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

被引:5
作者
Lundgren, Christine [1 ,2 ,3 ]
Tutzauer, Julia [3 ]
Church, Sarah E. [4 ]
Stal, Olle [2 ]
Ekholm, Maria [1 ,2 ]
Forsare, Carina [3 ]
Nordenskjold, Bo [2 ]
Ferno, Marten [3 ]
Bendahl, Par-Ola [3 ]
Ryden, Lisa [5 ,6 ]
机构
[1] Reg Jonkoping Cty, Dept Oncol, Jonkoping, Sweden
[2] Linkoping Univ, Dept Biomed & Clin Sci, Linkoping, Sweden
[3] Lund Univ, Dept Clin Sci Lund, Div Oncol, Bldg 404, S-22381 Lund, Sweden
[4] NanoString Technol Inc, Seattle, WA USA
[5] Lund Univ, Dept Clin Sci Lund, Div Surg, Lund, Sweden
[6] Skane Univ Hosp, Dept Surg, Malmo, Sweden
关键词
Gene expression signatures; Premenopausal; Tamoxifen; Prognostic; Predictive; ADJUVANT TAMOXIFEN; DISTANT RECURRENCE; ENDOCRINE THERAPY; PAM50; RISK; ESTROGEN; FOXA1; RESISTANCE; BENEFIT; MARKER; METAANALYSIS;
D O I
10.1186/s13058-023-01719-z
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Gene 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. Methods: RNA 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 (TM) 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. Results: In 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, q(interaction) = 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, q(interaction) = 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, q(interaction) = 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. Conclusions: Expression 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.
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页数:20
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