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

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, S., Chen, L., Ma, R. Z., Cao, W., Wang, X., Li, Y., Perry, J. K., Aleskandarany, M., Nolan, C. C., Rakha, E. A., Lobie, P. E., Chan, S. Y., Ellis, I. O., Hwang, L.-A., …Liu, D.-X. (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