Assessment of plasma ctDNA mutational profile and heterogeneity in renal cell carcinoma patients.

Abstract

e14544 Background: Renal cell carcinoma (RCC) is a common form of kidney cancer that presents significant challenges in both diagnosis and treatment. Despite advancements in therapy, approximately 30% of patients experience recurrence, underscoring the pressing need for improved disease management strategies. Incorporating genomic insights into RCC care offers a promising pathway for personalized treatment and more accurate disease prognostication. In addition to tissue biopsy, liquid biopsy using circulating tumor DNA (ctDNA) has emerged as a viable alternative, enabling personalized treatment decisions, longitudinal monitoring for early relapse detection, and treatment resistance. We compared comprehensive genomic profiling (CGP) using tissue DNA and ctDNA from RCC patients to explore their mutational landscape and enhance the standard of care. Methods: In this retrospective study, 30 patients (Pts) advanced RCC treated with standard of care underwent targeted hybrid-capture based genomic profiling using OncoIndx (1080 genes) CGP platform and OncoMonitor (108 gene) tumor panel either on tumor tissue or plasma ctDNA. Enriched libraries were sequenced (average depth: 5500 X for ctDNA; 2500 X for tissue DNA) in a pair end fashion (150 x2) on Illumina Nextseq 2000. Raw sequencing reads were converted into BAM files and processed for variant calling using a proprietary bioinformatics pipeline iCare. Variants were called according to ClinVar, ACMG and AMP databases. Results: Of the 30 samples sequenced, 24 (75%) were blood-derived, while 6 (25%) were tissue-derived (tDNA). Pathogenic mutations were detected in 23 samples (77%). Among these, the most frequent variants were loss-of-function (LOF) VHL mutations and TP53 mutations (23%), followed by MSH6 (16.6%) and SMAD4 (13%). A significant subset of samples (29.6%) exhibited pathogenic gain of function mutations in KRAS and BRAF (16.6%), along with variants in the PIK3CA pathway ( PIK3CA , PTEN , and AKT ) (13%), suggesting oncogenic signaling as a key driver. About 80 % samples had tumor suppressor (TS) mutations in at least one homologous recombination repair (HRR) pathway gene. Pathogenic variants in CHEK2 , PALB2 , and FANCA/FANCC were associated with high HRD scores (P = 0.03, Odds Ratio: 8.8). Interestingly, gain of function TP53 mutations and genomic instability (high HRD or TMB scores) was prevalent in metastatic tumors. ctDNA demonstrated a more diverse mutation profile compared to tissue DNA, reflecting broader tumor heterogeneity. Conclusions: The potential of ctDNA-based genomic profiling is of higher clinical implications for uncovering the mutational landscape and addressing the challenges of tumor heterogeneity in RCC. The key TS variants along with dysregulated KRAS and PIK3CA pathway mutations were enriched in ctDNA compared to tDNA. ctDNA offers a promising non-invasive approach for improved disease management in RCC.