Serial circulating tumor DNA (ctDNA) sequencing to monitor response and define acquired resistance to letrozole/abemaciclib in endometrial cancer (EC).
Authors: Panagiotis A. Konstantinopoulos, Mingyang Cai, Elizabeth Katherine Lee, Niya Xiong, Carolyn N. Krasner, Susana M. Campos, Joyce F. Liu, Neil S. Horowitz, Alexi A. Wright, Meghan Shea, Sara Bouberhan, Richard T. Penson, Oladapo O. Yeku, Hannah Sawyer, Martin Hayes, Madeline Polak, Cesar Martin Castro, SuChun Cheng, Caroline M. Weipert, Ursula A. Matulonis
Journal: Journal of Clinical Oncology (2024)

5592 Background: In a phase 2 study, letrozole/abemaciclib demonstrated an objective response rate (ORR) of 30% and median progression free survival (PFS) of 9.1 months in recurrent ER positive EC. While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response ( CTNNB1, KRAS,and CDKN2A mutations) and absence of response ( TP53mutations), circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. Methods: Serial plasma specimens were obtained at baseline, cycle 2 day 1 (C2D1), C3D1, C8D1, time of objective response, and at the time of progression from participants who consented for this optional collection. Samples were analyzed using the Guardant Infinity assay, which includes genotyping of &gt; 750 genes and methylation-based tumor fraction (TF). Treatment response was assessed using the Guardant methylation-informed Molecular Response algorithm. Patients with 50% or more decrease in ctDNA levels or with absolute low ctDNA levels were defined as achieving Molecular Response (MR). Comparison of survival curves was performed using the logrank test. Results: 99/102(97%) samples from 28 patients were successfully analyzed. Three samples were excluded from analysis for not meeting sequencing quality control thresholds. Detection of ctDNA at baseline, measured via methylation-based TF, was associated with worse median PFS, (ctDNA detected (n = 18): 3.5 months vs ctDNA undetected (n = 8): 16.5 months, p = 0.006, HR = 12.5) and overall survival (OS), (ctDNA detected: 11.6 months vs ctDNA undetected: not yet reached, p = 0.008, HR = 4.7e7). Patients who achieved MR after the first or second cycle of letrozole/abemaciclib therapy exhibited better median PFS (MR(n = 13): 12.8 vs not-MR(n = 10): 3.5 months, p &lt; 0.001, HR = 0.1) and were more likely to demonstrate clinical benefit (objective response and/or progression free survival for ≥6 months) from this regimen (MR: 84.6% vs not-MR: 10.0%, p &lt; 0.001, odds ratio (OR) = 49.5). ctDNA analysis of post-progression specimens identified several acquired genomic alterations associated with resistance to combined aromatase/CDK4&amp;6 inhibitor therapy, such as ESR1 mutations/amplification, RB1 mutations, ERBB2 amplification/mutations and CCNE1 amplification. Of note, 2 of the 3 patients with mismatch repair deficient (dMMR) ECs acquired ESR1 mutations at the time of progression; both patients had exhibited durable objective responses to therapy. Conclusions: Baseline and on-treatment ctDNA dynamics may provide an early indication of long-term outcomes and benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify genomic alterations of acquired resistance (such as ESR1, RB1, CCNE1,and ERBB2 alterations) that may guide selection of subsequent therapy.