Abstract Background: SETER/PR index of sensitivity to endocrine therapy (ET) measures endocrine receptor-related transcription from fixed paraffin-embedded tissue and is highly reproducible within and between laboratories. SETER/PR index is correlated with receptor ligand binding activity and predicts early pharmacodynamic response to ET and survival outcomes following ET in palliative and adjuvant treatment settings. We evaluated whether SETER/PR index predicts benefit from extended letrozole therapy (ELT) in the NSABP B-42 trial, which evaluated ELT vs placebo in HR+ postmenopausal breast cancer patients (pts) who had received 5 yrs of adjuvant ET with aromatase inhibitor (AI), or tamoxifen followed by AI. Methods: SETER/PR index was measured using the QuantiGene Plex bead-based hybridization assay (ThermoFisher) using two unstained sections and an H0.05. Results: Breast cancer blocks with tumor tissue were available from 1,556 eligible, HER2- pts, with 1,489 (96%) producing SETER/PR results that passed quality control and were included in the study cohort. There were no statistically significant differences in pt or tumor characteristics between the study cohort and the rest of the HER2 negative B-42 pts. ELT reduced the 10-yr rate of BCFI events by 4.2% in the study cohort (HR 0.69, 95%CI 0.51-0.94, p=0.016). Among 1,489 pts, 59% had SETER/PR index in the range 1.10-2.10 with 42% measuring ≥1.50. No difference in the ELT effect was observed between groups of pts identified by the primary inter-quartile range cut point (1.10 ≤SETER/PR index ≤2.10 vs other). Benefit from ELT was statistically significant in pts with SETER/PR index ≥1.50 (HR 0.53, 95%CI 0.32-0.88, p=0.014), but not in those with SETER/PR index 1.50 (HR 0.82, 95%CI 0.56-1.20, p=0.31), without significant treatment-by- SETER/PR index interaction (p=.14). Overall, the 10-yr absolute BCFI benefit from ELT was 7.1% in pts with SETER/PR index ≥1.50 (Placebo: 14.9%, Letrozole: 7.8%) and 2.1% in those with SETER/PR index 1.50 (Placebo: 14.5%, Letrozole 12.4%). When evaluated by nodal status, node-positive pts with SETER/PR index ≥1.50, had a 10.5% absolute reduction in the 10-yr BCFI events (Placebo:19.2%, Letrozole: 8.7%; HR 0.52, 95%CI 0.26-1.06), whereas those with SETER/PR index 1.50, had a 3% absolute reduction in the 10-yr BCFI events (Placebo:20.1%, Letrozole: 17.1%; HR 0.84, 95%CI 0.50-1.40). Node-negative pts with SETER/PR index ≥1.50 had a 5.2% absolute reduction in the 10-yr BCFI events (Placebo: 12.4%, Letrozole: 7.2%; HR 0.55, 95%CI 0.27-1.11), whereas those with SETER/PR index 1.50, had a 1.9% absolute reduction in the 10-yr BCFI events (Placebo:10.8%, Letrozole: 8.9%; HR 0.80, 95%CI 0.44-1.43). When evaluating the performance of SETER/PR index as a continuous measure, increasing values of SETER/PR index were associated with greater relative benefit from ELT (treatment-by- SETER/PR index per unit increase interaction HR 0.71, 95%CI 0.43-1.18). Conclusions: Benefit from ELT was enriched in the subset of pts with SETER/PR index ≥1.50. This supports the hypothesis that longer duration of endocrine therapy is more effective for pts with highly endocrine-sensitive cancers. NCT00382070 NCI UH3CA276603; U10 CA180868, -180822, UG1CA189867; U24CA196067; Korea Health Technology R 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS3-05.
Mamounas et al. (2026) studied this question.