Abstract PD5-02: 5-year outcomes and ctdna findings in the clever trial targeting disseminated dormant tumor cells

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Abstract Background: Breast cancer (BC) recurrence may follow a dormant phase in which quiescent cells reside in niches such as bone marrow (BM). Indeed, dormant BM disseminated tumor cells (DTCs) are independently associated with BC recurrence/death. The CLEVER trial demonstrated feasibility, safety and a reduction of DTCs with inhibition of autophagy (hydroxychloroquine (HCQ), and/or mTOR signaling (everolimus [EVE]) in DTC-positive BC survivors (DeMichele, Nature Medicine, 2025). We now present data on concurrent circulating tumor DNA (ctDNA) testing and additional follow up. Methods: The CLEVER trial (NCT03032406) is a randomized, phase II trial in high-risk patients (pts) diagnosed within 5 years with either triple negative disease (dx), HER2+ or ER+ dx with either positive lymph nodes (LN) or residual dx (RD) after neaodjuvant chemotherapy, or, for ER+ dx, Oncotype RS>25. Subjects completed all treatment except endocrine therapy. DTCs were detected in BM aspirate (BMA) by immunohistochemistry (IHC) with pan-CK antibody AE1/AE3. DTC-positive pts were randomized to six 28-day cycles (C) of HCQ (600 mg BID), EVE (10 mg daily) or both (+/- 3-month (m0) observation period. DTC assessment and blood collection occurred prior to C1 (baseline), after C3, C6, C12 (if applicable) and 6-mo after end of treatment (EOT); additional blood samples were collected after 12, 18, 24, 30 and 36 months of follow up. Plasma ctDNA was assessed using the RaDaR assay (NeoGenomics), with whole-exome sequencing performed on primary tumor tissue to identify somatic mutations subsequently used in ctDNA assessment. Results: 51 DTC-positive pts were randomized to HCQ (n=15), EVE (n=15) or HCQ+EVE (n=21). At a median follow-up of 77 months, 2/51 (6%) have had a recurrence (1 distant only, 1 locoregional + distant). Overall 5-year RFS is 96%; 89.5% for ER+/HER2-, 100% for TNBC and 100% HER2+/any ER; RFS HR for ER+/HER2- vs. TNBC 3.64 (0.33, 40.5). ctDNA testing could be performed on plasma from 32/51 pts (63%) during treatment and follow-up; all were ctDNA-negative at baseline. Of the 29 who had at least one post-treatment DTC assessment, 2 were DTC-positive post-treatment and neither has become ctDNA-positive. Amongst all timepoints at which both DTCs and ctDNA were assessed, the concordance between DTCs and ctDNA was 85%. Of the 2 pts with distant recurrence, 1 pt with ER+/HER2- dx on EVE withdrew after C2 for toxicity, became ctDNA-positive 9.6 mo after first DTC-positive result and 4.6 mo before recurrence; 1 pt with ER+/HER2- dx on HCQ was DTC-positive post-C6, was DTC-negative after additional 6C EVE + HCQ, became ctDNA-positive 24 mo after first DTC-positive test, developed locoregional recurrence 3 mo later, became ctDNA-negative following treatment, then ctDNA-positive 31 mo later and developed distant recurrence after another 16 mo. Of note, an additional pt with TNBC prior to study entry subsequently developed a new ER+/PR+/HER2- breast cancer and concurrent liver metastases 36 mo after last negative ctDNA test. Conclusions: With longer follow-up, recurrence after treatment targeting DTCs remains low and ctDNA monitoring post-treatment identified both patients with recurrence in advance of overt metastasis. Longitudinal BMA, ctDNA and follow-up are ongoing; confirmatory trials, NCT04523857 and NCT04841148 are enrolling. Citation Format: A. DeMichele, L. Bayne, E. Walinsky, L. Berry, S. DeLuca, C. G. Smith, A. Chevalier, B. Ambasager, P. Sanchez, J. Heaven, E. Chislock, T. Pan, J. Graves, G. Belka, J. Wang, E. Taranto, A. Nayak, M. Feldman, A. Clark, L. Chodosh. 5-year outcomes and ctdna findings in the clever trial targeting disseminated dormant tumor cells [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 PD5-02.

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