Abstract PD17-03: Cell-free DNA monitoring in a phase II study of adjuvant endocrine therapy with CDK 4/6 inhibitor ribociclib for localized HR+/HER2- breast cancer (LEADER)
Authors: Medford Arielle J. , Scarpetti Lauren , Niemierko Andrzej , Isakoff Steven J. , Moy Beverly , Wander Seth A. , Deluca Elizabeth , Abraham Elizabeth , Shin Jennifer , Schnipper Lowell , Comander Amy E. , Mulvey Therese , Spickard Erik , Kalashnikova Ekaterina , Rodriguez Angel , Ellisen Leif , Bardia Aditya , Spring Laura M. 
Published: March 2023

Abstract
Background: While adjuvant endocrine therapy (ET) reduces recurrence risk in hormone receptor-positive (HR+) breast cancer, many patients still experience disease recurrence. Adjuvant therapeutic advances are needed to improve outcomes. Meanwhile, monitoring for circulating tumor DNA (ctDNA) in the adjuvant setting may detect molecular residual disease and/or emergences of molecular recurrence from tumor dormancy. Cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors have shown efficacy in HR+/HER2- metastatic breast cancer, and abemaciclib is now approved for adjuvant use in high-risk HR+/HER2- breast cancer. Adjuvant clinical trials have evaluated upfront use of adjuvant CDK 4/6 inhibition; however, the optimal timing of adding a CDK 4/6 inhibitor for HR+/HER2- breast cancer remains unknown. We conducted a prospective phase II clinical trial to evaluate the addition of the CDK 4/6 inhibitor ribociclib in patients with at least one remaining year of adjuvant ET regardless of duration of ET prior to trial enrollment, and we prospectively collected plasma for ctDNA analysis. Methods: Eligible patients had Stage I-III HR+/HER2- breast cancer and had been on adjuvant ET (any number of years) with at least one year of treatment remaining. Patients were randomized to one of two ribociclib schedules: continuous (400 mg daily, 28-day cycle) or intermittent (600 mg daily days 1-21, 28-day cycle) for one year. Patients were concurrently treated with an aromatase inhibitor (plus GnRH agonist, if premenopausal). Time to recurrence was calculated using the Kaplan-Meier method. ctDNA monitoring was performed using the SignateraTM platform, a tumor-informed assay based on whole exome sequencing of the primary tumor for multiplex PCR-NGS ctDNA assay design with targeting of up to 16 single nucleotide variants. Plasma samples were collected at the start of ribociclib/ET and serially during follow-up visits. Results: Among 81 patients treated with adjuvant endocrine therapy and the CDK4/6 inhibitor ribociclib, 42 patients had samples suitable for ctDNA analysis: 3 (7%) had a single ctDNA test, 17 (40%) had 2 serial ctDNA tests, and 22 (52%) had 3 serial ctDNA tests. After a median follow-up of 20 months, 2 patients who received ribociclib (intermittent dosing) experienced disease recurrence with recurrence-free survival of 100% at 1 year from study entry and 97% (95% CI 88-99%) at 2 years. ctDNA was detected exclusively in the only 2 patients that experienced recurrence, with lead times of 7 months and 8 months prior to clinical recurrence. Both patients had no detectable ctDNA at the start of ribociclib/ET. One patient had detectable ctDNA [mean tumor molecules/mL (MTM/mL) = 0.1] while on ribociclib/ET for 5 months, after which she completed a full 12 months of treatment. One month after completing ribociclib/ET (8 months after ctDNA detection), she presented with metastases in the liver and bones. The second patient had 2 negative ctDNA tests at days 0 and 147 while receiving ribociclib/ET and became ctDNA positive (MTM/mL = 0.1) at day 350. She developed CNS-only metastatic disease 7 months after completing ribociclib/ET. Among the other 40 patients who did not have detectable ctDNA, none have experienced recurrence. Conclusions: Overall, only 2 patients had detectable ctDNA, and both patients developed recurrent metastatic disease after completion of ribociclib with ET. Notably, one of these patients developed CNS-only disease. While follow-up is early, the remaining patients did not have detectable ctDNA and have not developed recurrent disease. This study suggests monitoring for ctDNA may identify patients at increased risk for recurrence in the extended adjuvant period and potentially guide therapy escalation.
Citation Format: Arielle J. Medford, Lauren Scarpetti, Andrzej Niemierko, Steven J. Isakoff, Beverly Moy, Seth A. Wander, Elizabeth Deluca, Elizabeth Abraham, Jennifer Shin, Lowell Schnipper, Amy E. Comander, Therese Mulvey, Erik Spickard, Ekaterina Kalashnikova, Angel Rodriguez, Leif Ellisen, Aditya Bardia, Laura M. Spring. Cell-free DNA monitoring in a phase II study of adjuvant endocrine therapy with CDK 4/6 inhibitor ribociclib for localized HR+/HER2- breast cancer (LEADER) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-03.