Article | Published:

Molecular Diagnostics

SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment

British Journal of Cancer (2019) | Download Citation

Abstract

Background

SHON nuclear expression (SHON-Nuc+) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα+ breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT).

Methods

SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed.

Results

As previously reported, SHON-Nuc+ in high risk/ERα+ patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc [HR (95% CI) = 0.52 (0.34–0.78), = 0.002]. Meanwhile, in ERα patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto+) was significantly associated with a 50% death risk reduction compared with SHON-Cyto [HR (95% CI) = 0.50 (0.34–0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc or SHON-Cyto+ was associated with an increased pathological complete response (pCR) compared with SHON-Nuc+ [21 vs 4%; OR (95% CI) = 5.88 (1.28–27.03), p = 0.012], or SHON-Cyto [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18–25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc+ had a significantly lower distant relapse risk compared to those with SHON-Nuc [HR (95% CI) = 0.41 (0.19–0.87), p = 0.038], whereas SHON-Cyto+ patients had a significantly higher distant relapse risk compared to SHON-Cyto patients [HR (95% CI) = 4.63 (1.05–20.39), = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto+ was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13–44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc+ (p = 0.005), and between SHON-Nuc+ and tamoxifen therapy (p = 0.007), were both statistically significant.

Conclusion

SHON-Nuce+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT.

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Acknowledgements

The authors would like to thank the Breast Cancer Now Tissue Bank for the provision of breast cancer tissue samples for the study and all the participating patients of the study. The authors also thank Holly Perry for critical reading of the manuscript.

Author information

Affiliations

  1. Department of Clinical Oncology, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK

    • Tarek M. A. Abdel-Fatah
    • , Paul M. Moseley
    •  & Stephen Y. T. Chan
  2. National Liver Institute, Menoufyia University, Menoufyia, Egypt

    • Tarek M. A. Abdel-Fatah
  3. Auckland City Hospital, Auckland, New Zealand

    • Reuben J. Broom
  4. The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China

    • Jun Lu
    •  & Dong-Xu Liu
  5. The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, China

    • Baiqu Huang
  6. Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    • Lili Li
  7. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Breast Cancer in Shanghai, Cancer Institutes, Fudan University, Shanghai, China

    • Suling Liu
  8. Laboratory of Molecular Biology, Zhengzhou Normal University, Zhengzhou, China

    • Longxin Chen
  9. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

    • Runlin Z. Ma
  10. Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China

    • Wenming Cao
    •  & Xiaojia Wang
  11. The Centre for Biomedical and Chemical Sciences, School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand

    • Yan Li
    •  & Dong-Xu Liu
  12. Liggins Institute, University of Auckland, Auckland, New Zealand

    • Jo K. Perry
  13. Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Nottingham, UK

    • Mohammed Aleskandarany
    • , Christopher C. Nolan
    • , Ian O. Ellis
    •  & Andrew R. Green
  14. Department of Histopathology, School of Medicine, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK

    • Emad A. Rakha
  15. Tsinghua Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, China

    • Peter E. Lobie
  16. p53 Laboratory, Biomedical Sciences Institutes, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    • Le-Ann Hwang
    •  & David P. Lane

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Contributions

Conception and design: D-X.L., T.M.A.A-F., R.J.B., J.L., B.H., D.P.L., A.R.G. Development of methodology: D-X.L., T.M.A.A-F., M.A., L-A.H., C.C.N., A.R.G. Acquisition of data: D-X.L., T.M.A.A-F., M.A., L.L., L.C., W.C., X.W., L-A.H., P.M.M., C.C.N., S.Y.T.C., I.O.E., A.R.G. Analysis and interpretation of the data: D-X.L., T.M.A.A-F., R.J.B., M.A., J.L., B.H., S.L., D.P.L., J.K.P., P.E.L., S.Y.T.C., I.O.E., A.R.G. Writing, review, and/or revision of the manuscript: D-X.L., T.M.A.A-F., R.J.B., M.A., L.L., J.L., B.H., S.L., L.C., R.Z.M., W.C., X.W., L-A.H., D.P.L., Y.L., J.L., J.K.P., P.M.M., C.C.N., P.E.L., S.Y.T.C., I.O.E., A.R.G. Study supervision: D-X.L., J.L., B.H., R.Z.M., X.W., D.P.L., S.Y.T.C., I.O.E., A.R.G.

Competing interests

D.-X.L., T.M.A.A.-F., J.K.P., J.L., B.H., S.Y.T.C., A.R.G., and I.O.E. are named inventors on a PCT patent application PCT/NZ/2013/000188 and patent applications NZ603056, NZ616981, CN201380063947, AU2013332512, EP2013846652 and US15/103581; D.-X.L. and R.Z.M. are applicants for the applications PCT/NZ/2013/000188 and NZ616981; and D.-X.L. is the applicant for the application NZ603056. The remaining authors declare no competing interests.

Data availability

The data that support the findings of this study and materials described are available from the corresponding author upon reasonable request. Some restrictions may apply.

Ethics approval

All patients were consented as per hospital standard of care. This study was approved by the Hospital Research and Innovations Department and the Nottingham Research Ethics Committee 2 under the title "Development of a molecular genetic classification of BC" (REC Reference No C202313).

Funding

This work was supported by the Breast Cancer Foundation New Zealand (to D.-X.L. & R.J.B., no grant number), the New Zealand Breast Cancer Cure (to D.-X.L., no grant number), the Health Research Council of New Zealand (14/704 to D.-X.L., R.J.B., T.M.A.A.-F., J.L., A.R.G., S.Y.T.C. & I.O.E.), the Auckland Medical Research Foundation (1113022 to D-X.L.), the Margaret Morley Medical Trust (to D.-X.L., no grant number), the Maurice & Phyllis Paykel Trust (to D.-X.L., no grant number), the Kelliher Charitable Trust (to D.-X.L., no grant number), the Lottery Health Research of New Zealand (340942 to D.-X.L., I.O.E., A.R.G., S.Y.T.C. & T.M.A.A.-F.), the Biopharma Programme of the University of Auckland (to D.-X.L., no grant number), and the Shenzhen Development and Reform Commission Subject Construction Project (2017/1434 to P.E.L).

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding authors

Correspondence to Andrew R. Green or Dong-Xu Liu.

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DOI

https://doi.org/10.1038/s41416-019-0405-x