10510 Background: Babytam (BT), 5 mg/day for 3 years (y) is a popular choice for preventive therapy after breast DCIS/LCIS/ADH given its 10-y efficacy to prevent recurrence without adverse events (1). Here we investigated the effect of BT on serum biomarkers and their role as prognostic and predictive factors. Methods: In a phase-III trial of BT or placebo (P), 406 out of 500 women consented to blood sampling at baseline, 1 and 3 y. Serum estradiol (E2), SHBG, IGF-I, IGFBP-3 and their molar ratios were measured by CLIA. Biomarker changes were estimated with mixed-effects models for repeated measures and Incidence Rate Ratios (IRR) of the primary endpoint (invasive breast cancer or DCIS) were calculated after 5 and 10 y of follow-up with Poisson regression. Subgroup analyses were performed by interaction test. Results: There were no differences in event rates between women with blood samples and those w/out. Compared with P at 1 y, IGF-I/IGFBP-3 decreased by 0.039 (95%CI, 0.027-0.052), relative difference (rd), 22% (15-29) (p<0.001), whereas E2/SHBG increased by 2.967 (1.767-4.166), rd, 79% (47-111) in pre- and decreased by 0.121 (-1.117-0.874), rd, -9% (-84-66), in postmenopausal women on BT (p-interaction=0.001). The mean annual rate of events (x1000 PY) after 5 and 10 y follow-up according to baseline level of IGF-I/IGFBP-3 (all women) and E2/SHBG (postmenopausal). Conclusions: BT significantly lowers IGF-I/IGFBP-3 ratio, increases E2/SHBG in premenopause to a lesser extent than 20 mg/d and is effective in most subgroups regardless of baseline biomarker levels. While lower baseline IGF-I/IGFBP-3 levels were predictive of BT efficacy at 5 and 10 y, higher levels at 10 y were associated with a lower benefit of BT. E2/SHBG had a tendency to be prognostic and predictive of BT efficacy at 5 y, but softened down at 10 y. These biomarkers may help differentiate which women benefit most from BT. The role of IGF-I change as surrogate biomarker of BT effect requires further studies. 1. Lazzeroni et al: JCO 41:3116, 2023. Clinical trial information: NCT01357772 . [Table: see text]