Bracarda S, Sisani M, Marrocolo F, Hamzaj A, Del Buono S, Altavilla A. Clinical implications for a treatment algorithm and differential indication to hormone therapy and chemotherapy options in metastatic castrate-resistant prostate cancer: a personal view. Expert Rev Anticancer Ther. 2014;14(11):1283–94. doi:10.1586/14737140.2014.965686.

    Article  CAS  PubMed  Google Scholar 

  7. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147–54. doi:10.1016/S0140-6736(10)61389-X.

    Article  PubMed  Google Scholar 

  8. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13(10):983–92. doi:10.1016/S1470-2045(12)70379-0.

    Article  CAS  PubMed  Google Scholar 

  9. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152–60. doi:10.1016/S1470-2045(14)71205-7.

    Article  CAS  PubMed  Google Scholar 

  10. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97. doi:10.1056/NEJMoa1207506.

    Article  CAS  PubMed  Google Scholar 

  11. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–33. doi:10.1056/NEJMoa1405095.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Beer TM, Armstrong AJ, Sternberg CN, Higano CS, Rathkopf DE, Loriot Y, et al. Enzalutamide (ENZA) in men with chemotherapy-Naive metastatic castration-resistant prostate cancer (mCRPC): Final analysis of the phase 3 PREVAIL study. J Clin Oncol 33, 2015 (suppl; abstr 5036).

  13. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22. doi:10.1056/NEJMoa1001294.

    Article  CAS  PubMed  Google Scholar 

  14. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–23. doi:10.1056/NEJMoa1213755.

    Article  CAS  PubMed  Google Scholar 

  15. van Soest RJ, van Royen ME, de Morree ES, Moll JM, Teubel W, Wiemer EA, et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur J Cancer. 2013;49(18):3821–30. doi:10.1016/j.ejca.2013.09.026.

    Article  PubMed  Google Scholar 

  16. Bahl A, Masson S, Birtle A, Chowdhury S, de Bono J. Second-line treatment options in metastatic castration-resistant prostate cancer: a comparison of key trials with recently approved agents. Cancer Treat Rev. 2014;40(1):170–7. doi:10.1016/j.ctrv.2013.06.008.

    Article  CAS  PubMed  Google Scholar 

  17. Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, et al. The genomic complexity of primary human prostate cancer. Nature. 2011;470(7333):214–20. doi:10.1038/nature09744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A’Hern R, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69(7):2912–8. doi:10.1158/0008-5472.CAN-08-3667.

    Article  CAS  PubMed  Google Scholar 

  19. Reid AH, Attard G, Ambroisine L, Fisher G, Kovacs G, Brewer D, et al. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br J Cancer. 2010;102(4):678–84. doi:10.1038/sj.bjc.6605554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mehra R, Han B, Tomlins SA, Wang L, Menon A, Wasco MJ, et al. Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: molecular evidence for an independent group of diseases. Cancer Res. 2007;67(17):7991–5. doi:10.1158/0008-5472.CAN-07-2043.

    Article  CAS  PubMed  Google Scholar 

  21. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487(7406):239–43. doi:10.1038/nature11125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Leongamornlert D, Mahmud N, Tymrakiewicz M, Saunders E, Dadaev T, Castro E, et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer. 2012;106(10):1697–701. doi:10.1038/bjc.2012.146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kote-Jarai Z, Leongamornlert D, Saunders E, Tymrakiewicz M, Castro E, Mahmud N, et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011;105(8):1230–4. doi:10.1038/bjc.2011.383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Myers CE, Feldman R, Abbott BL, Reddy SK, Castro M. Frequency of BRCA mutations and co-occurring alterations in prostate cancer. J Clin Oncol 34, 2016 (suppl 2S; abstr 289).

  26. 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 Off J Am Soc Clin Oncol. 2015;33(3):244–50. doi:10.1200/JCO.2014.56.2728.

    Article  CAS  Google Scholar 

  27. Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006;25(43):5864–74. doi:10.1038/sj.onc.1209874.

    Article  CAS  PubMed  Google Scholar 

  28. Boulton SJ. Cellular functions of the BRCA tumour-suppressor proteins. Biochem Soc Trans. 2006;34(Pt 5):633–45. doi:10.1042/BST0340633.

    Article  CAS  PubMed  Google Scholar 

  29. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108(2):171–82.

    Article  CAS  PubMed  Google Scholar 

  30. Thorslund T, West SC. BRCA2: a universal recombinase regulator. Oncogene. 2007;26(56):7720–30. doi:10.1038/sj.onc.1210870.

    Article  CAS  PubMed  Google Scholar 

  31. Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 2004;95(11):866–71.

    Article  CAS  PubMed  Google Scholar 

  32. Martin AM, Blackwood MA, Antin-Ozerkis D, Shih HA, Calzone K, Colligon TA, et al. Germline mutations in BRCA1 and BRCA2 in breast-ovarian families from a breast cancer risk evaluation clinic. J Clin Oncol. 2001;19(8):2247–53.

    CAS  PubMed  Google Scholar 

  33. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med. 2003;348(23):2339–47. doi:10.1056/NEJMra012284.

    Article  CAS  PubMed  Google Scholar 

  34. Gudmundsson J, Johannesdottir G, Bergthorsson JT, Arason A, Ingvarsson S, Egilsson V, et al. Different tumor types from BRCA2 carriers show wild-type chromosome deletions on 13q12-q13. Cancer Res. 1995;55(21):4830–2.

    CAS  PubMed  Google Scholar 

  35. Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269–75. doi:10.1002/cncr.29041.

    Article  CAS  PubMed  Google Scholar 

  36. Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003;72(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  37. Agalliu I, Karlins E, Kwon EM, Iwasaki LM, Diamond A, Ostrander EA, et al. Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. Br J Cancer. 2007;97(6):826–31. doi:10.1038/sj.bjc.6603929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Giusti RM, Rutter JL, Duray PH, Freedman LS, Konichezky M, Fisher-Fischbein J, et al. A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet. 2003;40(10):787–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gallagher DJ, Gaudet MM, Pal P, Kirchhoff T, Balistreri L, Vora K, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. 2010;16(7):2115–21. doi:10.1158/1078-0432.CCR-09-2871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schayek H, Haugk K, Sun S, True LD, Plymate SR, Werner H. Tumor suppressor BRCA1 is expressed in prostate cancer and controls insulin-like growth factor I receptor (IGF-IR) gene transcription in an androgen receptor-dependent manner. Clin Cancer Res. 2009;15(5):1558–65. doi:10.1158/1078-0432.CCR-08-1440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Moro L, Arbini AA, Yao JL, di Sant’Agnese PA, Marra E, Greco M. Loss of BRCA2 promotes prostate cancer cell invasion through up-regulation of matrix metalloproteinase-9. Cancer Sci. 2008;99(3):553–63. doi:10.1111/j.1349-7006.2007.00719.x.

    Article  CAS  PubMed  Google Scholar 

  42. Tryggvadottir L, Vidarsdottir L, Thorgeirsson T, Jonasson JG, Olafsdottir EJ, Olafsdottir GH, et al. Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99(12):929–35. doi:10.1093/jnci/djm005.

    Article  CAS  PubMed  Google Scholar 

  43. Agalliu I, Gern R, Leanza S, Burk RD. Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations. Clin Cancer Res. 2009;15(3):1112–20. doi:10.1158/1078-0432.CCR-08-1822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Narod SA, Neuhausen S, Vichodez G, Armel S, Lynch HT, Ghadirian P, et al. Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer. 2008;99(2):371–4. doi:10.1038/sj.bjc.6604453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Edwards SM, Evans DG, Hope Q, Norman AR, Barbachano Y, Bullock S, et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010;103(6):918–24. doi:10.1038/sj.bjc.6605822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Thorne H, Willems AJ, Niedermayr E, Hoh IM, Li J, Clouston D, et al. Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev Res. 2011;4(7):1002–10. doi:10.1158/1940-6207.CAPR-10-0397.

    Article  CAS  Google Scholar 

  47. Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748–57. doi:10.1200/JCO.2012.43.1882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Castro E, Goh C, Leongamornlert D, Saunders E, Tymrakiewicz M, Dadaev T, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186–93. doi:10.1016/j.eururo.2014.10.022.

    Article  CAS  PubMed  Google Scholar 

  49. Kim SH, Park WS, Yun SI, Joo J, Joung JY, Seo HK, et al. Overexpression of BRCA1 or BRCA2 in prostatectomy specimens is predictive of biochemical recurrence after radical prostatectomy. Histopathology. 2015. doi:10.1111/his.12809.

    Google Scholar 

  50. Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH. Integrating genetic approaches into the discovery of anticancer drugs. Science. 1997;278(5340):1064–8.

    Article  CAS  PubMed  Google Scholar 

  51. 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. doi:10.1200/JCO.2008.20.7019.

    Article  CAS  PubMed  Google Scholar 

  52. Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557–65. doi:10.1001/jama.2011.1456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. “BRCAness” syndrome in ovarian cancer: a case–control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26(34):5530–6. doi:10.1200/JCO.2008.16.1703.

    Article  PubMed  Google Scholar 

  54. Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, et al. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20(11):2846–50. doi:10.1158/1078-0432.CCR-13-3309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sella A, Yarom N, Zisman A, Kovel S. Paclitaxel, estramustine and carboplatin combination chemotherapy after initial docetaxel-based chemotherapy in castration-resistant prostate cancer. Oncology. 2009;76(6):442–6. doi:10.1159/000217264.

    Article  CAS  PubMed  Google Scholar 

  56. Birtle AJ, Newby JC, Harland SJ. Epirubicin carboplatin and 5-fluorouracil (ECarboF) chemotherapy in metastatic hormone refractory prostate cancer. Br J Cancer. 2004;91(8):1472–6. doi:10.1038/sj.bjc.6602177.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, et al. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009;27(32):5431–8. doi:10.1200/JCO.2008.20.1228.

    Article  CAS  PubMed  Google Scholar 

  58. Scott CL, Swisher EM, Kaufmann SH. Poly (ADP-ribose) polymerase inhibitors: recent advances and future development. J Clin Oncol. 2015;33(12):1397–406. doi:10.1200/JCO.2014.58.8848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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. doi:10.1200/JCO.2009.26.9589.

    Article  CAS  PubMed  Google Scholar 

  60. Cheng HH, Pritchard CC, Boyd T, Nelson PS, Montgomery B. Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol. 2015. doi:10.1016/j.eururo.2015.11.022.

    Google Scholar 

  61. Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. BioEssays News Rev Mol Cell Dev Biol. 2004;26(8):882–93. doi:10.1002/bies.20085.

    Article  CAS  Google Scholar 

  62. Dantzer F, de La Rubia G, Menissier-De Murcia J, Hostomsky Z, de Murcia G, Schreiber V. Base excision repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1. Biochemistry. 2000;39(25):7559–69.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26(22):3785–90. doi:10.1200/JCO.2008.16.0812.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  CAS  PubMed  Google Scholar 

  66. Brody LC. Treating cancer by targeting a weakness. N Engl J Med. 2005;353(9):949–50. doi:10.1056/NEJMcibr052331.

    Article  CAS  PubMed  Google Scholar 

  67. 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.

    Article  CAS  PubMed  Google Scholar 

  68. 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.

    Article  CAS  PubMed  Google Scholar 

  69. 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.

    Article  CAS  PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  Google Scholar 

  71. 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.

    Article  CAS  Google Scholar 

  72. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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 Dis. 2012;2(12):1134–49. doi:10.1158/2159-8290.CD-12-0120.

    Article  CAS  Google Scholar 

  74. Hussain M, Daignault S, Twardowski P, Albany C, Stein MN, Kunju LP, et al. Co-targeting androgen receptor (AR) and DNA repair: a randomized ETS gene fusion-stratified trial of abiraterone + prednisone (Abi) +/− the PARP1 inhibitor veliparib for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) (NCI9012)--a University of Chicago phase II consortium trial. J Clin Oncol 34, 2016 (suppl; abstr 5010).

  75. Bancroft EK, Page EC, Castro E, Lilja H, Vickers A, Sjoberg D, et al. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. Eur Urol. 2014;66(3):489–99. doi:10.1016/j.eururo.2014.01.003.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Bancroft EK, Eeles RA. Corrigendum to “targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study” [Eur Urol 2014;66:489–99]. Eur Urol. 2015;67(6):e126. doi:10.1016/j.eururo.2014.12.001.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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.

    Article  CAS  PubMed  Google Scholar 

  79. Helleday T, Eshtad S, Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet. 2014;15(9):585–98. doi:10.1038/nrg3729.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata (AOUI), University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy

    Alessandra Modena, Roberto Iacovelli, Chiara Ciccarese, Emanuela Fantinel, Davide Bimbatti & Giampaolo Tortora

  2. Department of Pathology and Diagnostics, Azienda Ospedaliera Universitaria Integrata (AOUI), University of Verona, Verona, Italy

    Aldo Scarpa & Matteo Brunelli

  3. Division of Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy

    Francesco Massari

  4. Department of Pathology, Casa di Cura Pederzoli, Verona, Italy

    Guido Martignoni

Authors
  1. Alessandra Modena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberto Iacovelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aldo Scarpa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matteo Brunelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chiara Ciccarese
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emanuela Fantinel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Davide Bimbatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesco Massari
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guido Martignoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giampaolo Tortora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Iacovelli.

Ethics declarations

Funding

None.

Conflict of Interest

Alessandra Modena, Roberto Iacovelli, Aldo Scarpa, Matteo Brunelli, Chiara Ciccarese, Emanuela Fantinel, Davide Bimbatti, Francesco Massari, Guido Martignoni, and Giampaolo Tortora declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Modena, A., Iacovelli, R., Scarpa, A. et al. Investigating BRCA Mutations: A Breakthrough in Precision Medicine of Castration-Resistant Prostate Cancer. Targ Oncol 11, 569–577 (2016). https://doi.org/10.1007/s11523-016-0450-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-016-0450-9

Keywords

Search

Navigation