Drusbosky, Leylah

Abstract Purpose Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings. Materials and Methods From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation. Results All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease. Conclusion Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis. Implications for Practice Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.

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.