Circulating Tumor Dna As A Potential Biomarker Of Radiographic Tumor Burden In Small Cell Lung Cancer

Abstract Introduction Blood-based next generation sequencing assays of circulating tumor DNA (ctDNA) have the ability to detect canonical SCLC tumor-associated mutations1,2. In non-small cell lung cancer, mean variant allele frequency (VAF) of clonal mutations in ctDNA is associated with radiographic tumor volume (TV)3. We sought to characterize the relationship between ctDNA mean VAF and total-body tumor burden in patients with SCLC. Methods Patients with both limited- and extensive-stage SCLC were identified prospectively and underwent serial blood draws as part of an IRB-approved protocol (IRB #030763). Using our previously developed ctDNA assay, mean VAF was calculated from patient plasma by sequencing 14 genes (all coding exons of TP53, RB1, BRAF, KIT, NOTCH1-4, PIK3CA, PTEN, and copy number variations in FGFR1, MYC, MYCL1, and MYCN)1,4. Three-dimensional total-body tumor burden was determined from positron emission tomography and computed tomography scans obtained during routine care using a radiation oncology treatment-planning software (MIM), and tumor segmentations were verified by radiation oncologists. Univariate association and multivariable mixed effects regression analyses (including presence of bone metastases and treatment status) were performed to evaluate the association between mean VAF and overall TV. We performed separate analyses for mean VAF of all variants identified and of TP53 variants only. Results We analyzed 75 concordant scans and blood draws from 25 patients with SCLC. The median interval between imaging and blood collection was 1 day (mean 3.5, range 0-16). Univariate analysis showed a positive association between mean VAF of all variants and overall TV (Spearman's ρ=0.292, p<0.01). When considering only treatment-naïve and pre-treatment samples (n=11), the magnitude of association increased and remained significant (ρ=0.618, p=0.048). The relationship between mean VAF of all variants and overall TV remained significant when adjusting for treatment status and bone metastases (p=0.046). When considering only TP53 variants, an overall univariate correlation analysis did not show a significant association between mean VAF and overall TV (ρ=0.184, p=0.175). However, among treatment-naïve and pre-treatment samples (n=8) with TP53 variants, the association was significant (ρ=0.762, p=0.037). This association remained significant (p=0.021) after adjusting for treatment status and presence of bone metastasis, with VAF increasing 3.7% for each fold increase in TV (95% CI: 0.7-6.7%). Conclusion In our study mean VAF (both overall and TP53 variants only) was positively correlated with three-dimensional total-body tumor burden in patients with SCLC. These results suggest that mean VAF may provide a useful snapshot of overall tumor burden and represent a dynamic biomarker that could be followed to monitor for disease progression in patients with SCLC. References 1. Almodovar K, et al. Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer... J Thorac Oncol 2018;13:112-23. 2. Nong J, et al. ctDNA analysis depicts subclonal architecture...of small cell lung cancer. Nat Commun 2018;9:3114. 3. Abbosh C, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 2017;545:446-51. 4. George J, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47. Citation Format: Jarrod T. Smith, Aneri Balar, Dhairya A. Lakhani, Christien Kluwe, Zhiguo Zhao, Prasad Kopparapu, Karinna Almodovar, Anel Muterspaugh, Yingjun Yan, Sally York, Leora Horn, Sanja Antic, Caterina Bertucci, Tristan Shaffer, Lauren Hodsdon, Kavita Garg, Seyed Ali Hosseini, Lee Lim, Evan Osmundson, Pierre Massion, Christine Lovly, Wade Iams. Circulating tumor DNA as a potential biomarker of radiographic tumor burden in small cell lung cancer [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 715.