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

Author(s): Natasha B. Hunter, MD¹; Heather A. Parsons, MD^1,2; Leslie Cope, PhD³; Jenna V. Canzoniero, MD, MS³; Fabio C.P. Navarro, PhD⁴; Sherif El-Refai, PharmD, PhD⁴; Jesus D. Anampa, MD, MS⁵; Joseph A. Sparano, MD⁵; Mothaffar Rimawi, MD⁶; Anna Maria Storniolo, MD⁷; Candace Mainor, MD⁸; Rita Nanda, MD⁹; Angela DeMichele, MD, MSCE¹⁰; Gaorav P. Gupta, MD, PhD¹¹; Erica J. Stringer-Reasor, MD¹²; Filipa Lynce, MD^2,8; Erin F. Cobain, MD¹³; Shannon Puhalla, MD¹⁴; Rachel Jankowitz, MD^10,14; Brent Rexer, MD, PhD¹⁵; Ingrid Mayer, MD, , MSCI¹⁵; E. Shelley Hwang, MD, MPH, MBA¹⁶; Kimberly Blackwell, MD¹⁶; Walid El Ayass, MD¹⁷; Young Lee, MD¹⁸; Carol Tweed, MD¹⁸; Mary Wilkinson, MD^3,19; Angela Pennisi, MD¹⁹; Bonnie Sun, MD³; Pamela Wright, MD³; Julie R. Gralow, MD¹; Richard Chen, MD⁴; Sean M. Boyle, PhD⁴; Vered Stearns, MD³; Antonio C. Wolff, MD³; Ben Ho Park, MD, PhD¹⁵;

Source: DOI: 10.1200/JCO-25-02934

Dr. Anjan Patel's Thoughts

Primary objective not met, ctDNA clearance post- neoadjuvant therapy (NAT) cannot reliably predict pathologic complete response (pCR) and shouldn't be used to defer surgery. But the prognostic data are striking: post-NAT ctDNA positivity independently predicted recurrence in triple-negative breast cancer (TNBC) (HR 8.9), and the postsurgical landmark analysis is essentially binary, 100% of ctDNA-positive patients recurred while 94% of ctDNA-negative patients were disease-free at 5 years (HR 128). Not practice-changing yet pending prospective utility trials, but this strongly validates ultrasensitive ctDNA as a prognostic tool and a smart enrollment biomarker for future escalation/de-escalation trials.

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 (

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 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 extreme risk. These findings support ctDNA-guided therapeutic de-escalation and escalation strategies.

Author Affiliations

¹Fred Hutchinson Cancer Center, University of Washington, Seattle, WA; ²Dana Farber Cancer Institute, Boston, MA; ³Johns Hopkins University, Baltimore, MD; ⁴Personalis, Fremont, CA; ⁵Montefiore Einstein Comprehensive Cancer Center, Bronx, NY; ⁶Baylor College of Medicine, Houston, TX; ⁷Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN; ⁸Medstar Georgetown University-Hospital-Lombardi Comprehensive Cancer Center, Washington, DC; ⁹University of Chicago, Chicago, IL; ¹⁰University of Pennsylvania, Philadelphia, PA; ¹¹University of North Carolina, Chapel Hill, NC; ¹²University of Alabama Birmingham, Birmingham, AL; ¹³Rogel Cancer Center, University of Michigan, Ann Arbor, MI; ¹⁴University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA; ¹⁵Vanderbilt University Medical Center, Nashville, TN; ¹⁶Duke University and Duke Cancer Institute, Durham, NC; ¹⁷Tidal Health, Peninsula Regional Medical Center, Salisbury, MD; ¹⁸Anne Arundel Medical Center, Annapolis, MD; ¹⁹Inova Schar Cancer, Fairfax, VA

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