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

Abdel-Fatah, Tarek M.A.; Broom, Reuben J.; Lu, Jun; Moseley, Paul M.; Huang, Baiqu; Li, Lili; Liu, Suling; Chen, Longxin; Ma, Runlin Z; Cao, Wenming; Wang, Xiaojia; Li, Yan; Perry, Jo K.; Aleskandarany, Mohammed; Nolan, Christopher C; Rakha, Emad A; Lobie, Peter E; Chan, Stephen Y.T.; Ellis, Ian O; Hwang, Le-Ann; Lane, David P; Green, Andrew R; Liu, Dong-Xu

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


Authors

Tarek M.A. Abdel-Fatah

Reuben J. Broom

Jun Lu

Paul M. Moseley

Baiqu Huang

Lili Li

Suling Liu

Longxin Chen

Runlin Z Ma

Wenming Cao

Xiaojia Wang

Yan Li

Jo K. Perry

Mohammed Aleskandarany

Christopher C Nolan

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Peter E Lobie

Stephen Y.T. Chan

Le-Ann Hwang

David P Lane

Dong-Xu Liu



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, n=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), p=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), p=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-Nuc+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT.

Citation

Abdel-Fatah, T. M., Broom, R. J., Lu, J., Moseley, P. M., Huang, B., Li, L., …Liu, D. (2019). SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment. British Journal of Cancer, 120(7), 728–745. https://doi.org/10.1038/s41416-019-0405-x

Journal Article Type Article
Acceptance Date Jan 25, 2019
Online Publication Date Feb 28, 2019
Publication Date Feb 28, 2019
Deposit Date Jan 28, 2019
Publicly Available Date Aug 29, 2019
Journal British Journal of Cancer
Print ISSN 0007-0920
Electronic ISSN 1532-1827
Publisher Cancer Research UK
Peer Reviewed Peer Reviewed
Volume 120
Issue 7
Pages 728–745
DOI https://doi.org/10.1038/s41416-019-0405-x
Keywords Cancer Research; Oncology
Public URL https://nottingham-repository.worktribe.com/output/1499279
Publisher URL https://www.nature.com/articles/s41416-019-0405-x
Additional Information Received: 18 October 2018; Revised: 27 January 2019; Accepted: 29 January 2019; First Online: 28 February 2019; : 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.; : 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.; : 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).; : 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).; : 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).
Contract Date Jan 28, 2019

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