Abstract PD5-01: Personalized circulating tumor DNA (ctDNA) testing, intervention, and temporal dynamics in ER+/HER2- early-stage breast cancer (LEADER)

Abstract Background: Detectable ctDNA after definitive therapy for early breast cancer (eBC), termed molecular residual disease, is associated with a higher risk of cancer recurrence. The LEADER Phase II study (NCT03285412) aimed to evaluate the efficacy of adding the CDK4/6 inhibitor, ribociclib, to adjuvant endocrine therapy (aET) for patients (pts) with ER+/HER2- eBC with ctDNA positivity after definitive surgery. Methods: Pts with biopsy-proven ER+(≥10%)/HER2-, pathological stage IIA or higher eBC were enrolled in a ctDNA surveillance protocol as pre-screening for the LEADER study. All pts completed surgical resection prior to ctDNA testing and were receiving aET, which was performed using a tumor-informed assay (SignateraTM, Natera, Inc). Pts with detectable ctDNA during surveillance were then enrolled in LEADER and treated with 400mg ribociclib daily (continuous dosing) plus an aromatase inhibitor for 12 cycles. Imaging studies at the time of ctDNA detection were not required and left to the discretion of the treating physician. On-treatment plasma samples were collected serially (3, 6, and 12 months) during follow-up visits. The primary endpoint was the proportion of pts who had ctDNA clearance after completion of 12 cycles of adjuvant ribociclib in combination with endocrine therapy, and secondary endpoints included the proportion of pts who had a molecular response after 3 cycles on therapy, time to ctDNA clearance and recurrence-free survival. Results: A total of 162 pts registered and 152 had complete sample sets for assay design between 9/3/20 and 2/12/24 (prior to FDA approval of ribociclib for HR+/HER2- eBC). ctDNA testing was performed on 140 pts over a median of 11.4 (range: 0-35) months with a median of 2 (range: 1-4) tests per pt. In this cohort, 89% (125/140) had persistently ctDNA-negative results and experienced favorable distant recurrence-free survival (DRFS), measured from first screening ctDNA test, with a median clinical follow-up of 31.1 (range: 0-52.9) months, yielding a negative predictive value of 98.1% (103/105), assessed based on each individual’s status at last follow-up. A cumulative ctDNA detection rate of 11% (15/140) was observed during surveillance, with 87% (13/15) testing ctDNA-positive on their first surveillance time point. Of the 15 positive cases, 33% (5/15) were ineligible due to concomitant radiographic evidence of recurrence; 80% (4/5) of these were ctDNA-positive on their first test. The median ctDNA level of the 10 pts starting ribociclib was 7.7 (range: 0.12-163.8) mean tumor molecules (MTM)/mL. One pt was excluded due to early treatment discontinuation. Of the remaining 9 pts, 66% (6/9) and 33% (3/9) showed a ctDNA decrease (>25% baseline) and complete clearance after 3 months on ribociclib, respectively. Pts with favorable ctDNA dynamics (N=6; decrease/cleared) had lower pre-treatment ctDNA levels (median 4 MTM/mL) compared to pts with unfavorable dynamics (N=3; increase ctDNA) (median: 73.8 MTM/mL). DRFS measured from time of enrollment was 16.5 months in pts with favorable dynamics and 5.3 months for unfavorable dynamics; particularly for pts who achieved ctDNA clearance (N=3), the time to recurrence was longer (18.6 months) vs. those without clearance (7.2 months). Conclusions: ctDNA positivity during surveillance accurately identified pts at high risk of recurrence, while persistent ctDNA negativity was associated with numerically lower recurrence. Pts starting ribociclib with lower molecular levels of disease were more likely to exhibit ctDNA-decrease/clearance and delayed metastasis. These findings support the utility of ctDNA based molecular surveillance to evaluate therapeutic interception and monitoring treatment response in ER+/HER2− eBC. Citation Format: A. J. Medford, C. Scalise, S. Dhulekar, Z. Smolar, A. Niemierko, E. Kalashnikova, A. Rodriguez, L. M. Spring, J. Kim, A. Comander, A. Rosenstock, J. M. Peppercorn, J. A. Shin, L. Schnipper, H. Benjamin, S. J. Isakoff, L. W. Ellisen, D. Juric, B. Moy, M. C. Liu, A. Aleshin, A. Bardia. Personalized circulating tumor DNA (ctDNA) testing, intervention, and temporal dynamics in ER+/HER2- early-stage breast cancer (LEADER) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD5-01.