Artigo

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

Autor(es): Natasha B. Hunter, MD 1 ; Heather A. Parsons, MD 1,2 Sherif El-Refai, PharmD, PhD 4 Anna Maria Storniolo, MD 7 ; Leslie Cope, PhD 3 ; Jenna V. Canzoniero, MD, MS 3 ; Jesus D. Anampa, MD, MS 5 ; Joseph A. Sparano, MD 5 ; Fabio C.P. Navarro, PhD 4 ; Mothaffar Rimawi, MD 6 ; Candace Mainor, MD 8 ; Rita Nanda, MD 9 ; Angela DeMichele, MD, MSCE 10 ; ; ; Gaorav P. Gupta, MD, PhD 11 Erica J. Stringer-Reasor, MD 12 Brent Rexer, MD, PhD 15 ; Ingrid Mayer, MD, MSCI 15 ; Filipa Lynce, MD 2,8 ; Erin F. Cobain, MD 13 ; Shannon Puhalla, MD 14 ; Rachel Jankowitz, MD 10,14 ; E. Shelley Hwang, MD, MPH, MBA 16 ; ; ; Kimberly Blackwell, MD 16 ; Walid El Ayass, MD 17 ; Young Lee, MD 18 ; Carol Tweed, MD 18 Julie R. Gralow, MD 1 ; Mary Wilkinson, MD 3,19 ; Angela Pennisi, MD 19 ; Richard Chen, MD 4 ; Bonnie Sun, MD 3 ; Pamela Wright, MD 3 ; ; Sean M. Boyle, PhD 4 ; Vered Stearns, MD 3 Ben Ho Park, MD, PhD 15

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. Circu lating 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 5 .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.