Abstract PO2-14-06: CIRCULATING TUMOR DNA DYNAMICS IN THE FIRST TREATMENT LINE OF THE SONIA TRIAL
Authors: Jongbloed Elisabeth M , Stella Stefania , van Bergen Lotte , Beaufort Corine , Helmijr Jean , de Weerd Vanja , Erdkamp Frans , Heijns Joan , Kamm Yvonne , van Riel Anne-Marie , van Rossum-Schornagel Quirine , Jansen Maurice , Konings Inge RHM , Sonke Gabe , Martens John WM , Jager Agnes , Wilting Saskia M 
Published: May 2024

Abstract
Background and objective: CDK4/6 inhibitors (CDK4/6i) improve the outcome of patients with ER+/HER2- advanced breast cancer when added to endocrine therapy in the first line or second line of treatment. The recently reported SONIA trial shows no difference in progression free survival after two lines of treatment (PFS2), overall survival (OS) or quality of life benefit of CDK4/6i in first-line compared to second-line, while adverse events are substantially higher when CDK4/6i is added in the first-line. However, a subgroup of patients shows early progression on endocrine mono-treatment and not all patients respond equally well to CDK4/6i. This highlights the need for early response markers during the first weeks of treatment to reduce unnecessary toxicity while providing the most optimal care. In this SONIA side study, we aim to investigate whether we could identify patients who will progress rapidly during first line of therapy by using circulating tumor DNA (ctDNA) dynamics.
Methods: Blood samples were obtained from patients included in the SONIA trial in both the first line CDK4/6i + aromatase inhibitor (AI) combination arm (arm A) and the first line AI monotherapy arm (arm B) at three time points: before start, after two weeks and after three months of first line treatment. Cell free DNA (cfDNA) was isolated from all samples and subsequently baseline cfDNA was sequenced with the Oncomine™ Breast cfDNA Assay v2 (Thermofisher), a focused NGS panel of 10 genes. Dedicated dPCR assays were used to track an identified driver mutation over time.
Results: Blood samples of 332 patients (206 in arm A and 126 in arm B) before start of first line treatment and after two weeks of treatment were obtained. At baseline, in 142 of the 332 (42.7%) patients at least one somatic mutation was detected. In 30 patients two or more mutations were identified, in which case the mutation with the highest variant allele frequency (VAF) was followed over time. The most frequently mutated genes were PIK3CA (102 patients (30.7% of the total included cohort)), TP53 (32 patients (9.6%)), SF3B1 (8 patients (2.4%) and ESR1 (6 patients (1.8%)). The median observed VAF at baseline was 4.1% (IQR: 1.5%-13.1%). Of the 142 patients with detectable ctDNA at baseline, 141 patients and 100 patients, respectively, had blood samples taken after 2 weeks and after 3 months of treatment. After two weeks, the VAF of the tracked mutation was increased in 15.2% (14/92) of the patients in arm A and in 18.4% (9/49) of the patients in arm B. At the same time 40.2% (37/92) of the patients in arm A and 34.7% (17/49) of the patients in arm B had cleared ctDNA. No difference was observed between the arms for both an increase in VAF (P=0.63, Chi-square test) and ctDNA clearance (P=0.52, Chi-square test). After 3 months an increased VAF of the tracked mutation compared to baseline was observed in 6.3% (4/64) of the patients in arm A and 8.3% (3/36) of the patients in arm B. At this timepoint 59.4% (38/64) of the patients in arm A and 61.1% (22/36) of the patients in arm B had cleared ctDNA. No difference was observed between the arms for both ctDNA clearance (P=0.86, Chi-square test) and increase in VAF (P=0.70, Chi-square test) after three months.
Conclusions: ctDNA was detected at baseline in almost half of the patients in the SONIA study. Compared to baseline, a decreasing number of patients had an elevation of the VAF of the tracked mutation and an increasing number of patients showed ctDNA clearance from 2 weeks to 3 months after start of treatment. There was no difference between the two arms observed regarding ctDNA dynamics. Interestingly, irrespective of treatment arm, about 1/3rd of patients remained ctDNA-positive even after 3 months of treatment. Associations of these ctDNA data with the clinical outcome data are currently being evaluated and will be presented at the meeting.
Citation Format: Elisabeth M Jongbloed, Stefania Stella, Lotte van Bergen, Corine Beaufort, Jean Helmijr, Vanja de Weerd, Frans Erdkamp, Joan Heijns, Yvonne Kamm, Anne-Marie van Riel, Quirine van Rossum-Schornagel, Maurice Jansen, Inge RHM Konings, Gabe Sonke, John WM Martens, Agnes Jager, Saskia M Wilting. CIRCULATING TUMOR DNA DYNAMICS IN THE FIRST TREATMENT LINE OF THE SONIA TRIAL [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 PO2-14-06.