Dataset Information

Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer.

ABSTRACT:

Purpose

In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory.

Experimental design

Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed.

Results

ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-naïve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%-98%), specificity 88% (95% CI, 62%-98%)] with a median lead time of 84 days (interquartile range, 25-146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P = 0.011).

Conclusions

Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.

SUBMITTER: Groot VP

PROVIDER: S-EPMC7403524 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer.

Groot Vincent P VP Mosier Stacy S Javed Ammar A AA Teinor Jonathan A JA Gemenetzis Georgios G Ding Ding D Haley Lisa M LM Yu Jun J Burkhart Richard A RA Hasanain Alina A Debeljak Marija M Kamiyama Hirohiko H Narang Amol A Laheru Daniel A DA Zheng Lei L Lin Ming-Tseh MT Gocke Christopher D CD Fishman Elliot K EK Hruban Ralph H RH Goggins Michael G MG Molenaar I Quintus IQ Cameron John L JL Weiss Matthew J MJ Velculescu Victor E VE He Jin J Wolfgang Christopher L CL Eshleman James R JR

Clinical cancer research : an official journal of the American Association for Cancer Research 20190529 16

<h4>Purpose</h4>In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a <i>KRAS</i> ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory.<h4>Experimental design</h4>Digital-droplet PCR was used to detect the major PDAC-associated somatic <i>KRAS</i> mutations (G12D, G12 ...[more]

PMID: 31142500

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Project description:ImportanceSerial circulating tumor DNA (ctDNA) has emerged as a routine surveillance strategy for patients with resected colorectal cancer, but how serial ctDNA monitoring is associated with potential curative outcomes has not been formally assessed.ObjectiveTo examine whether there is a benefit of adding serial ctDNA assays to standard-of-care imaging surveillance for potential curative outcomes in patients with resected colorectal cancer.Design, setting, and participantsIn this single-center (City of Hope Comprehensive Cancer Center, Duarte, California), retrospective, case cohort study, patients with stage II to IV colorectal cancer underwent curative resection and were monitored with serial ctDNA assay and National Cancer Center Network (NCCN)-guided imaging surveillance from September 20, 2019, to April 3, 2024. The median duration of follow-up was 26 months (range, 2-54 months).InterventionsSerial ctDNA assays were performed every 3 months for 2 years and every 6 months for the 3 following years in conjunction with NCCN-guided radiographic surveillance.Main outcomes and measuresThe primary outcome was the proportion of patients with clinical benefit from ctDNA testing, defined as the proportion of patients with a newly positive ctDNA assay and negative scheduled imaging (most recent or concurrent) that subsequently led to early imaging confirmation of recurrence, followed by curative-intent intervention with no evidence of recurrence at the time of data cutoff. Recurrence was categorized by ctDNA recurrence, radiographic recurrence, or concurrent ctDNA and imaging recurrence. Salvage resections and associated durable remissions were described within each of the 3 categories. Descriptive statistics were used to characterize the patient population.ResultsIn total, 184 patients (median age, 59 years [range, 32-88 years]; 97 female [52.7%]) were included in this study, and 129 (70.1%) had stage II to III disease. Forty-five patients (24.5%) had ctDNA or imaging-confirmed recurrence. Of these 45 patients, 14 had radiographic recurrence with negative ctDNA, and 11 had concurrent ctDNA and imaging recurrence. Twenty of 45 patients had ctDNA positivity with negative imaging at first ctDNA positivity; 6 had reflex imaging that was positive for recurrence, and 14 continued with serial imaging and ctDNA monitoring. Ten of 14 patients had subsequent recurrent disease, 3 patients had a spontaneous clearance of ctDNA, and 1 patient remained imaging negative 7 months after positive ctDNA, after which she was lost to follow-up. Altogether, 11 of 20 patients with ctDNA recurrence without initial concurrent imaging recurrence had subsequent metastasectomy, and only 3 were disease-free at the cutoff date in April 2024, representing 1.6% of the surveilled population.Conclusions and relevanceIn this cohort study of patients with stage II to IV colorectal cancer who underwent curative-intent resection, the addition of serial tumor-informed ctDNA assay to the standard NCCN-recommended surveillance had limited clinical benefits. Additional prospective research is needed to clarify the value of ctDNA testing in the surveillance setting.

Project description:PurposeCirculating tumor DNA (ctDNA) sequencing provides a minimally invasive method for tumor molecular stratification. Commercial ctDNA sequencing is increasingly used in the clinic, but its accuracy in metastatic prostate cancer is untested. We compared the commercial Guardant360 ctDNA test against an academic sequencing approach for profiling metastatic prostate cancer.Patients and methodsPlasma cell-free DNA was collected between September 2016 and April 2018 from 24 patients with clinically progressive metastatic prostate cancer representing a range of clinical scenarios. Each sample was analyzed using Guardant360 and a research panel encompassing 73 prostate cancer genes. Concordance of somatic mutation and copy number calls was evaluated between the two approaches.ResultsTargeted sequencing independently confirmed 94% of somatic mutations identified by Guardant360 at an allele fraction greater than 1%. AR amplifications and mutations were detected with high concordance in 14 patients, with only three discordant subclonal mutations at an allele fraction lower than 0.5%. Many somatic mutations identified by Guardant360 at an allele fraction lower than 1% seemed to represent subclonal passenger events or non-prostate-derived clones. Most of the non-AR gene amplifications reported by Guardant360 represented single copy gains. The research approach detected several clinically relevant DNA repair gene alterations not reported by Guardant360, including four germline truncating BRCA2/ATM mutations, two somatic ATM stop gain mutations, one BRCA2 biallelic deletion, 11 BRCA2 stop gain reversal mutations in a patient treated with olaparib, and a hypermutator phenotype in a patient sample with 42 mutations per megabase.ConclusionGuardant360 accurately identifies somatic ctDNA mutations in patients with metastatic prostate cancer, but low allele frequency mutations should be interpreted with caution. Test utility in metastatic prostate cancer is currently limited by the lack of reporting on actionable deletions, rearrangements, and germline mutations.

Dataset Information

Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer.

Purpose

Experimental design

Results

Conclusions

Publications

Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer.

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