Current Breast Cancer Reports

, Volume 6, Issue 3, pp 139–145

Systemic Treatment Considerations for Women with BRCA1/2-Associated Breast Cancer

Translational Research (V Stearns, Section Editor)

Abstract

Both BRCA1 and BRCA2 proteins play a role in DNA damage response, and their deficiency leads to chromosomal instability and carcinogenesis. Hereditary mutations in either of these genes increase strikingly the lifetime risk of breast and ovarian cancer and to a lesser extent the risk of males’ breast and prostate cancer and of pancreatic cancer. It is generally accepted that when treated by standard therapy, the prognosis of BRCA- mutated breast cancer patients is equivalent to that of patients with sporadic disease. Increased sensitivity of BRCA-associated breast cancer to DNA damaging chemotherapy, especially platinum compounds, was demonstrated in preclinical models and in clinical trials. However, definitive evidence that would justify their advancement to clinical practice is lacking. Inhibitors of poly (ADP-ribose) polymerase target BRCA-deficient cells specifically. Multiple clinical trials with these compounds are ongoing, although none made its way to clinical practice yet. Hopefully, ongoing clinical research would eventually result in better treatment and improved prognosis.

Keywords

BRCA1 BRCA2 Tissue specificity Cancer predisposition Chemotherapy PARP inhibitors 

References

Papers of particular interest, published recently, have been highlighted as:• Of importance

  1. 1.
    Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.PubMedCrossRefGoogle Scholar
  2. 2.
    Futreal PA, Liu Q, Shattuck-Eidens D, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994;266:120–2.PubMedCrossRefGoogle Scholar
  3. 3.
    Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Thompson D, Easton DF. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94:1358–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117–30.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22:735–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Simchoni S, Friedman E, Kaufman B, et al. Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci U S A. 2006;103:3770–4.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Levy-Lahad E, Friedman E. Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2007;96:11–5.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Venkitaraman AR. Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu Rev Pathol. 2009;4:461–87.PubMedCrossRefGoogle Scholar
  10. 10.•
    Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2012;12:68–78. This comprehensive review describes the function of BRCA1 and BRCA2 in DNA damage response and genome integrity protection.CrossRefGoogle Scholar
  11. 11.
    Xu X, Weaver Z, Linke SP, et al. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell. 1999;3:389–95.PubMedCrossRefGoogle Scholar
  12. 12.
    Yu VP, Koehler M, Steinlein C, et al. Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev. 2000;14:1400–6.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Foulkes WD, Shuen AY. In brief: BRCA1 and BRCA2. J Pathol. 2013;230:347–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Pardo B, Gomez-Gonzalez B, Aguilera A. DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci. 2009;66:1039–56.PubMedCrossRefGoogle Scholar
  15. 15.
    Yang H, Jeffrey PD, Miller J, et al. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science. 2002;297:1837–48.PubMedCrossRefGoogle Scholar
  16. 16.
    Jensen RB, Carreira A, Kowalczykowski SC. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature. 2010;467:678–83.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Wang B, Matsuoka S, Ballif BA, et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science. 2007;316:1194–8.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Chen L, Nievera CJ, Lee AY, et al. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J Biol Chem. 2008;283:7713–20. 10 1074/jbc M710245200.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang F, Ma J, Wu J, et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009;19:524–9.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Tutt A, Bertwistle D, Valentine J, et al. Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. Embo J. 2001;20:4704–16.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4:814–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Caestecker KW, Van de Walle GR. The role of BRCA1 in DNA double-strand repair: past and present. Exp Cell Res. 2013;319:575–87.PubMedCrossRefGoogle Scholar
  23. 23.
    Osorio A, de la Hoya M, Rodriguez-Lopez R, et al. Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer. Int J Cancer. 2002;99:305–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Cavalli LR, Singh B, Isaacs C, et al. Loss of heterozygosity in normal breast epithelial tissue and benign breast lesions in BRCA1/2 carriers with breast cancer. Cancer Genet Cytogenet. 2004;149:38–43.PubMedCrossRefGoogle Scholar
  25. 25.
    Konishi H, Mohseni M, Tamaki A, et al. Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proc Natl Acad Sci U S A. 2011;108:17773–8.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Ludwig T, Chapman DL, Papaioannou VE, et al. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 1997;11:1226–41.PubMedCrossRefGoogle Scholar
  27. 27.
    Evers B, Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene. 2006;25:5885–97.PubMedCrossRefGoogle Scholar
  28. 28.
    Leegte B, van der Hout AH, Deffenbaugh AM, et al. Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations. J Med Genet. 2005;42:e20.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Spannuth WA, Thaker PH, Sood AK. Concomitant BRCA1 and BRCA2 gene mutations in an Ashkenazi Jewish woman with primary breast and ovarian cancer. Am J Obstet Gynecol. 2007;196:e6–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Greenblatt MS, Chappuis PO, Bond JP, et al. TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution. Cancer Res. 2001;61:4092–7.PubMedGoogle Scholar
  31. 31.
    Holstege H, Joosse SA, van Oostrom CT, et al. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res. 2009;69:3625–33.PubMedCrossRefGoogle Scholar
  32. 32.
    Monteiro AN. BRCA1: the enigma of tissue-specific tumor development. Trends Genet. 2003;19:312–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Elledge SJ, Amon A. The BRCA1 suppressor hypothesis: an explanation for the tissue-specific tumor development in BRCA1 patients. Cancer Cell. 2002;1:129–32.PubMedCrossRefGoogle Scholar
  34. 34.
    Palacios J, Robles-Frias MJ, Castilla MA, et al. The molecular pathology of hereditary breast cancer. Pathobiology. 2008;75:85–94.PubMedCrossRefGoogle Scholar
  35. 35.
    Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002;20:2310–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Honrado E, Benitez J, Palacios J. Histopathology of BRCA1- and BRCA2-associated breast cancer. Crit Rev Oncol Hematol. 2006;59:27–39.PubMedCrossRefGoogle Scholar
  37. 37.
    Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26:4282–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Molyneux G, Smalley MJ. The cell of origin of BRCA1 mutation-associated breast cancer: a cautionary tale of gene expression profiling. J Mammary Gland Biol Neoplasia. 2011;16:51–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Molyneux G, Geyer FC, Magnay FA, et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell. 2010;7:403–17.PubMedCrossRefGoogle Scholar
  40. 40.
    Lim E, Vaillant F, Wu D, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15:907–13.PubMedCrossRefGoogle Scholar
  41. 41.
    Saal LH, Gruvberger-Saal SK, Persson C, et al. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet. 2008;40:102–7.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Eerola H, Heikkila P, Tamminen A, et al. Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families. Breast Cancer Res. 2005;7:R93–100.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Bayraktar S, Gluck S. Systemic therapy options in BRCA mutation-associated breast cancer. Breast Cancer Res Treat. 2013;135:355–66.CrossRefGoogle Scholar
  44. 44.
    Chalasani P, Livingston R. Differential chemotherapeutic sensitivity for breast tumors with “BRCAness”: a review. Oncologist. 2013;18:909–16.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Tassone P, Tagliaferri P, Perricelli A, et al. BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer. 2003;88:1285–91.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Quinn JE, Kennedy RD, Mullan PB, et al. BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res. 2003;63:6221–8.PubMedGoogle Scholar
  47. 47.
    Kennedy RD, Quinn JE, Mullan PB, et al. The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst. 2004;96:1659–68.PubMedCrossRefGoogle Scholar
  48. 48.
    Foulkes WD. BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis. Fam Cancer. 2006;5:135–42.PubMedCrossRefGoogle Scholar
  49. 49.
    Kriege M, Seynaeve C, Meijers-Heijboer H, et al. Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2009;27:3764–71.PubMedCrossRefGoogle Scholar
  50. 50.
    Byrski T, Gronwald J, Huzarski T, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28:375–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Byrski T, Dent R, Blecharz P, 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. 2014;14:R110.CrossRefGoogle Scholar
  52. 52.
    Wysocki PJ, Korski K, Lamperska K, et al. Primary resistance to docetaxel-based chemotherapy in metastatic breast cancer patients correlates with a high frequency of BRCA1 mutations. Med Sci Monit. 2008;14:SC7–10.PubMedGoogle Scholar
  53. 53.
    Byrski T, Gronwald J, Huzarski T, et al. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat. 2008;108:289–96.PubMedCrossRefGoogle Scholar
  54. 54.
    Kriege M, Jager A, Hooning MJ, et al. The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer. 2012;118:899–907.PubMedCrossRefGoogle Scholar
  55. 55.•
    Arun B, Bayraktar S, Liu DD, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol. 2011;29:3739–46. This trial found that BRCA1 status and ER negativity were independent predictors of higher pCR rates to neo-adjuvant chemotherapy for breast cancer.PubMedCrossRefGoogle Scholar
  56. 56.
    Raphael J, Mazouni C, Caron O, et al. Should BRCA2 mutation carriers avoid neoadjuvant chemotherapy? Med Oncol. 2014;31:850.PubMedCrossRefGoogle Scholar
  57. 57.
    Esteller M, Silva JM, Dominguez G, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000;92:564–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Turner NC, Reis-Filho JS, Russell AM, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene. 2007;26:2126–32.PubMedCrossRefGoogle Scholar
  59. 59.
    Carey L, Winer E, Viale G, et al. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol. 2010;7:683–92.PubMedCrossRefGoogle Scholar
  60. 60.
    Curigliano G, Goldhirsch A. The triple-negative subtype: new ideas for the poorest prognosis breast cancer. J Natl Cancer Inst Monogr. 2011;2011:108–10.PubMedCrossRefGoogle Scholar
  61. 61.
    Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28:1145–53.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Sikov WM BD, Perou CM, Singh B, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). San Antonio Breast Cancer Symposium Abstracts. 2013;S5–01.Google Scholar
  63. 63.
    Carey LA. Targeted chemotherapy? Platinum in BRCA1-dysfunctional breast cancer. J Clin Oncol. 2010;28:361–3.PubMedCrossRefGoogle Scholar
  64. 64.•
    Goodwin PJ, Phillips KA, West DW, et al. Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol. 2012;30:19–26. A large population based trial demonstrated similar outcomes in BRCA1 mutation carriers and patients with sporadic disease. BRCA2 mutation carriers had worse prognosis than patients with sporadic disease at the same age, but similar when analysis was adjusted for the effects of tumor- and treatment-related variables.PubMedCrossRefGoogle Scholar
  65. 65.
    Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med. 2007;357:115–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Huzarski T, Byrski T, Gronwald J, et al. Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol. 2013;31:3191–6.PubMedCrossRefGoogle Scholar
  67. 67.
    El-Tamer M, Russo D, Troxel A, et al. Survival and recurrence after breast cancer in BRCA1/2 mutation carriers. Ann Surg Oncol. 2004;11:157–64.PubMedCrossRefGoogle Scholar
  68. 68.
    Veronesi A, de Giacomi C, Magri MD, et al. Familial breast cancer: characteristics and outcome of BRCA 1-2 positive and negative cases. BMC Cancer. 2005;5:70.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Brekelmans CT, Seynaeve C, Menke-Pluymers M, et al. Survival and prognostic factors in BRCA1-associated breast cancer. Ann Oncol. 2006;17:391–400.PubMedCrossRefGoogle Scholar
  70. 70.
    Bonadona V, Dussart-Moser S, Voirin N, et al. Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort and review. Breast Cancer Res Treat. 2007;101:233–45.PubMedCrossRefGoogle Scholar
  71. 71.
    Foulkes WD, Chappuis PO, Wong N, et al. Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome. Ann Oncol. 2000;11:307–13.PubMedCrossRefGoogle Scholar
  72. 72.
    Moller P, Borg A, Evans DG, et al. Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy. Int J Cancer. 2002;101:555–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Robson ME, Chappuis PO, Satagopan J, et al. A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res. 2004;6:R8–17.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.PubMedCrossRefGoogle Scholar
  75. 75.
    Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34.PubMedCrossRefGoogle Scholar
  76. 76.
    Tutt A, Robson M, Garber JE, 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.PubMedCrossRefGoogle Scholar
  77. 77.
    Gelmon KA, Tischkowitz M, Mackay H, 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.PubMedCrossRefGoogle Scholar
  78. 78.
    Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germ-line BRCA1/2 mutation: an open-label phase II study. ASCO Meet Abstr. 2013;31:11024.Google Scholar
  79. 79.
    O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205–14.PubMedCrossRefGoogle Scholar
  80. 80.
    Tan AR, Toppmeyer D, Stein MN, 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. ASCO Meet Abstr. 2011;29:3041.Google Scholar
  81. 81.
    Somlo G, Sparano JA, Cigler T, et al. ABT-888 (veliparib) in combination with carboplatin in patients with stage IV BRCA-associated breast cancer. A California Cancer Consortium Trial. ASCO Meet Abstr. 2012;30:1010.Google Scholar
  82. 82.
    Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. ASCO Meet Abstr. 2010;28:1019.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ella Evron
    • 1
  • Ayelet Avraham
    • 1
  • Shani Paluch-Shimon
    • 2
  1. 1.Department of OncologyAssaf Harofeh Medical CenterZerifinIsrael
  2. 2.Oncology InstituteChaim Sheba Medical CenterTel HashomerIsrael

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