Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2019

Open Access 01-12-2019 | Targeted Therapy | Short report

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

Authors: Hitendra Patel, Ryosuke Okamura, Paul Fanta, Charmi Patel, Richard B. Lanman, Victoria M. Raymond, Shumei Kato, Razelle Kurzrock

Published in: Journal of Hematology & Oncology | Issue 1/2019

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: a cancer journal for clinicians. 2019;69(1):7–34.
2.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer research. 2014;74(11):2913–21.PubMedCrossRef
3.
Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goere D, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2015;26(Suppl 5):v56–68.CrossRef
4.
Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. The New England journal of medicine. 2014;371(11):1039–49.PubMedCrossRef
5.
Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. Jama. 2013;310(14):1473–81.PubMedCrossRef
6.
Sinn M, Bahra M, Liersch T, Gellert K, Messmann H, Bechstein W, et al. CONKO-005: adjuvant chemotherapy with gemcitabine plus erlotinib versus gemcitabine alone in patients after R0 resection of pancreatic cancer: a multicenter randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(29):3330–7.CrossRef
7.
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England journal of medicine. 2011;364(19):1817–25.PubMedCrossRef
8.
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. The New England journal of medicine. 2013;369(18):1691–703.CrossRef
9.
10.
Blair AB, Groot VP, Gemenetzis G, Wei J, Cameron JL, Weiss MJ, et al. BRCA1/BRCA2 germline mutation carriers and sporadic pancreatic ductal adenocarcinoma. Journal of the American College of Surgeons. 2018;226(4):630–7.e1.PubMedPubMedCentralCrossRef
11.
Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, Holter S, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. British journal of cancer. 2014;111(6):1132–8.PubMedPubMedCentralCrossRef
12.
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501.PubMedPubMedCentralCrossRef
13.
14.
Lowery MA, Kelsen DP, Stadler ZK, Yu KH, Janjigian YY, Ludwig E, et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. The oncologist. 2011;16(10):1397–402.PubMedPubMedCentralCrossRef
15.
Zill OA, Greene C, Sebisanovic D, Siew LM, Leng J, Vu M, et al. Cell-free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer discovery. 2015;5(10):1040–8.PubMedPubMedCentralCrossRef
16.
17.
Kato S, Okamura R, Baumgartner JM, Patel H, Leichman L, Kelly K, et al. Analysis of circulating tumor DNA and clinical correlates in patients with esophageal, gastroesophageal junction, and gastric adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018;24(24):6248–56.CrossRef
18.
Kato S, Krishnamurthy N, Banks KC, De P, Williams K, Williams C, et al. Utility of genomic analysis in circulating tumor DNA from patients with carcinoma of unknown primary. Cancer research. 2017;77(16):4238–46.PubMedPubMedCentralCrossRef
19.
Schwaederle MC, Patel SP, Husain H, Ikeda M, Lanman RB, Banks KC, et al. Utility of genomic assessment of blood-derived circulating tumor DNA (ctDNA) in patients with advanced lung adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017;23(17):5101–11.CrossRef
20.
Kato S, Okamura R, Mareboina M, Lee S, Goodman A, Patel SP, et al. Revisiting epidermal growth factor receptor (EGFR) amplification as a target for anti-EGFR therapy: analysis of cell-free circulating tumor DNA in patients with advanced malignancies. JCO precision oncology. 2019;3.
21.
Kato S, Schwaederle MC, Fanta PT, Okamura R, Leichman L, Lippman SM, et al. Genomic assessment of blood-derived circulating tumor DNA in patients with colorectal cancers: correlation with tissue sequencing, therapeutic response, and survival. JCO precision oncology. 2019;3.
22.
Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, et al. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer discovery. 2016;6(2):147–53.PubMedCrossRef
23.
Pectasides E, Stachler MD, Derks S, Liu Y, Maron S, Islam M, et al. Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma. Cancer discovery. 2017.
24.
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. The New England journal of medicine. 2017;376(22):2109–21.PubMedCrossRef
25.
Schwaederle M, Parker BA, Schwab RB, Daniels GA, Piccioni DE, Kesari S, et al. Precision oncology: The UC San Diego Moores Cancer Center PREDICT Experience. Molecular cancer therapeutics. 2016;15(4):743–52.PubMedCrossRef
26.
Lanman RB, Mortimer SA, Zill OA, Sebisanovic D, Lopez R, Blau S, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PloS one. 2015;10(10):e0140712.PubMedPubMedCentralCrossRef
27.
Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nature biotechnology. 2013;31(11):1023–31.PubMedPubMedCentralCrossRef
28.
Thomas RK, Nickerson E, Simons JF, Janne PA, Tengs T, Yuza Y, et al. Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing. Nature medicine. 2006;12(7):852–5.PubMedCrossRef
29.
30.
Ideno N, Yamaguchi H, Ghosh B, Gupta S, Okumura T, Steffen DJ, et al. GNAS(R201C) Induces pancreatic cystic neoplasms in mice that express activated kras by inhibiting yap1 signaling. Gastroenterology. 2018;155(5):1593–607.e12.PubMedCrossRef
31.
Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. European journal of cancer (Oxford, England : 1990). 2014;50(12):2072–81.CrossRef
32.
Lodish MB, Stratakis CA. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. Best practice & research Clinical endocrinology & metabolism. 2010;24(3):439–49.CrossRef
33.
Hattori S, Ohmi N, Maekawa M, Hoshino M, Kawakita M, Nakamura S. Antibody against neurofibromatosis type 1 gene product reacts with a triton-insoluble GTPase activating protein toward ras p21. Biochemical and biophysical research communications. 1991;177(1):83–9.PubMedCrossRef
34.
Wilson CH, McIntyre RE, Arends MJ, Adams DJ. The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways. Oncogene. 2010;29(32):4567–75.PubMedPubMedCentralCrossRef
35.
Le Tourneau C, Kurzrock R. Targeted therapies: what have we learned from SHIVA? Nature reviews Clinical oncology. 2016;13(12):719–20.PubMedCrossRef
36.
Tsimberidou AM, Hong DS, Ye Y, Cartwright C, Wheler JJ, Falchook GS, et al. Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): an MD Anderson Precision Medicine Study. JCO precision oncology. 2017;2017.
37.
Wheler JJ, Janku F, Naing A, Li Y, Stephen B, Zinner R, et al. Cancer therapy directed by comprehensive genomic profiling: a single center study. Cancer research. 2016;76(13):3690–701.PubMedCrossRef
38.
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(15):1960–6.CrossRef
39.
Sicklick JK, Leyland-Jones B, Kato S, Hahn M, Williams C, De P, et al. Personalized, molecularly matched combination therapies for treatment-na. 2017 ASCO Annual Meeting: abst 2512; 2017.
40.
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (New York, NY). 2008;321(5897):1801–6.CrossRef
41.
Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53(4):549–54.PubMedCrossRef
42.
Chou A, Waddell N, Cowley MJ, Gill AJ, Chang DK, Patch AM, et al. Clinical and molecular characterization of HER2 amplified-pancreatic cancer. Genome medicine. 2013;5(8):78.PubMedPubMedCentralCrossRef
43.
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Science translational medicine. 2014;6(224):224ra24.PubMedPubMedCentralCrossRef
44.
Kruger S, Heinemann V, Ross C, Diehl F, Nagel D, Ormanns S, et al. Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer. Annals of oncology : official journal of the European Society for Medical Oncology. 2018;29(12):2348–55.CrossRef
45.
Mardinian K, Okamura R, Kato S, Kurzrock R. Temporal and spatial effects and survival outcomes associated with concordance between tissue and blood KRAS alterations in the pan-cancer setting. International journal of cancer. 2019.
46.
Chae YK, Davis AA, Jain S, Santa-Maria C, Flaum L, Beaubier N, et al. Concordance of genomic alterations by next-generation sequencing in tumor tissue versus circulating tumor DNA in breast cancer. Molecular cancer therapeutics. 2017;16(7):1412–20.PubMedCrossRef
47.
Schwaederle M, Husain H, Fanta PT, Piccioni DE, Kesari S, Schwab RB, et al. Use of liquid biopsies in clinical oncology: pilot experience in 168 patients. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(22):5497–505.CrossRef
48.
Del Re M, Tiseo M, Bordi P, D'Incecco A, Camerini A, Petrini I, et al. Contribution of KRAS mutations and c.2369C > T (p.T790 M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA. Oncotarget. 2017;8(8):13611–9.PubMed
49.
Vidal J, Muinelo L, Dalmases A, Jones F, Edelstein D, Iglesias M, et al. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Annals of oncology : official journal of the European Society for Medical Oncology. 2017;28(6):1325–32.CrossRef
50.
Kidess-Sigal E, Liu HE, Triboulet MM, Che J, Ramani VC, Visser BC, et al. Enumeration and targeted analysis of KRAS, BRAF and PIK3CA mutations in CTCs captured by a label-free platform: Comparison to ctDNA and tissue in metastatic colorectal cancer. Oncotarget. 2016;7(51):85349–64.PubMedPubMedCentralCrossRef
51.
Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nature reviews Clinical oncology. 2018;15(2):81–94.PubMedCrossRef
52.
Pietrasz D, Pecuchet N, Garlan F, Didelot A, Dubreuil O, Doat S, et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017;23(1):116–23.CrossRef
53.
Bernard V, Kim DU, San Lucas FA, Castillo J, Allenson K, Mulu FC, et al. Circulating nucleic acids are associated with outcomes of patients with pancreatic cancer. Gastroenterology. 2019;156(1):108–18.e4.PubMedCrossRef
54.
Chen H, Tu H, Meng ZQ, Chen Z, Wang P, Liu LM. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2010;36(7):657–62.CrossRef
55.
Earl J, Garcia-Nieto S, Martinez-Avila JC, Montans J, Sanjuanbenito A, Rodriguez-Garrote M, et al. Circulating tumor cells (Ctc) and kras mutant circulating free DNA (cfdna) detection in peripheral blood as biomarkers in patients diagnosed with exocrine pancreatic cancer. BMC cancer. 2015;15:797.PubMedPubMedCentralCrossRef
56.
Schwaederle M, Zhao M, Lee JJ, Lazar V, Leyland-Jones B, Schilsky RL, et al. Association of biomarker-based treatment strategies with response rates and progression-free survival in refractory malignant neoplasms: a meta-analysis. JAMA oncology. 2016;2(11):1452–9.PubMedCrossRef
57.
Jardim DL, Schwaederle M, Wei C, Lee JJ, Hong DS, Eggermont AM, et al. Impact of a biomarker-based strategy on oncology drug development: a meta-analysis of clinical trials leading to FDA approval. Journal of the National Cancer Institute. 2015;107(11).
58.
Schwaederle M, Zhao M, Lee JJ, Eggermont AM, Schilsky RL, Mendelsohn J, et al. Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(32):3817–25.CrossRef
59.
Sicklick JK, Kato S, Okamura R, Schwaederle M, Hahn ME, Williams CB, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nature medicine. 2019.
60.
Janne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crino L, et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. Jama. 2017;317(18):1844–53.PubMedPubMedCentralCrossRef
61.
Mangat PK, Halabi S, Bruinooge SS, Garrett-Mayer E, Alva A, Janeway KA, et al. Rationale and Design of the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. JCO precision oncology. 2018;2018.
62.
Farago AF, Piotrowska Z, Sequist LV. Unlocking the mystery of small-cell lung cancer transformations in EGFR mutant adenocarcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(26):2987–8.CrossRef
63.
Chung V, McDonough S, Philip PA, Cardin D, Wang-Gillam A, Hui L, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA oncology. 2017;3(4):516–22.PubMedPubMedCentralCrossRef
64.
Sonnenblick A, Kadouri L, Appelbaum L, Peretz T, Sagi M, Goldberg Y, et al. Complete remission, in BRCA2 mutation carrier with metastatic pancreatic adenocarcinoma, treated with cisplatin based therapy. Cancer biology & therapy. 2011;12(3):165–8.CrossRef
65.
Luo G, Lu Y, Jin K, Cheng H, Guo M, Liu Z, et al. Pancreatic cancer: BRCA mutation and personalized treatment. Expert review of anticancer therapy. 2015;15(10):1223–31.PubMedCrossRef
66.
Fogelman D, Sugar EA, Oliver G, Shah N, Klein A, Alewine C, et al. Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma. Cancer chemotherapy and pharmacology. 2015;76(3):489–98.PubMedPubMedCentralCrossRef
Metadata
Title
Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer
Authors
Hitendra Patel
Ryosuke Okamura
Paul Fanta
Charmi Patel
Richard B. Lanman
Victoria M. Raymond
Shumei Kato
Razelle Kurzrock
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-019-0824-4

Other articles of this Issue 1/2019

Journal of Hematology & Oncology 1/2019 Go to the issue

Review

Tumor-derived exosomes, myeloid-derived suppressor cells, and tumor microenvironment

Rapid communication

Targeting MYC activity in double-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors

Research

Downregulation of RNF128 activates Wnt/β-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma

Review

Molecular markers and potential therapeutic targets in non-WNT/non-SHH (group 3 and group 4) medulloblastomas

Research

lncRNA SNHG6 regulates EZH2 expression by sponging miR-26a/b and miR-214 in colorectal cancer

Research

Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment leading to osteoclastogenesis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits