Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer: data from the randomized SBII:2 trial

Breast Cancer Research

Research

Bo Nordenskjöld¹  Olle Stål¹  Maria Ekholm²  Christine Lundgren³  Pär-Ola Bendahl⁴  Julia Tutzauer⁴  Mårten Fernö⁴  Carina Forsare⁴  Lisa Rydén⁵  Sarah E. Church⁶ 

[1] Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden;Department of Oncology, Region Jönköping County, Jönköping, Sweden;Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden;Department of Oncology, Region Jönköping County, Jönköping, Sweden;Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden;Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Building 404, 223 81, Lund, Sweden;Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Building 404, 223 81, Lund, Sweden;Division of Surgery, Department of Clinical Sciences Lund, Lund University, Lund, Sweden;Department of Surgery, Skåne University Hospital, Malmö, Sweden;NanoString Technologies, Inc., Seattle, USA;

关键词: Gene expression signatures;    Premenopausal;    Tamoxifen;    Prognostic;    Predictive;   

DOI  :  10.1186/s13058-023-01719-z

 received in 2023-06-28, accepted in 2023-09-25,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundGene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer.MethodsRNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling (n = 437, NanoString Breast Cancer 360™ panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX signatures and tamoxifen effect were assessed in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+ /HER2−) tumors using Kaplan–Meier estimates and Cox regression. The prognostic effects of GEX signatures were studied in the entire cohort. False discovery rate adjustments (q-values) were applied to account for multiple hypothesis testing.ResultsIn patients with ER+/HER2− tumors, FOXA1 expression below the median was associated with an improved effect of tamoxifen after 10 years with regard to RFi (hazard ratio [HR]FOXA1(high) = 1.04, 95% CI = 0.61–1.76, HRFOXA1(low) = 0.30, 95% CI = 0.14–0.67, qinteraction = 0.0013), and a resembling trend was observed for AR (HRAR(high) = 1.15, 95% CI = 0.60–2.20, HRAR(low) = 0.42, 95% CI = 0.24–0.75, qinteraction = 0.87). Similar patterns were observed for OS. Tamoxifen was in the same subgroup most beneficial for RFi in patients with low ESR1 expression (HRRFi ESR1(high) = 0.76, 95% CI = 0.43–1.35, HRRFi, ESR1(low) = 0.56, 95% CI = 0.29–1.06, qinteraction = 0.37). Irrespective of molecular subtype, higher levels of ESR1, Mast cells, and PGR on a continuous scale were correlated with improved 10 years RFi (HRESR1 = 0.80, 95% CI = 0.69–0.92, q = 0.005; HRMast cells = 0.74, 95% CI = 0.65–0.85, q < 0.0001; and HRPGR = 0.78, 95% CI = 0.68–0.89, q = 0.002). For BC proliferation and Hypoxia, higher scores associated with worse outcomes (HRBCproliferation = 1.54, 95% CI = 1.33–1.79, q < 0.0001; HRHypoxia = 1.38, 95% CI = 1.20–1.58, q < 0.0001). The results were similar for OS.ConclusionsExpression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2− premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR, ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors.Trial registration This trial was retrospectively registered in the ISRCTN database the 6th of December 2019, trial ID: https://clinicaltrials.gov/ct2/show/ISRCTN12474687.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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