Dustin, Derek

3052 Background: Minimal residual disease (MRD) detected using circulating tumor DNA (ctDNA) is associated with increased breast cancer (BC) relapse risk in patients (pts) with early BC after curative-intent surgery. However, the clinical utility of ctDNA-based MRD testing for post-surgical surveillance and risk stratification remains incompletely defined. We used real-world data to evaluate the performance of Guardant Reveal, a tissue-free epigenomic assay for MRD detection, and the clinical significance of a positive MRD test (+MRD) in pts with resected early BC. Methods: Data of pts with resected stage I-IIIA BC in the Guardant InfinityAI Data Library who underwent Guardant Reveal testing between February 2023 and September 2025 was analyzed. Pts with ≥1 post-surgical MRD were included if they had either no distant metastatic BC recurrence with ≥1 year of follow up after the last MRD test or a documented distant metastatic BC postoperatively; pts with a new non-breast primary malignancy were excluded. Sensitivity was assessed by site of distant metastasis and interval from MRD test to recurrence; nodal recurrences were excluded due to claims data limitations. Specificity was assessed using all tests from pts without recurrence and ≥1 year of follow up after the last post-treatment MRD test. Claims data were used to infer treatment changes following +MRD. Results: A total of 822 pts was analyzed. 114 pts with real-world clinico-genomics data were evaluable for sensitivity and 708 for specificity. One-year sensitivity for distant metastatic recurrence was 71%, and was highest for bone-only (97%, 35/36 cases) or lung (89%, 8/9 cases) recurrences and lowest for brain-only recurrences (33%, 1/4 cases). Sensitivity within 12 months of recurrence was higher in hormone receptor-positive (HR+)/HER2-negative BC (79%) and stage IIIA BC (81%) and for multiple-organ versus single-organ metastasis (83% versus 69%). Sample-level specificity was 94%. Following +MRD, 41 pts did not initiate or switch systemic therapy; 29 had distant BC recurrence, including 24 within 90 days after +MRD. Twenty pts switched therapy within 90 days of +MRD; 19 recurred, including 17 within 90 days after +MRD. Among 10 pts with post-recurrence MRD testing, only 3 had +MRD. Conclusions: In a real-world cohort of pts with resected early-stage BC, a tissue-free epigenomic ctDNA MRD assay demonstrated high specificity and clinically meaningful sensitivity for distant metastatic recurrence, particularly for bone-only and lung metastases and in pts with HR+ BC. These findings support ctDNA-based MRD testing as a noninvasive tool for postsurgical surveillance and risk stratification in early BC.

Abstract Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US care centers. The most common treatment-related toxicity was rash (27% of patients). In most patients, the disease was effectively managed at low doses (0.5-1.0 mg trametinib daily). The response rate of the 17 evaluable patients was 71% (73% [8/11] without a detectable BRAFV600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, whereas the median progression-free and overall survival were not reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAFV600E or other BRAF alterations) or alterations in other genes involved in the MAPK pathway, eg, MAP2K, NF1, GNAS, or RAS. Most patients required lower than standard doses of trametinib but were responsive to lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.