Reproducible modulation of tissue Ki-67 across lung and prostate cancer interception trials.

10574 Background: The clinical utility of cancer interception is limited by the lack of validated surrogate endpoints that capture early biological response before histopathologic progression. While morphologic changes often require prolonged follow-up, Ki-67, a nuclear marker of cellular proliferation, provides a dynamic, tissue-based measure of epithelial proliferative activity. However, its reproducibility across high-risk tissue contexts remains debated. We evaluated the consistency of tissue Ki-67 modulation across two independent randomized trials in high-risk lung and prostate epithelia. Methods: We analyzed data from two prospective, randomized, placebo-controlled phase II cancer interception trials that prespecified tissue Ki-67 as an endpoint. In the lung cohort (NCT03232138; n=98), high-risk smokers with bronchial dysplasia were randomized to oral sulforaphane (200 μmol/day) or placebo for 6 months. In the prostate cohort (CAPFISH-3; n=58), patients with low-grade prostate cancer on active surveillance were randomized to long-chain omega-3 fatty acids (3 g/day) or placebo for 12 months. Paired tissue biopsies were obtained at baseline and study completion. Ki-67 expression was quantified by immunohistochemistry with central pathology review. Results: Baseline Ki-67 indices were comparable between intervention and placebo arms in both cohorts. Following the intervention, a statistically significant divergence in tissue proliferative activity was observed. In the lung cohort, sulforaphane treatment was associated with a 20% reduction in bronchial epithelial Ki-67, whereas the placebo arm demonstrated a 65% increase (P=0.014). In the prostate cohort, omega-3 supplementation resulted in a 15% reduction in intratumoral Ki-67, compared with a 24% increase in the control arm (P=0.043). Sub-analysis by staining intensity demonstrated preferential suppression among high-intensity (3+) Ki-67–positive cells, including a 44% reduction in the lung intervention arm. Ki-67 modulation correlated with baseline proliferative activity but not with baseline histopathologic features. No significant changes in histopathologic grade or dysplasia scores were observed. Conclusions: Tissue Ki-67 demonstrates consistent, reproducible modulation across randomized lung and prostate interception trials, preceding detectable morphologic change. These findings support Ki-67 as a practical early biologic endpoint for phase II cancer interception studies. Tissue Ki-67 modulation across randomized cancer interception trials. Cohort (n) Intervention Ki-67 change (Tx) Ki-67 change (Pbo) P value Lung (98) Sulforaphane −20% +65% 0.014 Prostate (58) Omega-3 −15% +24% 0.043 Abbreviations: Tx, treatment; Pbo, placebo.