Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker

Pietrasz, Daniel; Pécuchet, Nicolas; Garlan, Fanny; Didelot, Audrey; Dubreuil, Olivier; Doat, Solène; Imbert‐Bismut, Françoise; Karoui, Mehdi; Vaillant, Jean‐Christophe; Taly, Valérie; Laurent‐Puig, Pierre; Bachet, Jean‐Baptiste

doi:10.1158/1078-0432.ccr-16-0806

Cited by 217 publications

(222 citation statements)

References 33 publications

(36 reference statements)

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“…This provides a good representation of the patient population but might have resulted in lower detection rates. In most other studies with mPDAC patients, patient flow and selection methods were unclear, hampering comparisons . Our finding that higher ctDNA detection rates occurred in patients with liver metastases of PDAC has also been reported for colorectal cancer .…”

Section: Discussionmentioning

confidence: 58%

“…Studies reporting exclusively on mPDAC showed detection rates of 29.3–33% . When various tumor stages were studied, a sensitivity between 38.8% and 86.1% was determined for those patients with metastatic disease . This wide range may be explained by the various methods used.…”

Section: Discussionmentioning

confidence: 99%

“…As illustrated by the joint review of the American Society of Clinical Oncology and the College of American Pathologists, questions remain about the validity and reproducibility of ctDNA analysis, hampering clinical application . ctDNA detection rates vary widely depending on cancer type and analysis technique; for mPDAC, rates between 38.8% and 86.1% have been reported . In addition, ctDNA detection appears to have a strong prognostic value in patients with PDAC, but validation of this finding is required .…”

Section: Introductionmentioning

confidence: 99%

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Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

Strijker

Soer

Pastena

et al. 2019

Intl Journal of Cancer

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Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow‐up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell‐free DNA from plasma samples of 58 treatment‐naive mPDAC patients was isolated and sequenced using a custom‐made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross‐check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval [CI] 1.6–4.9) versus 8.4 (95% CI 1.6–15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95% CI 1.01–1.09, p = 0.005; HR 1.00, 95% CI 1.01–1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

Strijker

Soer

Pastena

et al. 2019

Intl Journal of Cancer

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“…Prior research has associated high MAF (>5%) with shorter OS across a variety of advanced solid tumors, including brain, lung, breast, and gastrointestinal, independent of intervening treatment . Other studies have also demonstrated the prognostic value of ctDNA MAF and that early changes in ctDNA levels can predict response to chemotherapy . Furthermore, early evidence suggests that MAF may serve as a dynamic biomarker, with early responders to durvalumab demonstrating a decrease in MAF after initiation of therapy .…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer

et al. 2019

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Background Tissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti‐programmed cell death‐1 protein receptor (PD‐1)/programmed cell death‐1 protein ligand (PD‐L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non‐small cell lung cancer (NSCLC). Materials and Methods A total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length. Results Higher ctDNA TMB was significantly correlated with smoking history (p < .05, chi‐squared test). Among patients treated with immune checkpoint inhibitors (n = 20), higher ctDNA TMB was significantly correlated with shorter progressive free survival (PFS) and overall survival (OS; 45 vs. 355 days; hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.3–24.6; p < .01, and OS 106 days vs. not reached; HR, 6.0; 95% CI, 1.3–27.1; p < .01, respectively). In a small independent validation cohort (n = 12), there was a nonsignificant numerical difference for higher ctDNA TMB predicting shorter OS but not PFS. ctDNA TMB was not correlated with RECIST tumor burden estimation in the subset of patients treated with immune checkpoint blockade. Conclusion The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes. Implications for Practice Biomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti‐PD‐1/PD‐L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood‐based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.

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“…Variant calling was conducted using the LoFreqV2 (LoFreq*) mutation caller [16]. Visualizations were created in R using custom scripts (available on request) employing Bioconductor package VariantAnnotation [17] as well as the plotting framework ggplot2 [18] and further adapted in Excel. After mutations were called, percent representation was established as (number of variant reads)/(number of reference reads + number of variant reads).…”

Section: Methodsmentioning

confidence: 99%

Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

et al. 2017

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Cancer is a heterogeneous disease harboring diverse subclonal populations that can be discriminated by their DNA mutations. Environmental pressure selects subclones that ultimately drive disease progression and tumor relapse. Circulating cell-free DNA (ccfDNA) can be used to approximate the mutational makeup of cancer lesions and can serve as a marker for monitoring disease progression at the molecular level without the need for invasively acquired samples from primary or metastatic lesions. This potential for molecular analysis makes ccfDNA attractive for the study of clonal evolution and for uncovering emerging therapeutic resistance or sensitivity. We assessed ccfDNA from colon and pancreatic adenocarcinoma patients using next generation sequencing of 56 cancer-associated genes at the time of primary resectable disease and metastatic progression and compared this to the mutational patterns of the primary tumor. 28%-47% of non-synonymous mutations in the primary tumors were also detected in the ccfDNA whilst 71%-78% mutations found in ccfDNA were not detected in the primary tumors. ccfDNA collected at the time of progression harbored 3-5 new mutations not detected in ccfDNA at the earlier collection time points. We conclude that incorporation of ccfDNA analysis provides crucial insights into the changing molecular makeup of progressive colon and pancreatic cancer.

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Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker

Abstract: ctDNA is an independent prognostic marker in advanced pancreatic adenocarcinoma. Furthermore, it arises as an indicator of shorter disease-free survival in resected patients when detected after surgery. Clin Cancer Res; 23(1); 116-23. ©2016 AACR.

Cited by 217 publications

References 33 publications

Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer

Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer

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