Clinical Oncology
Volume 18, Issue 3 , Pages 166-178 , April 2006

Radiobiology of Breast Cancer

  • A. Tutt

      Affiliations

    • Department of Oncology, Guys and St Thomas' Hospital, London, UK; and Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK
    • ,
  • J. Yarnold

      Affiliations

    • Section of Radiotherapy, Institute of Cancer Research, Sutton; and Royal Marsden Hospital, Sutton, UK
    • Corresponding Author InformationAuthor for correspondence: John Yarnold, Professor of Clinical Oncology, Academic Radiotherapy Department, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-(0)208-661-3388; Fax: +44-(0)208-661-3107.

References 

  1. Tozer GM, Bicknell R. Therapeutic targeting of the tumor vasculature. Semin Radiat Oncol. 2004;14:222–232
  2. Arriagada R, Mouriesse H, Sarrazin D, Clark RM, Deboer G. Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital. Int J Radiat Oncol Biol Phys. 1985;11:1751–1757
  3. Brahme A, Chavaudra J, Landberg T, et al. Accuracy requirements and quality assurance of external beam therapy with photons and electrons. Acta Oncol. 1988;(suppl 1):7–15
  4. Denham JW. The radiation dose–response relationship for control of primary breast cancer. Radiother Oncol. 1986;7:107–123
  5. EBCTCG . Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists Collaborative Group. Lancet. 2000;355:1757–1770
  6. Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med. 2001;345:1378–1387
  7. Cohen L. Radiotherapy in breast cancer. I. The dose–time relationship theoretical considerations. Br J Radiol. 1952;25:636–642
  8. Douglas BG, Castro JR. Novel fractionation schemes and high linear energy transfer. Prog Exp Tumor Res. 1984;28:152–165
  9. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol. 1989;62:679–694
  10. Yarnold JR, Owen JR, Ashton A, et al. Fraction sensitivity of change in breast appearance after radiotherapy for early breast cancer: long-term results of a randomised trial. Radiother Oncol. 2002;64(suppl 1):S25
  11. Owen JR, Yarnold JR, Ashton A, et al. Fractionation sensitivity of breast cancer: results of a randomised trial. Eur J Oncol. 2003;1(suppl):S9
  12. Whelan T, MacKenzie R, Julian J, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002;94:1143–1150
  13. Schnitt SJ, Connolly JL, Khettry U, et al. Pathologic findings on re-excision of the primary site in breast cancer patients considered for treatment by primary radiation therapy. Cancer. 1987;59:675–681
  14. Colleoni M, Rotmensz N, Robertson C, et al. Very young women (<35 years) with operable breast cancer: features of disease at presentation. Ann Oncol. 2002;13:273–279
  15. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol. 1998;16:441–452
  16. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet. 2000;355:528–533
  17. Houghton J, George WD, Cuzick J, Duggan C, Fentiman IS, Spittle M. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;362:95–102
  18. Veronesi U, Salvadori B, Luini A, et al. Conservative treatment of early breast cancer. Long-term results of 1232 cases treated with quadrantectomy, axillary dissection, and radiotherapy. Ann Surg. 1990;211:250–259
  19. van de Vijver MJ, Peterse JL, Mooi WJ, et al. Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med. 1988;319:1239–1245
  20. Vos CB, ter Haar NT, Rosenberg C, et al. Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type. Br J Cancer. 1999;81:1410–1418
  21. Rich T, Allen RL, Wyllie AH. Defying death after DNA damage. Nature. 2000;407:777–783
  22. Kanaar R, Hoeijmakers JH, van Gent DC. Molecular mechanisms of DNA double strand break repair. Trends Cell Biol. 1998;8:483–489
  23. Jackson SP. Sensing and repairing DNA double-strand breaks. Carcinogenesis. 2002;23:687–696
  24. Bradbury JM, Jackson SP. The complex matter of DNA double-strand break detection. Biochem Soc Trans. 2003;31(Pt 1):40–44
  25. Kang J, Ferguson D, Song H, et al. Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression. Mol Cell Biol. 2005;25:661–670
  26. Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421:499–506
  27. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003;3:155–168
  28. Taylor AM, Harnden DG, Arlett CF, et al. Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity. Nature. 1975;258:427–429
  29. Shayeghi M, Seal S, Regan J, et al. Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients. Br J Cancer. 1998;78:922–927
  30. Weissberg JB, Huang DD, Swift M. Radiosensitivity of normal tissues in ataxia-telangiectasia heterozygotes. Int J Radiat Oncol Biol Phys. 1998;42:1133–1136
  31. Bremer M, Klopper K, Yamini P, Bendix-Waltes R, Dork T, Karstens JH. Clinical radiosensitivity in breast cancer patients carrying pathogenic ATM gene mutations: no observation of increased radiation-induced acute or late effects. Radiother Oncol. 2003;69:155–160
  32. Weeks DE, Paterson MC, Lange K, et al. Assessment of chronic gamma radiosensitivity as an in vitro assay for heterozygote identification of ataxia-telangiectasia. Radiat Res. 1991;128:90–99
  33. Sun X, Becker-Catania SG, Chun HH, et al. Early diagnosis of ataxia-telangiectasia using radiosensitivity testing. J Pediatr. 2002;140:724–731
  34. Meyer A, John E, Dork T, Sohn C, Karstens JH, Bremer M. Breast cancer in female carriers of ATM gene alterations: outcome of adjuvant radiotherapy. Radiother Oncol. 2004;72:319–323
  35. Khanna KK, Jackson SP. DNA double-strand breaks: signalling, repair and the caner connection. Nat Genet. 2001;27:247–254
  36. Gatti RA, Tward A, Concannon P. Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab. 1999;68:419–423
  37. Buchholz TA, Weil MM, Ashorn CL, et al. A Ser49Cys variant in the ataxia telangiectasia, mutated, gene that is more common in patients with breast carcinoma compared with population controls. Cancer. 2004;100:1345–1351
  38. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF. Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci U S A. 2002;99:925–930
  39. Takai H, Naka K, Okada Y, et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 2002;21:5195–5205
  40. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. Low-penetrance susceptibility to breast cancer due to CHEK2(∗)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31:55–59
  41. McPherson JP, Lemmers B, Hirao A, et al. Collaboration of BRCA1 and Chk2 in tumorigenesis. Genes Dev. 2004;18:1144–1153
  42. Sullivan A, Yuille M, Repellin C, et al. Concomitant inactivation of p53 and Chk2 in breast cancer. Oncogene. 2002;21:1316–1324
  43. Staalesen V, Falck J, Geisler S, et al. Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Oncogene. 2004;23:8535–8544
  44. Shaul Y, Ben-Yehoyada M. Role of c-Abl in the DNA damage stress response. Cell Res. 2005;15:33–35
  45. Lee SE, Mitchell RA, Cheng A, Hendrickson EA. Evidence for DNA-PK-dependent and -independent DNA double-strand break repair pathways in mammalian cells as a function of the cell cycle. Mol Cell Biol. 1997;17:1425–1433
  46. Takata M, Sasaki MS, Sonoda E, et al. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 1998;17:5497–5508
  47. Riballo E, Kuhne M, Rief N, et al. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell. 2004;16:715–724
  48. Powell SN, Kachnic LA. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene. 2003;22:5784–5791
  49. 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;20:4704–4716
  50. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171–182
  51. Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A. Disruption of BRCA2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation. EMBO Rep. 2002;3:255–260
  52. Tutt A, Gabriel A, Bertwistle D, et al. Absence of BRCA2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr Biol. 1999;9:1107–1110
  53. Daniels MJ, Wang Y, Lee M, Venkitaraman AR. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science. 2004;306:876–879
  54. Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4:814–819
  55. 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;3:389–395
  56. Scully R, Ganesan S, Vlasakova K, Chen J, Socolovsky M, Livingston DM. Genetic analysis of BRCA1 function in a defined tumor cell line. Mol Cell. 1999;4:1093–1099
  57. Scully R, Xie A, Nagaraju G. Molecular functions of BRCA1 in the DNA damage response. Cancer Biol Ther. 2004;3:521–527
  58. Wang H, Zeng ZC, Bui TA, et al. Nonhomologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA2. Cancer Res. 2001;61:270–277
  59. Xia F, Taghian DG, DeFrank JS, et al. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc Natl Acad Sci U S A. 2001;98:8644–8649
  60. Chen CF, Chen PL, Zhong Q, Sharp ZD, Lee WH. Expression of BRC repeats in breast cancer cells disrupts the BRCA2-RAD51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control. J Biol Chem. 1999;274:32931–32935
  61. Tutt A, Connor F, Bertwistle D, et al. Cell cycle and genetic background dependence of the effect of loss of BRCA2 on ionizing radiation sensitivity. Oncogene. 2003;22:2926–2931
  62. Trenz K, Landgraf J, Speit G. Mutagen sensitivity of human lymphoblastoid cells with a BRCA1 mutation. Breast Cancer Res Treat. 2003;78:69–79
  63. Nieuwenhuis B, Van Assen-Bolt AJ, Van Waarde-Verhagen MA, et al. BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage. Int J Radiat Biol. 2002;78:285–295
  64. Tutt A, Ashworth A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med. 2002;8:571–576
  65. Pierce LJ, Strawderman M, Narod SA, et al. Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol. 2000;18:3360–3369
  66. Leong T, Whitty J, Keilar M, et al. Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients. Int J Radiat Oncol Biol Phys. 2000;48:959–965
  67. Kote-Jarai Z, Williams RD, Cattini N, et al. Gene expression profiling after radiation-induced DNA damage is strongly predictive of BRCA1 mutation carrier status. Clin Cancer Res. 2004;10:958–963
  68. Yuan ZM, Huang Y, Ishiko T, et al. Regulation of RAD51 function by c-Abl in response to DNA damage. J Biol Chem. 1998;273:3799–3802
  69. Kitao H, Yuan ZM. Regulation of ionizing radiation-induced RAD52 nuclear foci formation by c-Abl-mediated phosphorylation. J Biol Chem. 2002;277:48944–48948
  70. Foray N, Marot D, Randrianarison V, et al. Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. Mol Cell Biol. 2002;22:4020–4032
  71. Yuan SS, Chang HL, Lee EY. Ionizing radiation-induced RAD51 nuclear focus formation is cell cycle-regulated and defective in both ATM(−/−) and c-Abl(−/−) cells. Mutat Res. 2003;525:85–92
  72. Russell JS, Brady K, Burgan WE, et al. Gleevec-mediated inhibition of RAD51 expression and enhancement of tumor cell radiosensitivity. Cancer Res. 2003;63:7377–7378
  73. Linke SP, Sengupta S, Khabie N, et al. p53 interacts with hRAD51 and hRAD54, and directly modulates homologous recombination. Cancer Res. 2003;63:2596–2605
  74. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002;108:153–164
  75. Borresen-Dale AL. TP53 and breast cancer. Hum Mutat. 2003;21:292–300
  76. Gudkov AV, Komarova EA. The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer. 2003;3:117–129
  77. Maeda T, Matsubara H, Koide Y, et al. Radiosensitivity of human breast cancer cells transduced with wild-type p53 gene is influenced by the p53 status of parental cells. Anticancer Res. 2000;20:869–874
  78. Fei P, El-Deiry WS. P53 and radiation responses. Oncogene. 2003;22:5774–5783
  79. Fox SB, Smith K, Hollyer J, Greenall M, Hastrich D, Harris AL. The epidermal growth factor receptor as a prognostic marker: results of 370 patients and review of 3009 patients. Breast Cancer Res Treat. 1994;29:41–49
  80. Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys. 2004;59(suppl 2):21–26
  81. van der Groep P, Bouter A, van der Zanden R, et al. Re: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 2004;96:712–713author reply 714
  82. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–712
  83. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792
  84. Wakeling AE, Barker AJ, Davies DH, et al. Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res Treat. 1996;38:67–73
  85. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139
  86. Sartor CI. Epidermal growth factor family receptors and inhibitors: radiation response modulators. Semin Radiat Oncol. 2003;13:22–30
  87. Zhou H, Kim YS, Peletier A, McCall W, Earp HS, Sartor CI. Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys. 2004;58:344–352
  88. Liang K, Lu Y, Jin W, Ang KK, Milas L, Fan Z. Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther. 2003;2:1113–1120
  89. Pietras RJ, Poen JC, Gallardo D, Wongvipat PN, Lee HJ, Slamon DJ. Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res. 1999;59:1347–1355
  90. McHugh PJ, Spanswick VJ, Hartley JA. Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol. 2001;2:483–490
  91. Pegram MD, Slamon DJ. Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity. Semin Oncol. 1999;26(4 suppl 12):89–95
  92. Haffty BG, Brown F, Carter D, Flynn S. Evaluation of HER-2 neu oncoprotein expression as a prognostic indicator of local recurrence in conservatively treated breast cancer: a case–control study. Int J Radiat Oncol Biol Phys. 1996;35:751–757
  93. Buchholz TA, Huang EH, Berry D, et al. HER2/neu-positive disease does not increase risk of locoregional recurrence for patients treated with neoadjuvant doxorubicin-based chemotherapy, mastectomy, and radiotherapy. Int J Radiat Oncol Biol Phys. 2004;59:1337–1342
  94. Lambin PW. Molecular explanation of variation in the alpha/beta ratio. ESTRO News. 2004;58:13
  95. Thacker J, Wilkinson RE. The genetic basis of cellular recovery from radiation damage: response of the radiosensitive irs lines to low-dose-rate irradiation. Radiat Res. 1995;144:294–300

PII: S0936-6555(05)00447-4

doi: 10.1016/j.clon.2005.11.011

Clinical Oncology
Volume 18, Issue 3 , Pages 166-178 , April 2006

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