Breast Cancer Research and Treatment

, Volume 120, Issue 1, pp 119–126

Is the breast-conserving treatment with radiotherapy appropriate in BRCA1/2 mutation carriers? Long-term results and review of the literature

  • Youlia M. Kirova
  • Alexia Savignoni
  • Brigitte Sigal-Zafrani
  • Anne de La Rochefordiere
  • Rémy J. Salmon
  • Pascale This
  • Bernard Asselain
  • Dominique Stoppa-Lyonnet
  • Alain Fourquet
Clinical Trial

Abstract

As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, we investigated after long-term follow-up whether mutation status influenced the rate of ipsilateral and contralateral breast cancers after breast-conserving treatment (BCT). BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer who had undergone BCT and radiotherapy. Patients were matched to 261 controls with sporadic breast cancer according to age at diagnosis and year of treatment. Controls were followed up for at least as long as the interval between diagnosis and genetic screening in familial cases. Rates of ipsilateral and contralateral cancer between groups were compared by the log-rank test. The BRCA1/2 mutations occurred in 20.6% of tested patients. Tumours in mutation carriers were more likely to be grade III (P < 10−4) and oestrogen receptor negative (P = 0.005) than in non-carriers and controls. Overall median follow-up was 161 months. There was no significant difference in ipsilateral tumours between mutation carriers, non-carriers and controls (P = 0.13). On multivariate analysis, age was the most significant predictor for ipsilateral recurrence (P < 10−3). The rate of contralateral cancer was significantly higher in familial cases: 40.7% (mutation carriers), 20% (non-carriers), and 11% (controls) (P < 10−4). After 13.4 years of follow-up, the rate of ipsilateral tumours was no higher in mutation carriers than in non-carriers or controls. As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, BCT is a possible treatment option.

Keywords

BRCA1/2 mutations Breast-conserving treatment Radiotherapy Recurrence 

References

  1. 1.
    Robson ME (2002) Clinical considerations in the management of individuals at risk for hereditary breast and ovarian cancer. Cancer Control 9:457–465PubMedGoogle Scholar
  2. 2.
    Adem C, Reynolds C, Soderberg CL et al (2003) Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 97:1–11CrossRefPubMedGoogle Scholar
  3. 3.
    Chappuis PO, Nethercot V, Foules WD et al (2000) Clinico-pathological characteristics of BRCA1 and BRCA2-related breast cancer. Semin Surg Oncol 18:287–295CrossRefPubMedGoogle Scholar
  4. 4.
    Stoppa-Lyonnet D, Ansquer Y, Dreyfus H et al (2000) Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol 18:4053–4059PubMedGoogle Scholar
  5. 5.
    Foulkes WD, Chappuis PO, Wong N et al (2000) Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome. Ann Oncol 11:307–313CrossRefPubMedGoogle Scholar
  6. 6.
    Verhoog LC, Brekelmans CTM, Seynaeve C et al (1998) Survival and tumour characteristics of breast cancer patients with germline mutations of BRCA1. Lancet 351:316–321CrossRefPubMedGoogle Scholar
  7. 7.
    Breast Cancer Linkage Consortium (1997) Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349:1505–1510CrossRefGoogle Scholar
  8. 8.
    Lakhani SR, Jacquemier J, Sloane JP et al (1998) Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90:1138–1145CrossRefPubMedGoogle Scholar
  9. 9.
    Robson M, Chappuis PO, Satagopan J et al (2004) 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 6:R8–R17CrossRefPubMedGoogle Scholar
  10. 10.
    Venkitaraman A (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182CrossRefPubMedGoogle Scholar
  11. 11.
    Powel SN, Kachnic LA (2003) Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionising radiation. Oncogene 22:5784–5791CrossRefGoogle Scholar
  12. 12.
    Baeyens A, Thierens H, Claes K et al (2002) Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition. Br J Cancer 87:1379–1385CrossRefPubMedGoogle Scholar
  13. 13.
    Freneaux P, Stoppa-Lyonnet D, Mouret E et al (2000) Low expression of bcl-2 in Brca1-associated breast cancers. Br J Cancer 83:1318–1322CrossRefPubMedGoogle Scholar
  14. 14.
    Hedenfalk I, Duggan D, Chen Y et al (2001) Gene-expression profiles in hereditary breast cancer. N Engl J Med 344:539–548CrossRefPubMedGoogle Scholar
  15. 15.
    Cortez D, Wang Y, Qin J et al (1999) Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks. Science 286:1162–1166CrossRefPubMedGoogle Scholar
  16. 16.
    Scully R, Chen J, Ochs RL et al (1997) Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90:425–435CrossRefPubMedGoogle Scholar
  17. 17.
    Xu X, Weaver Z, Linke SP et al (1999) Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3:389–395CrossRefPubMedGoogle Scholar
  18. 18.
    Brodie SG, Xu X, Qiao W et al (2000) Multiple genetic changes are associated with mammary tumorigenesis in BRCA1 conditional knockout mice. Oncogene 20:7514–7523CrossRefGoogle Scholar
  19. 19.
    Fourquet A, Stoppa-Lyonnet D, Sigal-Zafrani B et al (2009) Familial invasive breast cancer: clinical response to induction chemotherapy or radiotherapy related to BRCA1 and BRCA2 mutations. Am J Clin Oncol 32:127–131CrossRefPubMedGoogle Scholar
  20. 20.
    Fisher B, Anderson S, Bryant J et al (2002) Twenty-year follow-up of a randomised trial comparing total mastectomy, lumpectomy and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233–1241CrossRefPubMedGoogle Scholar
  21. 21.
    Clark R, McCullock P, Levine M et al (1992) Randomised clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer. J Natl Cancer Inst 84:683–689CrossRefPubMedGoogle Scholar
  22. 22.
    Van Dongen JA, Voogd AC, Fentiman IS et al (2000) Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: EORTC 10801 trial. J Natl Cancer Inst 92:1143–1150CrossRefPubMedGoogle Scholar
  23. 23.
    Veronesi U, Cascinelli N, Mariani L et al (2002) Twenty-year follow-up of a randomised study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227–1232CrossRefPubMedGoogle Scholar
  24. 24.
    Jacobson JA, Danforth DN, Cowan KH et al (1995) Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 332:907–911CrossRefPubMedGoogle Scholar
  25. 25.
    Blichert-Toft M, Roce C, Anderson JA et al (1992) Danish randomised trial comparing breast conservation therapy with mastectomy: six years of life table analysis. Danish Breast Cancer Cooperative group. J Natl Cancer Inst Monograms 11:19–25Google Scholar
  26. 26.
    Arriagada R, Le MG, Guinebretière JM et al (2003) Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients. Ann Oncol 14:1617–1622CrossRefPubMedGoogle Scholar
  27. 27.
    Early Breast Cancer Trialists’ Collaborative Group (2005) 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 366:2087–2106Google Scholar
  28. 28.
    Kirova YM, Stoppa-Lyonnet D, Savignoni A et al (2005) Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Eur J Cancer 41:2304–2311CrossRefPubMedGoogle Scholar
  29. 29.
    Pierce LJ, Strawderman M, Narod SA et al (2000) Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18:3360–3369PubMedGoogle Scholar
  30. 30.
    Pierce L, Levin A, Rebbeck T et al (2006) Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 24:2437–2443CrossRefPubMedGoogle Scholar
  31. 31.
    Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C et al (2007) Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer 43(5):867–876CrossRefPubMedGoogle Scholar
  32. 32.
    Delaloge S, Kloos I, Ariane D et al (2003) Young age is the major predictor of local relapse among conservatively treated BRCA1-, BRCA2-, or non BRCA-linked hereditary breast cancer. ASCO Proc 22(abstr 41):11Google Scholar
  33. 33.
    Kirova YM, De Rycke Y, Gambotti L et al (2008) Second malignancies after breast cancer: the impact of different treatment modalities. Br J Cancer 98:870–874CrossRefPubMedGoogle Scholar
  34. 34.
    Kirova Y, Vilcoq JR, Asselain B et al (2005) Radiation-induced sarcomas (RIS) following radiotherapy for breast cancer: a large-scale single institution review. Cancer 104:856–863CrossRefPubMedGoogle Scholar
  35. 35.
    Thompson D, Easton DF (2002) The breast cancer linkage consortium: cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358–1365PubMedGoogle Scholar
  36. 36.
    Kirova YM, Fourquet A, Savignoni A et al (2006) Risk of second non breast malignancies (SNBM) in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Am J Immunol 2:61–63CrossRefGoogle Scholar
  37. 37.
    Haffty BG, Harrold E, Khan AJ et al (2002) Outcome of conservatively managed early-onset breast cancer by BRCA1/BRCA2 status. Lancet 359:1471–1477CrossRefPubMedGoogle Scholar
  38. 38.
    Seynaeve C, Verhoog LC, Van De Bosch LM et al (2004) Ipsilateral breast tumour recurrence in hereditary breast cancer following breast-conserving therapy. Eur J Cancer 40:1150–1158CrossRefPubMedGoogle Scholar
  39. 39.
    Bremer M, Doerk T, Sohn C et al (2003): Local relapse after postoperative radiotherapy in patients with bilateral breast cancer by BRCA1/2 status. ASCO Proc 22(abstr 42):11Google Scholar
  40. 40.
    Turner BC, Harrold E, Matloff E et al (1999) BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations. J Clin Oncol 17:3017–3024PubMedGoogle Scholar
  41. 41.
    Garcia-Etienne CA, Barile M, Gentilini OD et al (2009) Breast-conserving surgery in BRCA1/2 mutation carriers: are we approaching an answer? Ann Surg Oncol (in press)Google Scholar
  42. 42.
    Stoppa-Lyonnet D, Laurent-Puig P, Essioux L et al (1997) BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group. Am J Hum Genet 60:1021–1030PubMedGoogle Scholar
  43. 43.
    Wagner T, Stoppa-Lyonnet D, Fleischmann E et al (1999) Denaturing high-performance liquid chromatography detects reliably BRCA1 and BRCA2 mutations. Genomics 62:369–376CrossRefPubMedGoogle Scholar
  44. 44.
    Claus EB, Risch N, Thompson WD (1991) Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 48:232–242PubMedGoogle Scholar
  45. 45.
    Easton DF, Bishop DT, Ford D et al (1993) Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52:678–701PubMedGoogle Scholar
  46. 46.
    Salmon RJ, Asselain B, Le Gal M et al (1997) Twelve years experience of breast cancer at the Institut Curie: improvement of survival and value of screening mammographics. Breast 6:202–205CrossRefGoogle Scholar
  47. 47.
    Kirova Y, Servois V, Campana F et al (2006) CT- scan based localization of the internal mammary chain and supra clavicular nodes for breast cancer radiation therapy planning. Radiother Oncol 79:310–315CrossRefPubMedGoogle Scholar
  48. 48.
    Campana F, Kirova YM, Rosenwald JC et al (2005) Breast radiotherapy in the lateral decubitus position–a technique to prevent lung and heart irradiation. Int J Radiat Oncol Biol Phys 61:1348–1354PubMedGoogle Scholar
  49. 49.
    Kirova YM, Fournier-Bidoz N, Servois V et al (2008) How to boost the breast tumor bed? A multidisciplinary approach in 8 steps. Int J Radiat Oncol Biol Phys 72:494–500PubMedGoogle Scholar
  50. 50.
    Kaplan EL, Meier P (1958) Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  51. 51.
    Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170PubMedGoogle Scholar
  52. 52.
    Cox DR (1972) Regression models and life tables. J R Stat Soc 34:187–220Google Scholar
  53. 53.
    Narod SA, Brunet JS, Ghadirian P et al (2000) Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case–control study. Lancet 356:1876–1881CrossRefPubMedGoogle Scholar
  54. 54.
    Pierce L (2002) Radiotherapy for breast cancer in BRCA1/BRCA2 carriers: clinical issues and management dilemmas. Semin Radiat Oncol 12:352–361CrossRefPubMedGoogle Scholar
  55. 55.
    Meijers-Heijboer EJ, Verhoog LC, Brekelmans CTM et al (2000) Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355:2015–2020CrossRefPubMedGoogle Scholar
  56. 56.
    Reicht A (2009) Contralateral prophylactic mastectomy: caveat emptor. J Clin Oncol 27:1347–1349CrossRefGoogle Scholar
  57. 57.
    Drew Y, Calvert H (2008) The potential of PARP inhibitors in genetic breast and ovarian cancers. Ann N Y Acad Sci 1138:136–145CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Youlia M. Kirova
    • 1
  • Alexia Savignoni
    • 2
  • Brigitte Sigal-Zafrani
    • 3
  • Anne de La Rochefordiere
    • 1
  • Rémy J. Salmon
    • 4
  • Pascale This
    • 5
  • Bernard Asselain
    • 2
  • Dominique Stoppa-Lyonnet
    • 5
    • 6
  • Alain Fourquet
    • 1
  1. 1.Department of Radiation OncologyInstitut CurieParis Cedex 05France
  2. 2.Department of BiostatisticsInstitut CurieParis Cedex 05France
  3. 3.Department of PathologyInstitut CurieParis Cedex 05France
  4. 4.Department of SurgeryInstitut CurieParis Cedex 05France
  5. 5.Department of Oncology GeneticsInstitut CurieParis Cedex 05France
  6. 6.University Paris DescartesParisFrance

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