Abstract 4295: Early circulating tumor DNA dynamics as a real-time predictor of FOLFOX efficacy in advanced colorectal cancer patients
Authors: Moser Tina , Waldispuehl-Geigl Julie , Belic Jelena , Perakis Samantha , Weber Sabrina , Zhou Qing , Sill Heinz , Lax Sigurd , Kashofer Karl , Hoefler Gerald , Schoellnast Helmut , Bauernhofer Thomas , Heitzer Ellen , Geigl Jochen B. , Speicher Michael R. 
Published: September 2020

Abstract
Background: In recent years, various efforts have been made to identify biomarkers in metastatic colorectal cancer patients (mCRC), all with the goal of improving patients' outcomes, including maximizing therapeutic response and minimizing exposure to ineffective treatments. Nevertheless, there is still no valid biomarker for the early assessment of therapeutic efficacy in the patient management strategy. To address this issue, we aimed to describe the predictive value of circulating tumor DNA (ctDNA) on the efficacy of FOLFOX treatment in mCRC patients.
Patients and methods: A total of 11 patients with mCRC receiving FOLFOX therapy were included in this study. During the 48-hour FOLFOX cycle, we performed serial liquid biopsy-based ctDNA analysis before treatment start (T1) and at eight further time points (T2-T9). Among the 11 patients tested, all patients had detectable variants identified by either tumor tissue genotyping or baseline sample ctDNA sequencing for longitudinal analysis. We assessed genome-wide somatic copy number alterations (SCNAs) and highly sensitive sequencing approaches were utilized to monitor changes in the ctDNA mutant allele frequencies (mAFs) between baseline and on-treatment samples.
Results: We were able to clearly assess different mAF patterns across patients with either stable disease, partial response or progressive disease. However, we invariably observed an early and deep ctDNA mAF decrease in all patients, as comparing the baseline (T1) mAF levels with the mAFs at all time points revealed that the most significant ctDNA drop was 23 hours after treatment start, i.e. at time point T5 (p &lt;0.005). In addition, we observed in patients with stable disease or partial response (n=8) not only a significant decline of mAFs between T5 (p=0.0391) but also at T9 (52 hours after treatment start; p=0.0156) compared to the baseline sample. Conversely, mAFs of patients with progressive disease increased again within the next 29 hours (T9) after the initial ctDNA drop at time point T5, leading to higher ctDNA levels at T9 than the baseline values prior to treatment start.
Conclusion: Our observations clearly demonstrated for the first time that ctDNA dynamics allow real-time, individualized evaluation of treatment response using two early time points, i.e. at T5 and T9. Therefore, our data suggest that sequential ctDNA analysis can contribute to an improved patient treatment strategy. Nevertheless, further studies are clearly required to validate this promising early on-treatment indicator of therapeutic efficacy for CRC patients.
Citation Format: Tina Moser, Julie Waldispuehl-Geigl, Jelena Belic, Samantha Perakis, Sabrina Weber, Qing Zhou, Heinz Sill, Sigurd Lax, Karl Kashofer, Gerald Hoefler, Helmut Schoellnast, Thomas Bauernhofer, Ellen Heitzer, Jochen B. Geigl, Michael R. Speicher. Early circulating tumor DNA dynamics as a real-time predictor of FOLFOX efficacy in advanced colorectal cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4295.