Sperm associated antigen 5 (SPAG5) predicts resistance to endocrine therapy and sensitivity to chemotherapy in oestrogen receptor positive (ER+) breast cancer (BC): A tool for BC precision medicine


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Tarek Abdel-Fatah1,Graham Ball2,Amy McCart Reid3,Peter Simpson4,Sunil Lakhani4,Lorinc Pongor5,Balazs Gyorffy5,Paul Moseley1,Andrew Green6,Carlos Caldas7,Rebekah Webb1,Ian Ellis6,Stephen Chan1
1Clinical Oncology Department, University of Nottingham Hospitals NHS Trust,2John van Geest Cancer Research Centre, Nottingham Trent University, UK,3The University of Queensland, UQ Centre for Clinical Research, Herston, 4029, QLD, Australia,4The University of Queensland, School of Medicine, Herston, 4006, QLD, Australia,5MTA TTK Lendület Cancer Biomarker Research Group, Semmelweis University 2nd Department of Pediatrics, Budapest, Magyar, Hungary,6Histopathology department, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, UK,7University of Cambridge, and 5Cancer Research UK, Cambridge Research Institute, UK

Abstract

Background

SPAG5 amplification and over-expression is common in luminal B breast cancer.

Method

SPAG5 mRNA and protein expression and their association with over-all survival (OS) were determined in 4998 cases of ER+ BC. The association between the pathological complete response (pCR) to neoadjuvant anthracycline based chemotherapy (Neo-Adj-ACT) and SPAG5 expression (mRNA, protein) was evaluated in 1073 and 332 patients with ER+ BC respectively. The association between the dynamic response to the neoadjuvant endocrine therapy (Neo-Adj-ET) and SPAG5 mRNA expression was evaluated in 101 cases of ER+ BC. The association between distant relapse risk (DRR) and SPAG5 were tested in patients who received Neo-Adj-ACT or adjuvant chemotherapy in addition to 5-year adjuvant tamoxifen (mRNA: n=2819; protein: n=2501).

Results

SPAG5-overexpression (SPAG5+; mRNA, protein) were associated with shorter OS (HR: 1.31, and 1.90, ps<0.001); respectively). Multi-variable analyses confirmed that SPAG5+ mRNA and protein expression were associated with higher pCR to Neo-Adj-ACT (OR: 1.90; p=0.041 and 23.03; p<0.0001; respectively).  Down-regulation of SPAG5 has been observed after 2-weeks on Neo-Adj-ET and this predicted the dynamic clinical response .SPAG5 mRNA was highly expressed in non-responders vs., non-responders tumors (p=0.014). In patients received 5-year Tamoxifen with either lymph node positive (LN+) or LN negative (LN-), SPAG5+ BC (mRNA, protein) exhibited a two-fold increase in DRR (ps<0·0001).  In contrast, in patients received Adj-ACT in addition to 5-year of Tamoxifen with either LN+ or LN-, SPAG5+ (mRNA, protein) exhibited a similar DRR to that with low SPAG5.  ER+ patients with SPAG5+ mRNA, Adj-ACT in addition to 5-year of Tamoxifen has reduced 5-year-DRR by 28% for those with LN- (89% vs., 67%; p<0·001) and 22% for those with LN+ (76% vs., 54%; p<0·001), as compared to receiving 5-year Tamoxifen alone.

Conclusion

SPAG5 expression could be used as a prognostic and predictive tool for selecting and monitoring response to systemic therapies in ER+ BC.