Although a rapid decline in Ki67 after short-term preoperative endocrine therapy (ET) has been established as a prognostic and predictive marker in controlled studies, its reliability and usefulness in everyday oncology practice are still insufficiently defined. In this real-world analysis, we investigated early on-treatment Ki67 modulation after brief preoperative ET and explored its relationship with tumor biology—including intrinsic molecular subtype and risk of recurrence (ROR)—together with long-term clinical outcomes in patients with early estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2−) breast cancer. This retrospective, registry-based study included 230 consecutive patients with early ER+/HER2− breast cancer treated according to standard clinical protocols at the Breast Unit of the Clinic Barcelona Comprehensive Cancer Center between 2014 and 2023. All patients received neoadjuvant ET, consisting of either tamoxifen or an aromatase inhibitor (AI), administered for 2–12 weeks prior to definitive surgery. Clinicopathological data were collected and patients were stratified according to Ki67 dynamics into “responders” (post-treatment Ki67 between 0% and 10%) and those achieving “complete cell cycle arrest (CCCA)” (Ki67 ≤2.7%). Molecular intrinsic subtypes and ROR scores were derived using the PAM50/Prosigna assay. Event-free survival was evaluated using Kaplan–Meier estimates, and associations with outcomes were examined using Cox proportional hazards models.
The median duration of preoperative ET was 5 weeks (range 2–12 weeks). A reduction in Ki67 consistent with response was observed in 196 patients (85.2%), while 111 patients (48.3%) met criteria for CCCA. Endocrine responsiveness differed significantly by menopausal status, with postmenopausal women showing higher response rates than premenopausal patients (P = 0.004). Treatment allocation reflected this difference, as nearly all postmenopausal women (95.6%) received an AI, whereas tamoxifen was exclusively used in premenopausal patients. Ki67 suppression also varied across intrinsic subtypes, with Luminal A tumors demonstrating the most pronounced response (P = 0.047). Multivariable analyses identified postmenopausal status and higher baseline estrogen receptor expression as independent predictors of both Ki67 response and CCCA, while lower baseline ROR scores were specifically associated with achieving CCCA. After a median follow-up of 47 months, patients who achieved CCCA experienced significantly superior event-free survival [hazard ratio (HR) = 0.19; 95% CI (confidence interval), 0.05–0.72; P value = 0.012]. In a real-world clinical setting, short-duration preoperative endocrine therapy induces marked antiproliferative effects in early ER+/HER2− breast cancer. Early measurement of Ki67 suppression provides a practical surrogate of endocrine sensitivity, and attainment of complete cell cycle arrest delineates a subgroup with particularly favorable prognosis who may be appropriate candidates for treatment de-escalation approaches.
