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Familial Cancer

, Volume 8, Issue 3, pp 173–177 | Cite as

Response to neo-adjuvant chemotherapy in BRCA1 and BRCA2 related stage III breast cancer

  • Ayala Hubert
  • Bela Mali
  • Tamar Hamburger
  • Yakir Rottenberg
  • Beatrice Uziely
  • Tamar Peretz
  • Luna Kadouri
Article

Abstract

Pathological features and consequently, tumor response differ between BRCA1/2 carriers and sporadic breast cancer (BC) cases. It is expected that BRCA1/2 associated tumors will be more vulnerable to DNA damaging agents and irradiation due to their function in DNA repair. In addition, very high pathological complete response (pCR) rate of approximately 40–50% to neo-adjuvant chemotherapy were reported by two studies. We describe the clinical outcome, i.e.; complete response (cCR), major pathological response (more than 80% reduction in tumor mass), pathologiacl CR (pCR) and local control rates in 15 BRCA1 and 7 BRCA2 carriers, all diagnosed at stage III and treated with anthracyclin based chemotherapy, mastectomy, and irradiation. cCR were found in 6/15 carriers and in 1/7 BRCA2 carriers (P = 0.3). Rate of major pathological response were 4/15 (26.6%) in BRCA1 compared with none of BRCA2 carriers (P = 0.3). Of them, pCR was recorded in 2/15 of BRCA1 carriers. Clinical and pathological nodal involvements were lower in BRCA1 carriers. While all BRCA2 carriers remained node positive as compared to 50% of BRCA1 carriers (P = 0.047), overall survival was similar in both groups. However, approximately 1/3 of BRCA1 carriers did not respond to chemotherapy and 4/15 died within 5 years of diagnosis. We found a non-significant higher clinical and pathological response rate among BRCA1 carriers in response to neo-adjuvant chemotherapy compared with BRCA2 carriers. Our results suggest chemoresistance of approximately a 1/3 of BRCA1 associated tumors. Tumors of BRCA2 carriers are resistant to chemotherapy, while the estrogen receptor positive nature of tumors results in better post recurrence survival.

Keywords

BRCA1/2 Breast cancer Neo-adjuvant chemotherapy Response 

References

  1. 1.
    Marcus JN, Watson P, Page DL et al (1996) Hereditary breast cancer: pathology, prognosis and BRCA1 and BRCA2 gene linkage. Cancer 77:697–709. doi:10.1002/(SICI)1097-0142(19960215)77:4<697::AID-CNCR16>3.0.CO;2-WPubMedCrossRefGoogle Scholar
  2. 2.
    Hamann U, Sinn HP (2000) Survival and tumor characteristics of German hereditary breast cancer patients. Breast Cancer Res Treat 59:185–192. doi: 10.1023/A:1006350518190 PubMedCrossRefGoogle Scholar
  3. 3.
    Rennert G, Bisland-Naggan S, Barnett-Griness O et al (2007) Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 357:115–123. doi: 10.1056/NEJMoa070608 PubMedCrossRefGoogle Scholar
  4. 4.
    Foulkes WD, Wong N, Brunet JS et al (1997) Germline mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer. Clin Cancer Res 3:2465–2469PubMedGoogle Scholar
  5. 5.
    Stoppa-Lyonnet D, Ansquer Y, Dreyfus H et al (2000) Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol 18:4035–4039Google Scholar
  6. 6.
    Robson ME, 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–R17. doi: 10.1186/bcr658 PubMedCrossRefGoogle Scholar
  7. 7.
    Boyd D, Somoda Y, Federici MG et al (2000) Clinicopathologic features of BRCA linked and sporadic ovarian cancer. J Am Med Assoc 283:2260–2265. doi: 10.1001/jama.283.17.2260 CrossRefGoogle Scholar
  8. 8.
    McGuire V, Whitmore AS, Norris R, Oakley-Girvan I (2000) Survival in epithelial ovarian cancer patients with prior breast cancer. Am J Epidemiol 152:528–532. doi: 10.1093/aje/152.6.528 PubMedCrossRefGoogle Scholar
  9. 9.
    Ben David Y, Chetrit A, Hirsh-Yechezkel G et al (2003) Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20:463–466. doi: 10.1200/JCO.20.2.463 CrossRefGoogle Scholar
  10. 10.
    Foulkes DF (2006) BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis. Fam Cancer 5:135–142. doi: 10.1007/s10689-005-2832-5 PubMedCrossRefGoogle Scholar
  11. 11.
    Lakhani SR, Jacquemier J, Sloane JP et al (1998) Multifactortial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90:1138–1145. doi: 10.1093/jnci/90.15.1138 PubMedCrossRefGoogle Scholar
  12. 12.
    Levine DA, Federici MG, Reuter VE, Boyd J (2002) Cell proliferation and apoptosis in BRCA-associated hereditary ovarian cancer. Gynecol Oncol 85:431–434. doi: 10.1006/gyno.2002.6646 PubMedCrossRefGoogle Scholar
  13. 13.
    Foulkes WD, Metcalfe K, Hanna W et al (2003) Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinoma. Cancer 98(8):1569–1577. doi: 10.1002/cncr.11688 PubMedCrossRefGoogle Scholar
  14. 14.
    Chappuis DO, Goffin J, Wong N, Perret C (2002) A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 39:608–610. doi: 10.1136/jmg.39.8.608 PubMedCrossRefGoogle Scholar
  15. 15.
    Delaloge S, Pelissier P, Kloos I et al (2002) BRCA1 linked breast cancer is highly more chemosensitive than its BRCA2-linked or sporadic counterparts. 27th ESMO, Niece, France, Abstract no. 120Google Scholar
  16. 16.
    Rouzier R, Perou CM, Symmans WF et al (2005) Breat cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11(16):5678–5685. doi: 10.1158/1078-0432.CCR-04-2421 PubMedCrossRefGoogle Scholar
  17. 17.
    Carey LA, Dees EC, Sawyer L et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334. doi: 10.1158/1078-0432.CCR-06-1109 PubMedCrossRefGoogle Scholar
  18. 18.
    Liedtke C, Mazouni C, Hess KR et al (2008) Response to neoadjuvant chemotherapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281. doi: 10.1200/JCO.2007.14.4147 PubMedCrossRefGoogle Scholar
  19. 19.
    Bremer M, Steinmann D, Dork T, Borger J, Rades D, Karstens JH (2001) Bilateral breast carcinoma and local recurrence: prevalence of BRCA-1 and BRCA-2 gene mutations in an unselected patient sample. Strahlenther Onkol 177:325–329. German. doi: 10.1007/PL00002414 Google Scholar
  20. 20.
    MacLachlan TK, Takimor R, El-Deiry WS (2002) BRCA1 directs a selective p53-dependent transcriptional response towards growth arrest and DNA repair targets. Mol Cell Biol 22:4280–4292. doi: 10.1128/MCB.22.12.4280-4292.2002 PubMedCrossRefGoogle Scholar
  21. 21.
    Fabbro M, Schuechner S, Av WW, Henderson BR (2004) BARD1 regulates BRCA1 apoptosis function by a mechanism involving nuclear retention. Exp Cell Res 298:661–673. doi: 10.1016/j.yexcr.2004.05.004 PubMedCrossRefGoogle Scholar
  22. 22.
    Greenblatt MS, Chappuis PO, Bond JP et al (2001) TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germline mutations: distinctive spectrum and structural distributions. Cancer Res 61:4092–4097PubMedGoogle Scholar
  23. 23.
    Buller RE, Lallas TA, Shahin MS et al (2001) The P53 mutation spectrum associated with BRCA1 mutation ovarian cancer. Clin Cancer Res 7:831–838PubMedGoogle Scholar
  24. 24.
    Saal L, Grunberger-Saal SK, Persson C et al (2008) Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers deficient DSB repair. Nat Genet 40(1):102–107. doi: 10.1038/ng.2007.39 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Ayala Hubert
    • 1
  • Bela Mali
    • 2
  • Tamar Hamburger
    • 1
  • Yakir Rottenberg
    • 1
  • Beatrice Uziely
    • 1
  • Tamar Peretz
    • 1
  • Luna Kadouri
    • 1
  1. 1.Sharett Institute of OncologyHebrew University-Hadassah Medical CenterJerusalemIsrael
  2. 2.Pathology DepartmentHebrew University-Hadassah Medical CenterJerusalemIsrael

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