Abstract PS06-01: Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer

Abstract Background Two years of adjuvant abemaciclib + endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer (EBC) in the monarchE trial (NCT03155997). The benefit of abemaciclib was sustained beyond completion of treatment and deepened in magnitude at 4 years for IDFS and DRFS. This pilot study investigated the technical feasibility of ctDNA detection beginning prior to study treatment, as well as rates of persistence and clearance in a subset of EBC pts from monarchE using the clinically validated SignateraTM ctDNA assay. Methods Samples were analyzed from a selected subset of pts (n=178; 84 from abemaciclib+ET arm; 94 ET alone) who had blood collected both before initiating protocol directed therapy, Visit 1 (V1; randomization + ≤ 3 days) and near completion of the 2-year treatment period, Visit 27 (V27; 24 months +/- 5 days from V1). This cohort of pts was enriched for overall IDFS events compared to the total monarchE study population, however pts with relapses occurring prior to V27 were excluded. Primary tumors from selected pts were subjected to whole exome sequencing (WES). Selected samples included those from pts with a range of tumor mutation burden. Cell-free DNA was extracted from 356 plasma samples. A Signatera ctDNA assay was developed for each pt based on up to 16 variants detected by WES from each baseline tumor sample. Results The IDFS event rate for the selected subset (n=178) was 39.3% (abemaciclib+ET 34.5% 29/84 and ET alone 43.6% 41/94). Ten pts (5.6%) were initially ctDNA+ and 42 pts (23.6%) were persistently (7 pts, 3.9%) or became (35 pts, 19.7%) ctDNA+ at V27. Notably, 70% of pts who were initially ctDNA+ and 100% of pts who were either persistently ctDNA+ or became ctDNA+ experienced recurrence (see Table 1). In contrast, none of the 3 pts that cleared ctDNA+ developed recurrence. In pts persistently ctDNA negative (neg), 28 (21.1%) experienced recurrence. Overall, 10% (7/70) of pts with IDFS events were initially ctDNA+ and 50% (35/70) had detectable ctDNA at V27. Conclusions Detection of ctDNA soon after completing neoadjuvant chemotherapy was infrequent, but also associated with a high-risk of recurrence. ctDNA positivity was common at the end of the 2-year treatment period and was highly prognostic with all pts subsequently developing disease recurrence. Importantly, ~30% of pts with early ctDNA detection ultimately dropped below detection limits during the 2-year treatment period and none developed recurrence. Although some pts remained persistently ctDNA neg during this study and experienced recurrence, the delay in recurrence may indicate longitudinal benefit from remaining ctDNA neg. Future planned analysis of an expanded cohort reflective of the intent to treat population including additional timepoints within the 2-year treatment period will further define how ctDNA dynamics may identify pts at high-risk of recurrence. Table 1. Summary of Subset Positivity Rates. + positive; - negative; NA, not applicable. Citation Format: Sherene Loi, Stephen Johnston, Carlos Arteaga, Stephanie Graff, Sarat Chandarlapaty, Matthew Goetz, Christine Desmedt, Jorge Reis-Filho, Hironobu Sasano, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Deli Liu, Lacey M. Litchfield, Nicholas Turner. Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-01.