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. 2019 Dec 4;12(1):130.
doi: 10.1186/s13045-019-0824-4.

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

Hitendra Patel  1 , Ryosuke Okamura  2 , Paul Fanta  1 , Charmi Patel  3 , Richard B Lanman  4 , Victoria M Raymond  4 , Shumei Kato  1 , Razelle Kurzrock  1
Affiliations

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

Hitendra Patel et al. J Hematol Oncol. .

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.

Keywords: Circulating tumor DNA; KRAS; Molecular oncology; Next-generation sequencing; Pancreatic cancer; Targeted therapy.

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Conflict of interest statement

RK has the following disclosure information: Leadership (CureMatch, Inc); Stock and Other Ownership Interests ( IDbyDNA, CureMatch, Inc., and Soluventis); Consulting or Advisory Role (Gaido, LOXO, X-Biotech, Actuate Therapeutics, Roche, NeoMed, and Soluventis); Speaker’s fee (Roche); Research Funding (Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, and OmniSeq [All insts]). RBL has a leadership position at Guardant Health and RBL and VMR are employees and own stock at Guardant Health. The other authors have no competing interests to this work.

Figures

Fig. 1
Fig. 1
Frequency (% of patients) of characterized alterations in pancreatic ductal adenocarcinoma (ctDNA [N = 112] and tissue DNA [N = 66]). Only genes altered in ≥ 2 patients were shown in tissue DNA
Fig. 2
Fig. 2
Kaplan-Meier curve for overall survival from ctDNA analysis depending on total %ctDNA (characterized alterations only) dichotomized at the median among patients with advanced pancreatic ductal adenocarcinoma (N = 94)
Fig. 3
Fig. 3
A representative PDAC case who underwent a matched targeted therapy based on ctDNA analysis. An 83-year-old man treated with the MEK inhibitor trametinib as single-agent therapy [ID#111]; he had alterations in GNAS, KRAS, and NF1, all of which can activate the MEK pathway. The patient showed improvement in symptoms, CA19-9, and %ctDNA in the altered genes. CT scans with contrast could not be performed due to renal insufficiency. Treatment is ongoing at 26+ weeks
See this image and copyright information in PMC

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