Abstract PS2-07-06: Prevalence and dynamics of circulating tumor DNA among patients with triple-negative breast cancer undergoing preoperative systemic therapy with or without immunotherapy

Abstract Background: Preoperative systemic therapy (PST) with immunotherapy (IO) is the current standard-of-care for patients (pts) with early-stage triple-negative breast cancer (TNBC). Circulating tumor DNA (ctDNA) persistence in the (neo)adjuvant setting is associated with residual disease at surgery and a higher risk of recurrence. However, studies of ctDNA in TNBC have not evaluated treatment in the modern, IO-containing era. We tested the performance of a highly sensitive assay to evaluate the prevalence and dynamics of ctDNA in the neoadjuvant TNBC setting with and without IO. Methods: We prospectively enrolled and retrospectively identified patients with TNBC receiving PST in an IRB-approved, multi-center registry. Plasma samples were collected at diagnosis (baseline), 4-7 weeks after start of PST (on-treatment), at completion of PST and before surgery (preop), within 3 months after surgery (postop), and every 6 months during follow-up. ctDNA was measured using the Pathlight assay (SAGA Dx), a tumor-informed assay based on structural variants identified from 15X whole-genome sequencing of tumor/normal samples, to detect and quantify minimal residual disease. The primary endpoint was ctDNA detection rate during and after PST. Results: We evaluated 444 plasma samples from 80/97 (82.5%) pts with >1 plasma sample, sufficient tumor tissue and available buffy coat. Pts were a median of 50.4 years old, and 34 (42.5%) had stage III disease. Pts were enrolled between 2019 and 2024, and due to a change in standard treatment, 31 (38.8%) pts received cytotoxic chemotherapy (CT) alone, while 49 (61.2%) pts received an IO-containing regimen. At the time of surgery, 49 (61.3%) pts had pathologic complete response (pCR). Personalized ctDNA assays were designed targeting 5-16 structural variants (median 12). ctDNA was detected at baseline in 71/76 (93.4%; 95% CI 85.3 - 97.8) pts, on-treatment in 24/70 (34.3%; 95% CI 23.3-46.6) pts, preop in 7/53 (13.2%; 95% CI 5.5-25.3) pts, and postop in 8/59 (13.6%; 95% CI 6.0-25.0) pts. Among pts who were ctDNA-positive (ctDNA+) at baseline with a paired on-treatment sample (n = 62), 37 (59.7%) pts cleared ctDNA by the on-treatment timepoint. All pts who cleared on-treatment remained ctDNA-negative at the preop timepoint, when available (n = 26). Among pts who were ctDNA+ at baseline with a paired preop sample (n = 46), 39 (84.8%) pts cleared ctDNA at completion of PST. The negative predictive value (NPV) of ctDNA clearance for pCR by the on-treatment timepoint was 78.4% (29/37; 95% CI 61.8-90.2), while the NPV at the preop timepoint was 71.8% (28/39; 95% CI 55.1-85.0). On IO- vs non-IO containing regimens, the NPV of ctDNA clearance at the on-treatment timepoint was 85.7% (18/21; 95% CI 63.7-97.0) for IO-containing regimens and 68.8% (11/16; 95% CI 41.3-89.0) for pts undergoing cytotoxic CT alone. Among pts with residual disease at surgery (n = 31), 19 (61.3 %) underwent adjuvant therapy including IO. 6/19 pts remained ctDNA+ after surgery, with persistent ctDNA in all subsequent samples until clinical recurrence. Median postoperative follow-up was 26.2 (IQR 18.6, 37.3) months. Of 8 pts who remained ctDNA+ after surgery, 7 (87.5%) had a clinical recurrence with a median lead time of 10.9 (IQR 6.1, 16.4) months. All (n = 10) pts experiencing distant recurrence were ctDNA+ prior to the event. Follow-up is ongoing. Conclusions: ctDNA detection rate was high among pts with TNBC receiving PST. In pts with residual disease, ctDNA detected after surgery persisted despite adjuvant therapy; all such pts developed disease recurrence. This study highlights ctDNA as a promising biomarker for personalized risk assessment and systemic treatment guidance in pts with early-stage TNBC receiving modern preoperative systemic therapy. Citation Format: T. R. Yoo, S. Morganti, Q. Jin, A. Patel, C. Snow, K. Santos, C. Stever, O. Cunningham, T. Rahman, J. Tejeda-Zanudo, J. Baginska, J. Bsat, M. Luo, I. G. Martino, B. M. Drummey, S. A. Virani, K. Howarth, C. Rushton, S. Birkeälv, S. Woodhouse, G. Putcha, E. Christoforou, S. Kirschner, A. Moeini, N. Ahmad, N. Tung, N. Sinclair, M. Constantinou, M. R. Faggen, S. Sinclair, S. Lo, J. L. Meisel, E. Winer, E. A. Mittendorf, N. Tayob, U. N. Lin, S. M. Tolaney, A. Garrido-Castro, H. A. Parsons. Prevalence and dynamics of circulating tumor DNA among patients with triple-negative breast cancer undergoing preoperative systemic therapy with or without immunotherapy [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 PS2-07-06.