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Prospective evaluation of circulating cell-free DNA sequencing in patients with metastatic renal cell carcinoma treated with pazopanib plus abexinostat.
Background: Renal cell carcinoma (RCC) exhibits somatic alterations in genes controlling hypoxia and chromatin states including VHL. Analysis of circulating cell-free DNA (cfDNA) as a means to detect these and other potentially actionable mutations in RCC across histologic subtypes has not been previously fully characterized. Methods: cfDNA was isolated from pretreatment and post-progression plasma samples of sixteen patients with metastatic RCC (N = 12 clear cell; N = 4 papillary) enrolled on a clinical trial of pazopanib and abexinostat (NCT01543763) and analyzed using a cfDNA next-generation sequencing (NGS) panel of 68 genes (Guardant Health). The lower limit of detection was 0.1% mutant allele frequency (MAF) at each nucleotide position. Results: 16 pretreatment and 5 post-progression samples were evaluable. 49 somatic mutations were reported across the entire cohort (mean = 3.06 mutations per patient; range: 0-7). Somatic alterations were detected in 94% (n = 15) of pretreatment samples and 4 of 5 post-progression samples with mean cfDNA MAFs of 0.70% (range = 0.1% - 5.6%) and 1.65% (range 0.10-5.5%) respectively. The most frequently mutated genes were VHL (44% of patients), TP53 (38%), FGFR2 (38%), and KRAS (19%). Evidence of PI3K pathway activation was detected in 25% of pts (N = 2 with activating PIK3CA mutations; N = 2 with PTEN loss-of-function). Activating mutations in MET and IDH1 were identified in two of the four pts with papillary RCC. 2 of 5 pts analyzed to date had novel somatic mutations detected at the time of progression. Conclusions: Analysis of cfDNA in metastatic renal cell carcinoma yields similar frequency of VHL mutations compared to TCGA, as well as potentially actionable mutations across both clear cell and papillary RCC subtypes. PI3K pathway alterations are common and suggest the potential to select patients for combination PI3K/VEGF targeting approach. Detection of novel, actionable mutations using cfDNA at the time of progression is feasible and may provide insights into mechanisms of resistance by non-invasive methods. Longitudinal analysis of the entire study cohort and correlations with radiographic response are ongoing. Clinical trial information: NCT01543763
Abstracts by Jim Leng:
Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: A phase 1 study in advanced solid tumor malignancies.Meeting: 2016 ASCO Annual Meeting | Abstract No: 2519
Early, molecular detection of cancer utilizing circulating cell-free DNA assay with ultra high accuracy and sensitivity.Meeting: 2016 ASCO Annual Meeting | Abstract No: 11540Category: Tumor Biology - Circulating Biomarkers
Efficacy and hematologic toxicity of carboplatin and talazoparib combination therapy in BRCA mutated patients.Meeting: 2016 ASCO Annual Meeting | Abstract No: 2557