Single arm prospective study evaluating the relationship of ctDNA molecular complete response (mCR) and pathologic complete response (pCR) in a diverse early triple-negative breast cancer patient (TNBC) population receiving neoadjuvant chemotherapy (NAC).

Abstract

e12553 Background: Chemotherapy plus pembrolizumab in neoadjuvant and adjuvant settings (Keynote-522) is standard of care for early-stage triple-negative breast cancer (TNBC), improving pathologic complete response (pCR) and overall survival (OS). Circulating tumor DNA (ctDNA) may provide a minimally invasive tool to assess early response, guide therapy de-escalation, and detect recurrence. Methods: This single-center, prospective pilot study enrolled 31 patients with early-stage TNBC undergoing NAC. ctDNA was collected at baseline, every 3 weeks during NAC, and every 4-12 weeks in the adjuvant setting using a tumor-informed test. Primary endpoints were concordance between mCR and pCR. Secondary endpoints included mCR at 3, 6, and 9 weeks, imaging CR (iCR) correlation, and event-free survival (EFS). Treatments included paclitaxel-carboplatin-pembrolizumab (tcP) followed by doxorubicin-cyclophosphamide-pembrolizumab (ACP) or ACP before tcP. This report presents EFS outcomes comparing patients who achieved mCR with those who did not after NAC. Results: Of 31 enrolled patients, 29 had sufficient tissue for ctDNA analysis. Of these, 64% were African American (AA), 34.4% Caucasian (CA), and 3.4% Asian. After NAC, 48% (14/29) achieved pCR, and 66% (19/29) demonstrated favorable pathologic response (RCB 0/1). All patients with RCB 0/1 achieved ctDNA clearance at 6 weeks, increasing to 86% (25/29) post-surgery. After a median follow-up of 20 months from initiation of NAC, there were six recurrence or death events, with 83% (5/6) occurring in patients who did not achieve mCR. Among these, 66% (4/6) were due to local or systemic progression, and one patient died from unrelated causes before completing NAC. The estimated EFS was 37.5% for ctDNA positive patients versus 95.2% for ctDNA negative patients (hazard ratio (HR): 17; p-value: 0.0096). HR is inflated due to the scarcity of events. When analyzing the correlation between pCR and survival, all four events occurred exclusively in patients who did not achieve pCR (4/12, 33.3%), with no events in those who achieved pCR (0/15). This resulted in a significant survival advantage for patients who achieved pCR (log-rank p = 0.0081). Conclusions: These findings demonstrate that ctDNA clearance and pCR are powerful predictors of improved EFS in early-stage TNBC patients receiving neoadjuvant therapy. The correlation between mCR and survival outcomes suggests that ctDNA monitoring could be valuable for risk stratification and treatment decisions.