Advertisement

Breast Cancer Research and Treatment

, Volume 140, Issue 2, pp 253–262 | Cite as

Immunohistochemical BAG1 expression improves the estimation of residual risk by IHC4 in postmenopausal patients treated with anastrazole or tamoxifen: a TransATAC study

  • Maria AfentakisEmail author
  • Mitch Dowsett
  • Ivana Sestak
  • Janine Salter
  • Tony Howell
  • Aman Buzdar
  • John Forbes
  • Jack Cuzick
Preclinical Study

Abstract

BAG1 is a multifunctional anti-apoptotic protein located on chromosome 9q12, which binds to Bcl-2. BAG1 is present as a separate module in the GHI-RS 21-gene panel. It may provide additional prognostic information as an immunohistochemical marker when added to IHC4. Analysis of BAG1 was performed on archival tumour blocks from patients from the anastrozole and tamoxifen arms of the ATAC trial of 5 years endocrine therapy in postmenopausal women with oestrogen receptor (ER)-positive primary breast cancer. Staining was scored separately as nuclear or cytoplasmic. Statistical analyses were performed on data from median 10-year follow-up with distant recurrence as primary endpoint. Data on both nuclear and cytoplasmic BAG1 as well as the IHC4 markers (ER, PgR, HER2 and Ki67) were available on 963 ER-positive cases of which 860 were HER2-negative. Cytoplasmic and nuclear BAG1 were highly correlated (Spearman r = 0.79, p < 00001). Women with higher BAG1 expression developed 30 % fewer distant recurrences compared to those with low expression. Nuclear BAG1 contributed significantly to the clinical and IHC4 models with added information being greater in node-positive cases. Similar results were seen if all recurrences were the endpoints. BAG1 expression provides significant prognostic information when added to the classical clinicopathological parameters and IHC4, particularly in node-positive patients.

Keywords

BAG1 Breast cancer TransATAC study Distance recurrence IHC4 

Notes

Acknowledgments

This study is supported by the Royal Marsden National Institute for Health Research Biomedical Research Centre, Cancer Research UK Programme Grant No: C569-10404, and Grants from Breakthrough Breast Cancer and AstraZeneca. The authors are grateful to Professor Michael Baum for his guidance and advice throughout the ATAC trial.

Disclosures

JC receives trial support and sits on an advisory board for AstraZeneca. MD has received lecture fees and research grants from AstraZeneca in the last 2 years. All remaining authors have declared no conflict of interest.

Supplementary material

10549_2013_2628_MOESM1_ESM.xls (26 kb)
Supplementary Table 1: Univariate and multivariate analysis of cytoplasmic and nuclear BAG1 (considered as positive or negative). (XLS 26 kb)
10549_2013_2628_MOESM2_ESM.xlsx (41 kb)
Supplementary Table 2: Univariate and multivariate analysis of cytoplasmic and nuclear BAG1 (considered as positive or negative). (XLSX 41 kb)

References

  1. 1.
    Dowsett M, Goldhirsch A, Hayes DF et al (2007) International Web-based consultation on priorities for translational breast cancer research. Breast Cancer Res 9(6):R81PubMedCrossRefGoogle Scholar
  2. 2.
    Cuzick J, Sestak I, Baum M et al (2010) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 11(12):1135–1141PubMedCrossRefGoogle Scholar
  3. 3.
    Dowsett M, Cuzick J, Wale C et al (2010) Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol 28(11):1829–1834PubMedCrossRefGoogle Scholar
  4. 4.
    Tang SC, Beck J, Murphy S et al (2004) BAG-1 expression correlates with Bcl-2, p53, differentiation, estrogen and progesterone receptors in invasive breast carcinoma. Breast Cancer Res Treat 84(3):203–213PubMedCrossRefGoogle Scholar
  5. 5.
    Dowsett M, Allred C, Knox J et al (2008) Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the arimidex, tamoxifen, alone or in combination trial. J Clin Oncol 26(7):1059–1065PubMedCrossRefGoogle Scholar
  6. 6.
    Cuzick J, Dowsett M, Pineda S et al (2011) Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the genomic health recurrence score in early breast cancer. J Clin Oncol 29(32):4273–4278PubMedCrossRefGoogle Scholar
  7. 7.
    Christiansen J, Bartlett JMS, Gustavson M et al. (2012) Validation of IHC4 algorithms for prediction of risk of recurrence in early breast cancer using both conventional and quantitative IHC approaches. J Clin Oncol 30 (suppl: abstract 517):2977–2298Google Scholar
  8. 8.
    Paik S, Shak S, Tang G et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826PubMedCrossRefGoogle Scholar
  9. 9.
    Townsend PA, Stephanou A, Packham G et al (2005) BAG-1: a multi-functional pro-survival molecule. Int J Biochem Cell Biol 37(2):251–259PubMedCrossRefGoogle Scholar
  10. 10.
    Townsend PA, Dublin E, Hart IR et al (2002) BAG-I expression in human breast cancer: interrelationship between BAG-1 RNA, protein, HSC70 expression and clinico-pathological data. J Pathol 197(1):51–59PubMedCrossRefGoogle Scholar
  11. 11.
    Nadler Y, Camp RL, Giltnane JM et al (2008) Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer. Breast Cancer Res 10(2):R35PubMedCrossRefGoogle Scholar
  12. 12.
    Tang SC (2002) BAG-1, an anti-apoptotic tumour marker. IUBMB Life 53(2):99–105PubMedCrossRefGoogle Scholar
  13. 13.
    Millar EK, Anderson LR, McNeil CM et al (2009) BAG-1 predicts patient outcome and tamoxifen responsiveness in ER-positive invasive ductal carcinoma of the breast. Br J Cancer 100(1):123–133PubMedCrossRefGoogle Scholar
  14. 14.
    Gee JM, Aleskandarany MA, Finlay P et al. (2010) Immunohistochemical markers progesterone, HER2, Ki67 and Bcl-2-associated anthogene 1 and prediction of adjuvant tamoxifen treatment outcome in ER+ early breast cancer In: San Antonio breast cancer symposium, San AntonioGoogle Scholar
  15. 15.
    Barton S, Zabaglo L, A’Hern R et al (2012) Assessment of the contribution of the IHC4+C score to decision making in clinical practice in early breast cancer. Br J Cancer 106(11):1760–1765PubMedCrossRefGoogle Scholar
  16. 16.
    Harper-Wynne CL, Sacks NP, Shenton K et al (2002) Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. J Clin Oncol 20(4):1026–1035PubMedCrossRefGoogle Scholar
  17. 17.
    Petry IB, Fieber E, Schmidt M et al (2010) ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer. Clin Cancer Res 16(2):451–460PubMedCrossRefGoogle Scholar
  18. 18.
    Cutress RI, Townsend PA, Sharp A et al (2003) The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription. Oncogene 22(32):4973–4982PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Maria Afentakis
    • 1
    Email author
  • Mitch Dowsett
    • 1
  • Ivana Sestak
    • 2
  • Janine Salter
    • 1
  • Tony Howell
    • 3
  • Aman Buzdar
    • 4
  • John Forbes
    • 5
  • Jack Cuzick
    • 2
  1. 1.Department of Academic BiochemistryThe Royal Marsden HospitalLondonUK
  2. 2.Wolfson Institute of Prevention MedicineQueen Mary University of LondonLondonUK
  3. 3.Department of Medical Oncology, School of Cancer and Enabling ScienceChristie Hospital NHS TrustManchesterUK
  4. 4.MD Anderson Cancer CenterUniversity of TexasHoustonUSA
  5. 5.School of Medicine and Public HealthThe University of NewcastleCallagenAustralia

Personalised recommendations