Serial cell-free DNA (cfDNA) sampling in advanced pancreatic ductal adenocarcinoma (PDAC) patients may predict therapeutic outcome.

Abstract

423 Background: Advanced PDAC remains a deadly disease with a 5-year survival rate of less than 10%. cfDNA - based next generation sequencing (NGS) may identify actionable alterations in patients with PDAC. In this study, we aim to determine the feasibility of utilizing serial cfDNA NGS testing and its potential relevance in predicting therapeutics outcomes. Methods: A total of 23 PDAC patients with PDAC cfDNA isolated from plasma collected at diagnosis and upon disease progression to first line SOC therapy and were analyzed on a 73-74 gene NGS panel (Guardant Health). Changes in molecular profiles from baseline to progression were analyzed for overall survival, progression free survival (PFS), and treatment response. PFS and OS were analyzed using the Kaplan-Meier method and the log-rank test was used to compare the survival of different groups of patients. All p-values were two-sided. Analyses were performed using R (version 3.5.1, R Foundation, Vienna, Austria). Results: In this retrospective study, the 1-year probability of survival was 71% (median 473 days) and the 1-year PFS was 14% (median 212 days). TP53 and KRAS were the most frequently mutated genes identified in baseline samples, with 78% prevalence for each. Patients with clearance of TP53 17% (3/18) patients and/or KRAS 33% (6/18) patients clones after first line therapy significantly increases PFS (p=0.0056 and p=0.037, with HR of 0.087 and 0.32, respectively). However, appearance of TP53 or KRAS alterations upon progression does not significantly affect overall survival or PFS. Conclusions: The preliminary results from this study suggest that cfDNA clearance of TP53 and/or KRAS alterations may predict for improved PFS in PDAC. Confirmation of these findings in larger studies is warranted.

Is Cell-Free DNA Testing in Pancreatic Ductal Adenocarcinoma Ready for Prime Time?

“…Most studies focused on mut- KRAS variants (detected by PCR) before the era of NGS-based studies. Although some studies have demonstrated that mut- KRAS detection, concentration, and MAF can provide insight into outcomes and treatment responses in patients with PDA, other larger studies and meta-analyses have indicated the importance of other mutations [ 27 , 28 , 75 , 77 , 85 , 86 ]. Efforts should be made to identify those in cfDNAs and develop panels of specific mutations instead of relying on only mut- KRAS variants in future studies.…”

“…KRAS , TP53 , and CDK2NA were the top three mutated genes in tissue and blood. In a similar study ( n = 23), the prevalence of detected mutations was higher, at 78% for both TP53 and KRAS [ 27 ]. This study used an NGS panel from a different company (Guardant Health, Redwood City, CA, USA) than the previous study.…”

“…In contrast, in aPDA, mut- KRAS positivity has been found to have no prognostic value, but mut- KRAS + detection has been found to indicate poorer outcomes. Other studies have demonstrated that the detection of TP53 and HER2 exon 17, with or without mut- KRAS variants, is significantly associated with patient outcomes [ 27 , 28 ].…”

“…Watanabe et al showed that its (mut- KRAS ) detection after 6 months significantly correlates with unfavorable therapeutic responses to first line chemotherapy [ 81 ]. In a different study, TP53 and/or KRAS clearance, compared with a lack of clearance, have been associated with better patient response and outcomes [ 27 ].…”

Highlights from ASCO-GI 2021 from EORTC Gastrointestinal tract cancer group

“…Most common were gene alterations in TP53 (53.7%), KRAS (40.3%), CDKN2a (6.5%), and in genes of the homologous recombinant DNA damage repair pathway (HR-DDR) in 12.3%. In addition, serial measurements with clearance of mTP53 or mKRAS cfDNA seemed to be predictive of increased PFS (HR 0.087 and 0.32 with p = 0.0056 and p = 0.037, respectively) in a small retrospective analysis of 23 patients under systemic treatment [36].…”