Impact of circulating tumor DNA (ctDNA) surveillance on clinical care for patients with stage I-III breast cancer: Findings from a multi-institutional study.
Authors: Lipsyc-Sharf Marla , Fitzsimmons Kasey , Medford Arielle J , Podany Emily L , Sedrak Mina S. , McAndrew Nicholas Patrick , Callahan Rena Desai , Kapoor Nimmi S. , Master Aashini K. , Rivero-Hinojosa Samuel , Fielder Janie , Rodriguez Angel A , Liu Minetta C. , Knape Justine , Donahue Jeannine , Gianni Caterina , Davis Andrew A. , Cristofanilli Massimo , Bardia Aditya 
Published: May 2024

549 Background: Tumor-informed ctDNA-based detection of minimal residual disease (MRD) in the adjuvant setting for patients (pts) with early breast cancer (EBC) is strongly associated with recurrence. However, the clinical impact of early ctDNA detection and potential therapeutic intervention remains unclear. In this multi-institution retrospective analysis, we investigated whether ctDNA detection in the adjuvant setting impacted the care of pts with EBC. Methods: This multisite (4 geographically distinct regions in the US) study included ptswith stage I-III EBC who had adjuvant MRD testing between 11/2020 - 01/2024. A personalized, tumor-informed 16-plex PCR assay (Signatera) was used for plasma ctDNA detection. All tests were ordered in the real-world clinical setting. Data were obtained by retrospective review of electronic medical records. Results: As of 01/2024, 464 EBC pts had tumor-informed ctDNA testing to monitor MRD. Of these, 58 pts (13%) were ctDNA+ at ≥1 timepoint post-surgery: 7 (12%) with stage I EBC, 25 (43%) stage II, 26 (45%) with stage III. Tumor subtypes included HR+/HER2- (38; 65%), HR-/HER2- (17; 30%), and HER2+ (3; 5%). Of the ctDNA+ group, most pts (47; 81%) had testing at >1 timepoint (median 3; range 1-20 timepoints). Overall, 28 (48%) had ctDNA+ at all timepoints, 11 (19%) were persistently ctDNA+ after initial ≥1 negative result (ctDNA-), and 19 (33%) cleared ctDNA after initial ≥1 ctDNA+ result. Adjuvant ctDNA+ results impacted the care plan in 53/58 (91%) pts. 45/58 (78%) had restaging imaging within 1 year of a ctDNA+ result, and 25/45 (56%) had radiographic evidence of recurrence at that time: 23 distant and 2 local recurrences. 10/25 (40%) of these recurrences were in pts with HR-/HER2- EBC. Of 20 pts that were ctDNA+ despite no radiographic evidence of recurrence (MRD+ corresponding to molecular recurrence), 17/20 (85%) had HR+/HER2- EBC. At least 5/20 (25%) had increased imaging surveillance after ctDNA+ results, and at least 14/20 (70%) had repeat ctDNA testing. In 9/20 (45%) pts with molecular recurrence, providers changed therapy based on the ctDNA+ result, including enrollment into a clinical trial. 5/9 (56%) of these pts had a subsequent ctDNA clearance, 4 (80%) of whom remained without radiologic evidence of disease (median follow-up 12.53 (range 6.08-21.6) months from time of ctDNA+). 3/9 pts had persistent ctDNA+ despite change in therapy and all 3/3 (100%) of these pts had a radiographic recurrence. Conclusions: In this multi-institutional study, ctDNA detection impacted clinical care in most pts. A subset of pts had a change in systemic therapy with subsequent ctDNA clearance which was associated with better prognosis compared to those without ctDNA clearance. Further validation of these findings in additional datasets and clinical trial(s) are needed to inform incorporation of ctDNA testing into routine care.