Abstract PS1-12-05: Liquid Biopsy-Based Molecular Profiling Using Guardant360 CDx at Progression on CDK4/6i+ET: Findings from the AGO-B CAPTOR Study

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Abstract Background: CDK4/6 inhibitors in combination with endocrine therapy have become the standard first-line treatment for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer. While ribociclib is supported by the most robust overall survival data across multiple phase III trials, mechanisms of resistance and biomarkers for treatment efficacy remain incompletely understood. Liquid biopsies, particularly of circulating tumor DNA (ctDNA) analysis, offer an opportunity to characterize tumor evolution and identify actionable genomic alterations at clinically relevant timepoints. The AGO-B “Comprehensive Analysis of Spatial, Temporal and Molecular Patterns of Ribociclib Efficacy and Resistance in Advanced Breast Cancer Patients” (CAPTOR) trial (NCT05452213) is a single-arm, open-label phase IV study of patients with advanced HR+/HER2- breast cancer who were treated with ribociclib and endocrine therapy. Methods: Patients with HR+/HER2- advanced breast cancer receiving first-line treatment with ribociclib plus endocrine therapy were prospectively enrolled in the CAPTOR trial. At time of progression or end of treatment (EoT) patient were eligible for a Guardant360 CDx test. The test was initiated at physicians’ discretion. Blood samples were collected using Streck cfDNA BCT tubes and shipped to the GUARDANT Health central laboratory. ctDNA was extracted and sequenced using the FDA-approved Guardant360 CDx assay, covering 74 cancer-related genes and detecting single nucleotide variants (SNVs), insertions/deletions (indels), gene fusions, and copy number alterations. Testing results were returned to the treating physician via the GUARDANT health portal or via PDF upload into the CAPTOR electronic case report form. Results: Guardant360 CDx testing was initiated for 37 patients between December 2024 and June 2025. Of those, two were cancelled due to shipment delays and four were not yet processed at time of interim analysis, resulting in 31 successful ctDNA GUARDANT tests. The median time till receipt of samples at the GUARDANT central laboratory was 3 days (range 1-8) and the median time till report of test results was 12 days (range 7-53). Thirty (97%) had at least one alteration in the analyzed genes. The most frequent genes affected were PIK3CA (N=15, 48%), TP52 (N=12, 39%) and ESR1 (N=10, 32%). Two patients (6%) had a BRCA1 and three (10%) a BRCA2 mutation. Of those, one patient each had a potentially germline mutation in BRCA1 (41.5% variant allele frequency [VAF]) or BRCA2 (47.59% VAF). The median VAF was 0.83 (range 0.02-47.59). For twenty-two (71%) patients at least one alteration was detected with an approved indication in breast cancer. Twelve (39%) had an indication for Alpelisib due to an activating mutation in PIK3CA, nine (29%) an indication for Elacestrant based on an activating mutation in ESR1, sixteen (52%) an indication for Capivasertib due to PIK3CA, AKT1 or PTEN mutation and one patient (3%) had a ERBB2 amplification resulting in an indication for an anti-HER2 treatment. Of those, with a treatment indication based on ctDNA test results, treatment information after progress or EoT was available from seventeen (77%) patients. Of those, seven (41%) received treatment in accordance with ctDNA test result (29% Capivasertib, 6% Trastuzumab, 6% Elacestrant). Discussion: These interim results demonstrate the feasibility and clinical utility of Guardant360-based ctDNA testing at progression or end of therapy within the CAPTOR trial. A high proportion of patients showed actionable alterations, and nearly half of those with available follow-up received targeted treatment in line with the ctDNA findings. Citation Format: V. Mueller, H. Huebner, P. Ziegler, S. Uhrig, S. Brucker, V. Thewes, L. L. Volmer, A. Hartkopf, T. Engler, C. C. Hack, I. Juhasz-Boess, H. Kolberg, D. Lueftner, M. P. Lux, M. Schmidt, H. Tesch, M. Thill, M. Untch, P. Wimberger, S. Heublein, I. Nel, H. Neubauer, B. Rack, J. C. Radosa, F. Taran, B. Aktas, N. Ditsch, L. Haeberle, I. Sava-Piroddi, R. Weinhold, C. Mann, E. Belleville, K. Lüdtke-Heckenkamp, M. van Mackelenbergh, R. Pihusch, C. Schem, K. Apel, H. Wagner, A. Schneeweiss, T. Lotz, W. Janni, T. N. Fehm, P. A. Fasching, B. Lex. Liquid Biopsy-Based Molecular Profiling Using Guardant360 CDx at Progression on CDK4/6i+ET: Findings from the AGO-B CAPTOR Study [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 PS1-12-05.

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