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    Original Investigation
    July 7, 2020

    Association of Sperm-Associated Antigen 5 and Treatment Response in Patients With Estrogen Receptor–Positive Breast Cancer

    Author Affiliations
    • 1Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
    • 2Department of Pathology, National Liver Institute, Menoufyia University, Al Minufya, Egypt
    • 3John van Geest Cancer Research Centre, Nottingham Trent University School of Science and Technology, Nottingham United Kingdom
    • 4Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia
    • 5UQ Centre for Clinical Research, Faculty of Research, The University of Queensland, Herston, Australia
    • 6Pathology Queensland, The Royal Brisbane and Women’s Hospital, Herston, Australia
    • 7Lendület Cancer Biomarker Research Group, Second Department of Pediatrics, Semmelweis University, Budapest, Hungary
    • 8Nottingham Breast Cancer Research Center, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham, United Kingdom
    • 9Department of Oncology and Cancer Research, UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
    JAMA Netw Open. 2020;3(7):e209486. doi:10.1001/jamanetworkopen.2020.9486
    Key Points español 中文 (chinese)

    Question  Are sperm-associated antigen 5 (SPAG5) transcript or protein expressions associated with treatment response in patients with estrogen receptor–positive breast cancer?

    Findings  In this cohort study including 12 720 patients with estrogen receptor–positive breast cancer, SPAG5 transcript and SPAG5 protein overexpressions were associated with worse outcomes in patients who received endocrine therapy alone. Overexpressions of SPAG5 transcript or SPAG5 protein were associated with resistance to endocrine therapy but sensitivity to anthracycline-based combination chemotherapy, and downregulation of SPAG5 during the course of preoperative systemic therapies was associated with clinical benefit.

    Meaning  These findings suggest that SPAG5 transcript or SPAG5 protein expression could be used as a clinical tool for selecting and monitoring response to neoadjuvant therapies and guide adjuvant therapy in estrogen receptor–positive breast cancer.


    Importance  There is no proven test that can guide the optimal treatment, either endocrine therapy or chemotherapy, for estrogen receptor–positive breast cancer.

    Objective  To investigate the associations of sperm-associated antigen 5 (SPAG5) transcript and SPAG5 protein expressions with treatment response in systemic therapy for estrogen receptor–positive breast cancer.

    Design, Settings, and Participants  This retrospective cohort study included patients with estrogen receptor–positive breast cancer who received 5 years of adjuvant endocrine therapy with or without neoadjuvant anthracycline-based combination chemotherapy (NACT) derived from 11 cohorts from December 1, 1986, to November 28, 2019. The associations of SPAG5 transcript and SPAG5 protein expression with pathological complete response to NACT were evaluated, as was the association of SPAG5 mRNA expression with response to neoadjuvant endocrine therapy. The associations of distal relapse–free survival with SPAG5 transcript or SPAG5 protein expressions were analyzed. Data were analyzed from September 9, 2015, to November 28, 2019.

    Main Outcomes and Measures  The primary outcomes were breast cancer–specific survival, distal relapse–free survival, pathological complete response, and clinical response. Outcomes were examined using Kaplan-Meier, multivariable logistic, and Cox regression models.

    Results  This study included 12 720 women aged 24 to 78 years (mean [SD] age, 58.46 [12.45] years) with estrogen receptor–positive breast cancer, including 1073 women with SPAG5 transcript expression and 361 women with SPAG5 protein expression of locally advanced disease stage IIA through IIIC. Women with SPAG5 transcript and SPAG5 protein expressions achieved higher pathological complete response compared with those without SPAG5 transcript or SPAG5 protein expressions (transcript: odds ratio, 2.45 [95% CI, 1.71-3.51]; P < .001; protein: odds ratio, 7.32 [95% CI, 3.33-16.22]; P < .001). Adding adjuvant anthracycline chemotherapy to adjuvant endocrine therapy for SPAG5 mRNA expression in estrogen receptor–positive breast cancer was associated with prolonged 5-year distal relapse–free survival in patients without lymph node involvement (hazard ratio, 0.34 [95% CI, 0.14-0.87]; P = .03) and patients with lymph node involvement (hazard ratio, 0.35 [95% CI, 0.18-0.68]; P = .002) compared with receiving 5-year endocrine therapy alone. Mean (SD) SPAG5 transcript was found to be downregulated after 2 weeks of neoadjuvant endocrine therapy compared with pretreatment levels in 68 of 92 patients (74%) (0.23 [0.18] vs 0.34 [0.24]; P < .001).

    Conclusions and Relevance  These findings suggest that SPAG5 transcript and SPAG5 protein expressions could be used to guide the optimal therapies for estrogen receptor–positive breast cancer. Retrospective and prospective clinical trials are warranted.