Faculty Collaboration Database

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer. J Hematol Oncol 2019 Dec 04;12(1):130

Date

12/06/2019

Pubmed ID

31801585

Pubmed Central ID

PMC6894333

DOI

10.1186/s13045-019-0824-4

Scopus ID

2-s2.0-85076053435 (requires institutional sign-in at Scopus site)   62 Citations

Abstract

BACKGROUND: Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy.

METHODS: ctDNA was analyzed in 112 patients with PDAC (54-73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed.

RESULTS: The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0-6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85-10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months.

CONCLUSIONS: Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.

Author List

Patel H, Okamura R, Fanta P, Patel C, Lanman RB, Raymond VM, Kato S, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
Carcinoma, Pancreatic Ductal
Circulating Tumor DNA
Combined Modality Therapy
DNA, Neoplasm
Female
Follow-Up Studies
High-Throughput Nucleotide Sequencing
Humans
Liquid Biopsy
Male
Middle Aged
Mutation
Pancreatic Neoplasms
Prognosis
Survival Rate