Abstract 2328: Predictive effect of IGFBP-3 on low-dose tamoxifen efficacy in non-invasive breast cancer in the phase III Tam-01 trial

Abstract Tamoxifen 5 mg/d (Babytam) decreases the incidence of new breast cancer events by 42% in women with breast intraepithelial neoplasia with limited toxicity, providing a new treatment option in these disorders. However, predictive biomarkers of Babytam efficacy are lacking. We studied whether baseline IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3), estradiol, sex hormone-binding globulin (SHBG), and their ratios predict Babytam efficacy on breast cancer events in a pre-planned secondary analysis.Within a 1:1 placebo-controlled, randomized trial of Babytam or placebo given for 3 years after surgery in women with ADH or LCIS or DCIS, 406/500 participants consented to blood sampling at baseline, at 1 and 3 years. Serum IGF-I, IGFBP-3, estradiol, SHBG levels and their ratios were measured by chemiluminescent immune assays. Biomarker changes were estimated using mixed-effects models, and Incidence Rate Ratios (IRR) were calculated after 10 years of follow-up with Poisson regression. Subgroup analyses were performed using an interaction test and subpopulation treatment effect pattern plot.Baseline levels of IGFBP-3 in the three top quartiles (≥3.44 ug/mL), but not in the lower quartile, predicted greater Babytam efficacy compared to placebo (p-interaction=0.006, Table 1). Baseline IGF-I, estradiol, or SHBG were not predictive of Babytam efficacy, whereas the IGF-I/IGFBP-3 ratio was borderline significant (p-interaction=0.067).High baseline levels of IGFBP-3 (≥3.44 ug/mL) predicted Babytam efficacy and may help differentiate which women benefit most from this treatment. Table 1. Mean event rate (x1000 person-years) by treatment arm and baseline IGF-I, IGFBP-3, E2, SHBG, and IGF-I/IGFBP-3 and E2/SHBG ratio at 10 year follow-up. 10y follow-up BabyTam Placebo IRR (95% CI) IGF-I†, ng/mL ≤median (127.3) 11.8 (6.3-21.9) 20.9 (13.2-33.2) 0.49 (0.22-1.11) >median 11.0 (5.9-20.5) 21.5 (13.5-34.0) 0.52 (0.23-1.15) IRR (95% CI) 0.90 (0.35-2.31) 1.09 (0.53-2.22) Pinteraction=0.967 IGFBP-3†, ug/mL Q1 (≤3.43) 10.6 (4.0-28.3) 8.8 (3.3-23.4) 1.24 (0.33-4.66) Q2 (3.44 to 4.21) 21.4 (11.5-39.8) 25.5 (13.3-49.0) 0.75 (0.30-1.85) Q3 (4.22 to 4.91) 11.6 (4.8-27.8) 20.6 (10.3-41.3) 0.59 (0.18-1.98) Q4 (≥4.92) 2.2 (0.3-15.9) 30.7 (18.2-51.8) 0.07 (0.01-0.52)** IRR (95% CI) 0.71 (0.50-1.01) 1.36 (1.02-1.82)* Pinteraction=0.006 IGF-I/IGFBP-3† ≤median (0.167) 7.7 (3.7-16.2) 26.3 (17.2-40.4) 0.29 (0.13-0.69)** >median 15.9 (9.2-27.4) 16.4 (9.7-27.7) 0.89 (0.41-1.94) IRR (95% CI) 1.72 (0.67-4.40) 0.60 (0.30-1.20) Pinteraction=0.067 E2†, pg/mL ≤median (15.8) 7.9 (3.7-16.5) 21.1 (13.3-33.5) 0.38 (0.16-0.91)* >median 15.0 (8.7-25.8) 21.3 (13.4-33.8) 0.62 (0.29-1.34) IRR (95% CI) 1.47 (0.54-3.96) 0.90 (0.39-2.11) Pinteraction=0.390 SHBG†, nMol/L ≤median (60.2) 13.2 (7.3-23.8) 25.2 (16.4-36.8) 0.50 (0.24-1.05) >median 9.7 (5.1-18.7) 17.3 (10.5-28.8) 0.54 (0.23-1.30) IRR (95%CI) 0.67 (0.24-1.90) 0.77 (0.32-1.85) Pinteraction=0.801 E2/SHBG† ≤median (1.37) 9.4 (4.7-18.9) 19.3 (12.0-31.1) 0.49 (0.21-1.16) >median 13.2 (7.5-23.2) 23.2 (14.8-36.4) 0.52 (0.24-1.10) IRR (95% CI) 0.91 (0.33-2.50) 1.09 (0.51-2.35) Pinteraction=0.977 Citation Format: Harriet Johansson, Debora Macis, Martino Oliva, Matteo Puntoni, Eva Blondeaux, Aliana Guerrieri-Gonzaga, Valentina Aristarco, Irene Maria Briata, Tania Buttiron-Webber, Alessio Carbone, Luca Boni, Matteo Lazzeroni, Davide Serrano, Livia Giordano, Maria Digennaro, Laura Cortesi, Francesco Millo, Katia Cagossi, Giuseppe Aprile, Fabio Falcini, Elisa Gallerani, Bernardo Bonanni, Andrea De Censi. Predictive effect of IGFBP-3 on low-dose tamoxifen efficacy in non-invasive breast cancer in the phase III Tam-01 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2328.