Multicenter prospective study of ultrasensitive circulating tumor DNA assessment of breast cancer minimal residual disease

Patients with stage II/III HER2-positive or triple-negative breast cancer (TNBC) frequently receive neoadjuvant therapy (NAT). Although pathologic complete response (pCR) correlate with improved outcomes, many non-pCR patients have long-term survival. Circulating tumor DNA (ctDNA) minimal residual disease (MRD) assessment may provide additional risk stratification. The multicenter prospective Pathologic Response Evaluation and Detection in Circulating Tumor-DNA (PREDICT-DNA) study evaluated ctDNA (at baseline, after NAT, and after surgery) as a biomarker of treatment response using a ultrasensitive (≤ 100 ppm) assay. The primary objective was to determine if the negative predictive value (NPV) of post-NAT ctDNA for pCR was ≥ 90%. Of 220 pCR evaluable patients (48% HER2-positive, 52% TNBC); 91 (41%) had pCR. The primary objective was not met; although all patients with pCR were ctDNA-negative after NAT, 40% of non-pCR patients were also ctDNA-negative (NPV 60%). A prespecified secondary objective for the TNBC cohort was to assess associations between ctDNA and 5-year invasive disease-free survival (IDFS). This objective was met; detectable ctDNA after NAT was prognostic for recurrence (HR 8.9; p=0.001) independent of pCR. Additionally, detectable ctDNA after surgery identified patients at high recurrence risk (HR 128; p<0.001), while ctDNA-negative patients after surgery had 94% 5-year IDFS. The authors conclude that ctDNA assessment provides prognostic stratification, identifying patients with exceptional outcomes and those at extreme risk. These findings support ctDNA-guided therapeutic de-escalation and escalation strategies.