The Pathologic Response Evaluation and Detection in Circulating Tumor-DNA Study: Ultrasensitive Circulating Tumor-DNA Assessment of Breast Cancer Minimal Residual Disease

Document Type

Article

Subject Area(s)

Humans; Female; Neoplasm, Residual; Circulating Tumor DNA (blood); Pathologic Complete Response; Prospective Studies; Biomarkers, Tumor (blood, genetics); Disease-Free Survival; Neoadjuvant Therapy; Triple Negative Breast Neoplasms (pathology, blood, genetics, therapy); Middle Aged; Erb-b2 Receptor Tyrosine Kinases; Adult; Aged; Breast Neoplasms (pathology, blood, genetics, therapy); Predictive Value of Tests; Neoplasm Staging

Abstract

PURPOSE:

Patients with stage II/III human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer (TNBC) frequently receive neoadjuvant therapy (NAT). Although pathologic complete response (pCR) correlates with improved outcomes, many non-pCR patients have long-term survival. Circulating tumor-DNA (ctDNA) minimal residual disease (MRD) assessment may provide additional or superior risk stratification.

METHODS:

Pathologic Response Evaluation and Detection in Circulating Tumor-DNA is a prospective, multicenter study evaluating ctDNA as a biomarker of treatment response using a tumor-informed, ultrasensitive (< 100 parts per million) assay. The primary objective was to determine whether the negative predictive value (NPV) of post-NAT ctDNA for pCR was ≥90%. A prespecified secondary objective for the TNBC cohort was to assess associations between ctDNA and 5-year invasive disease-free survival (IDFS). ctDNA was evaluated at baseline, after NAT before surgery, and after surgery.

RESULTS:

Of 227 enrolled patients, 220 were evaluable for pCR (48% HER2-positive; 52% TNBC) and 91 patients (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% [95% CI, 0.50 to 0.69]). However, the prespecified secondary objective was met. Detectable ctDNA after NAT was prognostic for recurrence (hazard ratio [HR], 8.9 [95% CI, 2.4 to 33]; P = .001), independent of pCR. Additionally, detectable ctDNA after surgery identified patients at extremely high recurrence risk (HR, 128 [95% CI, 15 to 1,083]; P < .001), while ctDNA-negative patients after surgery had 94% 5-year IDFS.

CONCLUSION:

In HER2-positive breast cancer and TNBC, ctDNA after NAT does not discriminate pCR from non-pCR. However, ctDNA provides markedly superior prognostic stratification, identifying patients with exceptional outcomes and those at extreme risk. These findings support ctDNA-guided therapeutic de-escalation and escalation strategies.

Digital Object Identifier (DOI)

https://doi.org/10.1200/JCO-25-02934

APA Citation

Hunter, N. B., Parsons, H. A., Cope, L., Canzoniero, J. V., Navarro, F. C. P., El-Refai, S., Anampa, J. D., Sparano, J. A., Rimawi, M., Storniolo, A. M., Mainor, C., Nanda, R., DeMichele, A., Gupta, G. P., Stringer-Reasor, E. J., Lynce, F., Cobain, E. F., Puhalla, S., Jankowitz, R., … Park, B. H. (2026). The Pathologic Response Evaluation and Detection in Circulating Tumor-DNA study: Ultrasensitive circulating tumor-DNA assessment of breast cancer minimal residual disease. Journal of Clinical Oncology, JCO2502934. https://doi.org/10.1200/JCO-25-02934

Rights

© 2026 by American Society of Clinical Oncology.

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