Circulating tumor DNA and late recurrence in high-risk, hormone receptor-positive, HER2-negative breast cancer: An updated analysis of the CHiRP study.

3055 Background: Risk of recurrence for patients (pts) with HR+/HER2- breast cancer persists for decades. Most distant recurrences occur in the ‘late’ adjuvant setting, > 5 years (yrs) from diagnosis. In CHiRP (ASCO 2022), we showed that minimal residual disease (MRD) was detectable in the late adjuvant setting: ctDNA was detected in 8/83 (9.6%) pts in the cohort and 6/8 (75%) pts with positive ctDNA (+ctDNA) had developed distant recurrence when initially reported (median follow-up 2 years from first plasma sample collected on study). Here, we report updated clinical outcomes and investigate the meaning of a ctDNA test result during surveillance with longer follow-up. Methods: In CHiRP, pts with stage II-III HR+/HER2- breast cancer at high risk of recurrence diagnosed > 5 yrs prior with no evidence of recurrence were prospectively identified. All pts provided informed consent for prospective plasma collection every 6-12 months at routine follow-up visits for batched, retrospective ctDNA testing using RaDaR, a tumor-informed whole exome sequencing-based assay. Pts were followed at the discretion of the clinical provider without any routine surveillance imaging, as per guideline-concordant care. See CHiRP ASCO 2022 presentation for additional methods. Results: Of 83 pts in the analytic cohort, 57 (68.7%) pts had stage III disease, and most (n = 75, 90.4%) underwent (neo)adjuvant chemotherapy. All pts received endocrine therapy. In this update, median follow-up from first sample collection was 4.4 yrs (interquartile range 4.0, 4.9). 214 plasma samples were collected prior to any known recurrences and included in this analysis. 8/83 (9.6%) pts had +ctDNA at any timepoint including 4/83 (4.8%) with +ctDNA on first study plasma sample. In pts initially ctDNA-negative (-ctDNA; n = 4), median time from first sample collection to MRD detection was 1.29 yrs (range, 0.72 – 3.05). During follow-up, 8 (9.6%) pts developed distant recurrence and 1 (1.2%) pt had a local recurrence. With additional follow-up included in this update, all 8/8(100%) pts with +ctDNA developed distant recurrence with a median lead time of 1.39 years (range 0.01 – 4.24). Among -ctDNA plasma samples with > 2 yrs of follow-up (n = 185), the negative predictive value (NPV) of a -ctDNA test for lack of clinical recurrence for > 2 yrs post-test was 98.4% (3/185). The NPV indicating freedom from recurrence > 1 and > 3 yrs was 100% (0/196) and 96.6% (5/147), respectively. Conclusions: In pts with high-risk HR+/HER2- breast cancer in the late adjuvant setting, all pts with +ctDNA developed distant metastasis. A -ctDNA test was strongly associated with lack of recurrence over a 3 yr follow-up period. Future studies are needed to determine if ctDNA-guided intervention can impact clinical outcomes for early-stage breast cancer and to determine the optimal role of MRD surveillance during follow-up.