Familial Cancer

, Volume 5, Issue 2, pp 135–142 | Cite as

BRCA1 and BRCA2: Chemosensitivity, Treatment Outcomes and Prognosis

  • William D. FoulkesEmail author


BRCA1 and BRCA2 are important breast and ovarian cancer susceptibility genes, and mutations in these two genes confer lifetime risks of breast cancer of up to 80% and ovarian cancer risks of up to 40%. Clinico-pathological studies have identified features that are specific to BRCA1-related breast cancer, but this has been more difficult for BRCA2-related breast cancer. Ovarian cancers due to BRCA1 or BRCA2 mutations cannot usually be distinguished from their non-hereditary counterparts on morphological grounds, but micro-array data suggest that differences do exist. Prognostic studies have shown that breast cancer in a BRCA1 mutation carrier is likely to have a similar, or worse, outcome than that occurring in a BRCA2- or non-carrier of the same age. By contrast, most studies indicate that women developing a BRCA1/2-related ovarian cancer have an improved survival compared with non-carriers, particularly if they receive platinum-based therapy. In support of this, in vitro chemo-sensitivity studies have found that human cells lacking BRCA1 may be particularly sensitive to cisplatinum and to other drugs that cause double-strand breaks in DNA. Nevertheless, in breast cancer, little is known regarding clinically important differences in response to chemotherapy between BRCA1/2 mutation carriers and non-carriers, and between different chemotherapeutic regimens within existing series of BRCA1/2 mutation carriers. There are no published prospective studies. It is hoped that, in the near future, randomised controlled trials will be started with the aim of answering these important clinical questions.

Key words

chemotherapy hereditary breast and ovarian cancer oncology survival 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Narod, SA, Foulkes, WD 2004BRCA1 and BRCA2: 1994 and beyondNat Rev Cancer466576PubMedCrossRefGoogle Scholar
  2. 2.
    Andermann, A, Narod, SA 2002Genetic counselling for familial breast and ovarian cancer in OntarioJ Med Genet396956PubMedCrossRefGoogle Scholar
  3. 3.
    Evans, DG, Howell, A 2004Are BRCA1- and BRCA2-related breast cancers associated with increased mortality?Breast Cancer Res6E7PubMedCrossRefGoogle Scholar
  4. 4.
    Sorlie, T, Perou, CM, Tibshirani, R,  et al. 2001Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implicationsProc Natl Acad Sci USA981086974PubMedCrossRefGoogle Scholar
  5. 5.
    Veer, LJ, Dai, HY, Vijver, MJ,  et al. 2002Gene expression profiling predicts clinical outcome of breast cancerNature4155306CrossRefGoogle Scholar
  6. 6.
    Sotiriou, C, Neo, SY, McShane, LM,  et al. 2003Breast cancer classification and prognosis based on gene expression profiles from a population-based studyProc Natl Acad Sci USA100103938PubMedCrossRefGoogle Scholar
  7. 7.
    Hedenfalk, I, Duggan, D, Chen, Y,  et al. 2001Gene-expression profiles in hereditary breast cancerN Engl J Med34453948PubMedCrossRefGoogle Scholar
  8. 8.
    Sotiriou, C, Khanna, C, Jazaeri, AA,  et al. 2002Core biopsies can be used to distinguish differences in expression profiling by cDNA microarraysJ Mol Diagn4306PubMedGoogle Scholar
  9. 9.
    Lakhani, SR, Vijver, MJ, Jacquemier, J,  et al. 2002The 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 BRCA2J Clin Oncol2023108PubMedCrossRefGoogle Scholar
  10. 10.
    Foulkes, WD, Metcalfe, K, Hanna, W,  et al. 2003Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinomaCancer98156977PubMedCrossRefGoogle Scholar
  11. 11.
    Chappuis, PO, Nethercot, V, Foulkes, WD 2000Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancerSemin Surg Oncol1828795PubMedCrossRefGoogle Scholar
  12. 12.
    Chappuis, PO, Kapusta, L, Begin, LR,  et al. 2000Germline BRCA1/2 mutations and p27(Kip1) protein levels independently predict outcome after breast cancerJ Clin Oncol18404552PubMedGoogle Scholar
  13. 13.
    Greenblatt, MS, Chappuis, PO, Bond, JP,  et al. 2001TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distributionCancer Res6140927PubMedGoogle Scholar
  14. 14.
    Foulkes, WD, Brunet, JS, Stefansson, IM,  et al. 2004The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancerCancer Res648305PubMedCrossRefGoogle Scholar
  15. 15.
    Sorlie, T, Tibshirani, R, Parker, J,  et al. 2003Repeated observation of breast tumor subtypes in independent gene expression data setsProc Natl Acad Sci USA100841823PubMedCrossRefGoogle Scholar
  16. 16.
    Foulkes, WD, Stefansson, IM, Chappuis, PO,  et al. 2003Germline BRCA1 mutations and a basal epithelial phenotype in breast cancerJ Natl Cancer Inst9514825PubMedGoogle Scholar
  17. 17.
    Goffin, JR, Straume, O, Chappuis, PO,  et al. 2003Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancerBr J Cancer8910314PubMedCrossRefGoogle Scholar
  18. 18.
    Grushko, TA, Dignam, JJ, Das, S,  et al. 2004MYC is amplified in BRCA1-associated breast cancersClin Cancer Res10499507PubMedCrossRefGoogle Scholar
  19. 19.
    Adem, C, Soderberg, CL, Hafner, K,  et al. 2004ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriersGenes Chromosomes Cancer41111PubMedCrossRefGoogle Scholar
  20. 20.
    Korsching, E, Packeisen, J, Agelopoulos, K,  et al. 2002Cytogenetic alterations and cytokeratin expression patterns in breast cancer: Integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesisLab Invest82152533PubMedGoogle Scholar
  21. 21.
    Signoretti, S, Marcotullio, L, Richardson, A,  et al. 2002Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancerJ Clin Invest11063341PubMedCrossRefGoogle Scholar
  22. 22.
    Malzahn, K, Mitze, M, Thoenes, M, Moll, R 1998Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomasVirchows Arch Int J Pathol43311929CrossRefGoogle Scholar
  23. 23.
    Dairkee, SH, Mayall, BH, Smith, HS, Hackett, AJ 1987Monoclonal marker that predicts early recurrence of breast-cancerLancet1514PubMedGoogle Scholar
  24. 24.
    Rijn, M, Perou, CM, Tibshirani, R,  et al. 2002Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcomeAm J Pathol16119916PubMedGoogle Scholar
  25. 25.
    Lakhani, SR, Jacquemier, J, Sloane, JP,  et al. 1998Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutationsJ Natl Cancer Inst90113845PubMedCrossRefGoogle Scholar
  26. 26.
    Vaziri, SA, Tubbs, RR, Darlington, G, Casey, G 2001Absence of CCND1 gene amplification in breast tumours of BRCA1 mutation carriersMol Pathol5425963PubMedCrossRefGoogle Scholar
  27. 27.
    Desper, R, Khan, J, Schaffer, AA 2004Tumor classification using phylogenetic methods on expression dataJ Theor Biol22847796PubMedCrossRefGoogle Scholar
  28. 28.
    Fedier, A, Steiner, RA, Schwarz, VA,  et al. 2003The effect of loss of Brca1 on the sensitivity to anticancer agents in p53-deficient cellsInt J Oncol22116973PubMedGoogle Scholar
  29. 29.
    Quinn, JE, Kennedy, RD, Mullan, PB,  et al. 2003BRCA1 functions as a differential modulator of chemotherapy-induced apoptosisCancer Res6362218PubMedGoogle Scholar
  30. 30.
    Thangaraju, M, Kaufmann, SH, Couch, FJ 2000BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell linesJ Biol Chem2753348796PubMedCrossRefGoogle Scholar
  31. 31.
    Zhou, C, Smith, JL, Liu, J 2003Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1Oncogene222396404PubMedCrossRefGoogle Scholar
  32. 32.
    Tassone, P, Tagliaferri, P, Perricelli, A,  et al. 2003BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cellsBr J Cancer88128591PubMedCrossRefGoogle Scholar
  33. 33.
    Samouelian V, Maugard CM, Jolicoeur M et al. Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2, TGFbeta-RII, KRAS2, TP53 and/or CDNK2A. Cancer Chemother Pharmacol 2004Google Scholar
  34. 34.
    Husain, A, He, G, Venkatraman, ES, Spriggs, DR 1998BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II)Cancer Res5811203PubMedGoogle Scholar
  35. 35.
    Bhattacharyya, A, Ear, US, Koller, BH,  et al. 2000The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross- linking agent cisplatinJ Biol Chem27523899903PubMedCrossRefGoogle Scholar
  36. 36.
    Abbott, DW, Freeman, ML, Holt, JT 1998Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cellsJ Natl Cancer Inst9097885PubMedCrossRefGoogle Scholar
  37. 37.
    Moynahan, ME, Cui, TY, Jasin, M 2001Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutationCancer Res61484250PubMedGoogle Scholar
  38. 38.
    Patel, KJ, Yu, VP, Lee, H,  et al. 1998Involvement of Brca2 in DNA repairMol Cell134757PubMedCrossRefGoogle Scholar
  39. 39.
    Scully, R, Livingston, DM 2000In search of the tumour-suppressor functions of BRCA1 and BRCA2Nature40842932PubMedCrossRefGoogle Scholar
  40. 40.
    Xu, X, Qiao, W, Linke, SP,  et al. 2001Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesisNat Genet2826671PubMedCrossRefGoogle Scholar
  41. 41.
    Cortez, D, Wang, Y, Qin, J, Elledge, SJ 1999Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaksScience28611626PubMedCrossRefGoogle Scholar
  42. 42.
    Khanna, KK, Jackson, SP 2001DNA double-strand breaks: Signaling, repair and the cancer connectionNat Genet2724754PubMedCrossRefGoogle Scholar
  43. 43.
    Yuan, SSF, Lee, SY, Chen, G,  et al. 1999BRCA2 is required for ionizing radiation-induced assembly of rad51 complex in vivoCancer Res59354751PubMedGoogle Scholar
  44. 44.
    Freneaux, P, Stoppa-Lyonnet, D, Mouret, E,  et al. 2000Low expression of bcl-2 in Brca1-associated breast cancersBr J Cancer83131822PubMedCrossRefGoogle Scholar
  45. 45.
    Hanawalt, PC 2001Revisiting the rodent repairadoxEnviron Mol Mutagen388996PubMedCrossRefGoogle Scholar
  46. 46.
    Egawa, C, Motomura, K, Miyoshi, Y,  et al. 2003Increased expression of BRCA1 mRNA predicts favorable response to anthracycline-containing chemotherapy in breast cancersBreast Cancer Res Treat784550PubMedCrossRefGoogle Scholar
  47. 47.
    Catteau, A, Harris, WH, Xu, CF, Solomon, E 1999Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: Correlation with disease characteristicsOncogene18195765PubMedCrossRefGoogle Scholar
  48. 48.
    Esteller, M, Silva, JM, Dominguez, G,  et al. 2000Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumorsJ Natl Cancer Inst925649(see comments)PubMedCrossRefGoogle Scholar
  49. 49.
    Esteller, M, Garcia-Foncillas, J, Andion, E,  et al. 2000Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agentsN Engl J Med34313504PubMedCrossRefGoogle Scholar
  50. 50.
    Geisler, S, Lonning, PE, Aas, T,  et al. 2001Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancerCancer Res61250512PubMedGoogle Scholar
  51. 51.
    Geisler, S, Borresen-Dale, AL, Johnsen, H,  et al. 2003TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancerClin Cancer Res955828PubMedGoogle Scholar
  52. 52.
    Henning, W, Sturzbecher, HW 2003Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistanceToxicology19391109PubMedCrossRefGoogle Scholar
  53. 53.
    Levy-Lahad, E, Lahad, A, Eisenberg, S,  et al. 2001A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriersProc Natl Acad Sci USA9832326PubMedCrossRefGoogle Scholar
  54. 54.
    Wang, WW, Spurdle, AB, Kolachana, P,  et al. 2001A single nucleotide polymorphism in the 5′ untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriersCancer Epidemiol Biomarkers Prev1095560PubMedGoogle Scholar
  55. 55.
    Kadouri, L, Kote-Jarai, Z, Hubert, A,  et al. 2004A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriersBr J Cancer9020025PubMedCrossRefGoogle Scholar
  56. 56.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 Apr 14; 434(9035): 913–7Google Scholar
  57. 57.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 14; 434(7035): 917–21Google Scholar
  58. 58.
    Chappuis, PO, Goffin, J, Wong, N,  et al. 2002A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancerJ Med Genet3960810PubMedCrossRefGoogle Scholar
  59. 59.
    Warner, E, Trudeau, M, Holloway, C 2003Sensitivity of BRCA-1- related breast cancer to neoadjuvant chemotherapy: Practical implicationsBreast J95078PubMedCrossRefGoogle Scholar
  60. 60.
    Robson, ME, Chappuis, PO, Satagopan, J,  et al. 2004A combined analysis of outcome following breast cancer: Differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatmentBreast Cancer Res6R8R17PubMedCrossRefGoogle Scholar
  61. 61.
    Boyd, J, Sonoda, Y, Federici, MG,  et al. 2000Clinicopathologic features of BRCA-linked and sporadic ovarian cancerJAMA28322605PubMedCrossRefGoogle Scholar
  62. 62.
    Ramus, SJ, Fishman, A, Pharoah, PD,  et al. 2001Ovarian cancer survival in Ashkenazi Jewish patients with BRCA1 and BRCA2 mutationsEur J Surg Oncol2727881PubMedCrossRefGoogle Scholar
  63. 63.
    Ben David, Y, Chetrit, A, Hirsh-Yechezkel, G,  et al. 2002Effect of BRCA mutations on the length of survival in epithelial ovarian tumorsJ Clin Oncol204636PubMedCrossRefGoogle Scholar
  64. 64.
    Cass, I, Baldwin, RL, Varkey, T,  et al. 2003Improved survival in women with BRCA-associated ovarian carcinomaCancer97218795PubMedCrossRefGoogle Scholar
  65. 65.
    Wolff, AC, Davidson, NE 2002Preoperative therapy in breast cancer: Lessons from the treatment of locally advanced diseaseOncologist723945PubMedCrossRefGoogle Scholar
  66. 66.
    Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN Pusztai L. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005 Aug 15; 11(16): 5678–85Google Scholar
  67. 67.
    Buchholz, TA,  et al. 2005The nuclear transcription factor kappaB/bc1-2 pathway correlates with pathologic complete response to doxorubicin-based neoadjuvant chemotherapy in human breast cancerClin Cancer Res.1183988402PubMedCrossRefGoogle Scholar
  68. 68.
    Moyano, JV,  et al. 2006AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancerJ Clin Invest.116261270PubMedCrossRefGoogle Scholar
  69. 69.
    Chang, HY,  et al. 2005Robustness, Scalability, and integration of a wound-response gene expression signature in predicting breast cancer survivalProc Natl Acad Sci U.S.A.10237383743PubMedCrossRefGoogle Scholar
  70. 70.
    Rodriguez-Pinilla, SM,  et al. 2006Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomasClin Cancer Res.1215331539PubMedCrossRefGoogle Scholar
  71. 71.
    Banerjee S et al (2006) Basal-like breast carcinomas: clinical outcome and response to chemotherapy. J clin PatholGoogle Scholar
  72. 72.
    Pharoah, PD, Easton, DF, Stockton, DL,  et al. 1999Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study GroupCancer Res5986871PubMedGoogle Scholar
  73. 73.
    Zweemer, RP, Verheijen, RH, Coebergh, JW,  et al. 2001Survival analysis in familial ovarian cancer, a case control studyEur J Obstet Gynecol Reprod Biol9821923PubMedCrossRefGoogle Scholar
  74. 74.
    Wojciechowska-Lacka, A, Markowska, J, Skasko, E,  et al. 2003Frequent disease progression and early recurrence in patients with familial ovarian cancer primarily treated with paclitaxel and cis- or carboplatin (preliminary report)Eur J Gynaecol Oncol24214PubMedGoogle Scholar
  75. 75.
    Tischkowitz, MD, Hodgson, SV 2003Fanconi anaemiaJ Med Genet40110PubMedCrossRefGoogle Scholar
  76. 76.
    Howlett, NG, Taniguchi, T, Olson, S,  et al. 2002Biallelic inactivation of BRCA2 in Fanconi anemiaScience2976069PubMedCrossRefGoogle Scholar
  77. 77.
    Venkitaraman, AR 2004Tracing the network connecting BRCA and Fanconi anaemia proteinsNat Rev Cancer426676PubMedCrossRefGoogle Scholar
  78. 78.
    Taniguchi, T, Tischkowitz, M, Ameziane, N,  et al. 2003Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumorsNat Med956874PubMedCrossRefGoogle Scholar
  79. 79.
    Hilton, JL, Geisler, JP, Rathe, JA,  et al. 2002Inactivation of BRCA1 and BRCA2 in ovarian cancerJ Natl Cancer Inst941396406PubMedGoogle Scholar
  80. 80.
    Robson, ME, Boyd, J, Borgen, PI, Cody, HS,III 2001Hereditary breast cancerCurr Probl Surg38387480PubMedCrossRefGoogle Scholar
  81. 81.
    Foulkes, WD, Rosenblatt, J, Chappuis, PO 2001The contribution of inherited factors to the clinicopathological features and behavior of breast cancerJ Mammary Gland Biol Neoplasia645365PubMedCrossRefGoogle Scholar
  82. 82.
    Lakhani SR, Gusterson BA, Jacquemier J et al. The pathology of familial breast cancer: Histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin Cancer Res 2000; 6(3): 782–9Google Scholar
  83. 83.
    CHEK2*1100delC and susceptibility to breast cancer: A collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 2004; 74(6): 1175–82Google Scholar
  84. 84.
    Schwartz, MD, Lerman, C, Brogan, B,  et al. 2004Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patientsJ Clin Oncol2218239PubMedCrossRefGoogle Scholar
  85. 85.
    Weigelt, B, Hu, Z, He, X, Livasy, C, Carey, LA, Ewend, MG, Glas, AM, Perou, CM, Van’t Veer, LJ 2005Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancerCancer Res.6591558PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  1. 1.Program in Cancer Genetics, Departments of Oncology and Human GeneticsMcGill UniversityMontrealCanada

Personalised recommendations