Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival

Botrus, Gehan; Usón, Pedro Luiz Serrano; Raman, Puneet; Kaufman, Adrienne; Kosiorek, Heidi E.; Yin, Jun; Fu, Yu; Majeed, Umair; Sonbol, Mohamad Bassam; Ahn, Daniel H.; Chang, Isabela; Drusbosky, Leylah; Dada, Hiba I.; Starr, Jason S.; Borad, Mitesh J.; Mody, Kabir; Bekaii‐Saab, Tanios

doi:10.3389/fonc.2021.794009

Cited by 8 publications

(9 citation statements)

References 48 publications

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“…Specifically, detection of circulating tumor DNA (ctDNA) in the blood of patients with breast, colorectal, and lung cancer, among others, has demonstrated therapeutic use in diagnosing patient relapses. In the setting of PAC, the prognostic and predictive value of ctDNA as a clinically meaningful biomarker has been inconsistent ( 7 , 8 ). Additional sources of DNA and RNA in circulation have been revealed recently in exosomes, which are microvesicles.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

et al. 2022

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PurposePancreatic cancer is an aggressive solid tumor with a severe prognosis. Although tumor biomarkers are often used to identify advanced pancreatic cancer, this is not accurate, and the currently used biomarkers are not indicative of prognosis. The present study evaluated circulating tumor DNA (ctDNA) as a biomarker for prognosis prediction and disease monitoring in metastatic pancreatic adenocarcinoma (PAC).MethodsFrom 2017 to 2018, 40 patients with metastatic PAC were enrolled, and tumor tissue and blood samples were collected from 40 and 35 patients, respectively. CtDNA was sequenced by next-generation sequencing (NGS) with a 425-gene capture panel. The association of clinical characteristics, laboratory indicators, and dynamic ctDNA with patient outcomes was analyzed.ResultsMutations in KRAS (87.5%, N = 35) and TP53 (77.5%, N = 31) were most common in 40 tumor tissue. Patients’ ECOG score, CA19-9, CEA, neutrophil-lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR) levels and mutations in ≥ 3 driver genes were strongly correlated with patients’ overall survival (OS). Patients’ gender, ECOG score, CA19-9, and CEA levels were associated with progression-free survival (PFS) (P<0.05). In 35 blood samples, univariate analysis showed a significant association between ECOG score, CA19-9, KRAS or CDKN2A mutation in ctDNA and OS and between CA19-9, CDKN2A or SMAD4 mutation in ctDNA and PFS. Cox hazard proportion model showed that patients’ CDKN2A mutation in ctDNA (HR=16.1, 95% CI=4.4-59.1, P<0.001), ECOG score (HR=6.2, 95% CI=2.4-15.7, P<0.001) and tumor location (HR=0.4, 95% CI=0.1-0.9, P=0.027) were significantly associated with OS. Patients’ CDKN2A mutation in ctDNA (HR=6.8, 95% CI=2.3-19.9, P=0.001), SMAD4 mutation in ctDNA (HR=3.0, 95% CI=1.1-7.9, P=0.031) and metastatic organ (HR=0.4, 95% CI=0.2-1.0, P=0.046) were significantly associated with PFS. Longitudinal changes in gene mutation allelic frequency (MAF) value were evaluated in 24 patients. Detection of progression disease (PD) by ctDNA was 0.9 months earlier than by radiological imaging (mean PFS: 4.6m vs 5.5m, P=0.004, paired t-test).ConclusionsThe ctDNA has the potential as a specific survival predictive marker for metastatic PAC patients. Longitudinal ctDNA tracking could potentially help identify disease progression and be a valuable complement for routine clinical markers and imaging.

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Section: Introductionmentioning

confidence: 99%

Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

et al. 2022

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“…Tumors that express GATA6 , either detected by RNA sequencing or immunohistochemistry, are defined as classical subtype, and tend to have higher responses to FOLFIRINOX, in opposite of the basal-like subtype, which have low expression or do not express GATA6 , and have worse outcomes 8 , 17 , 18 . Finally, circulating cell-free tumor DNA could be a factor to stratify patients with better outcomes in future prospective trials, and possibly select patients that have benefit to neoadjuvant approaches 19 – 22 . Although biomarker selection could improve the outcomes of neoadjuvant treatment, a randomized phase III trial with no biomarker selection is ongoing, with preoperative versus adjuvant modified FOLFIRINOX in resectable pancreatic cancer (NCT04340141).…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis

Usón

Carvalho

Fernandes

et al. 2022

Sci Rep

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Neoadjuvant chemotherapy is considered a new treatment option for potentially resectable pancreatic cancer. However, data are not well established on overall survival and delaying surgery in resectable pancreatic cancer, as well as on those patients that ultimately cannot undergo surgery. We analyzed pancreatic cancer patients treated in a tertiary hospital from January 2016 to December 2020. Patients with resectable stage I and II pancreatic cancer were evaluated regarding surgery, neoadjuvant treatment, and other clinical demographics. The survival function was estimated using the Kaplan–Meier method, and the relationship between the variables of interest and the overall survival (OS) was assessed by adopting the proportional regression Cox models. A total of 216 patients were evaluated. 81 of them with resectable/borderline resectable disease and 135 with unresectable /metastatic disease at diagnosis. Median OS for stage I and II disease were 36 and 28 months, respectively. For resectable pancreatic cancer median OS was 28 months, for borderline resectable pancreatic cancer median OS was 11 months. Median OS for stage III (locally advanced) and stage IV (metastatic) were 10 and 7 months, respectively (p < 0.0001). Median OS of 9 months were obtained for patients with stage I and II that did not undergo surgery compared to 25 months in patients that underwent surgery in any time (p < 0.001). Comparing patients with localized disease, median OS for patients treated with upfront surgery was 28 months, compared to 15 months in patients treated with neoadjuvant approach (p = 0.04). Most patients that did not undergo surgery have decline of performance status or disease progression on neoadjuvant treatment. On multivariable analysis in pancreatic cancer stages I and II, including age, sex, borderline or resectable disease, CA 19–9, positive lymph nodes and neoadjuvant treatment, the surgery was the only factor associated with improved overall survival (p = 0.04). Upfront surgery should still be considered a standard of care approach for resectable pancreatic cancer. Biomarker driven studies and randomized trials with combination therapies are necessary to address neoadjuvant chemotherapy and delaying surgery in purely resectable pancreatic cancer.

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“…This might be due to the number of patients in our cohort being smaller and comprising patients treated in the first line and later lines. Further, a significant association between the respective mutated gene locus and PFS could explain the discrepancy between different study results depending on the coverage of the screening method ( 23 ). Botrus et al.…”

Section: Discussionmentioning

confidence: 99%

“…Botrus et al. found a median PFS of 5.8 vs. 12.9 months ( KRAS ), 5.9 vs. 10.9 months ( TP53 ), and 3.7 vs. 8.2 months ( CCND2 ) ( 23 ). Moreover, within patients with KRAS mutation, having two or more alterations resulted in a further reduction of PFS to 3.7 months ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

“…Further, a significant association between the respective mutated gene locus and PFS could explain the discrepancy between different study results depending on the coverage of the screening method (23). Botrus et al found a median PFS of 5.8 vs. 12.9 months (KRAS), 5.9 vs. 10.9 months (TP53), and 3.7 vs. 8.2 months (CCND2) (23). Moreover, within patients with KRAS mutation, having two or more alterations resulted in a further reduction of PFS to 3.7 months (23).…”

Section: Prognostic Impact Of Pretherapeutic Circulating Tumor Dna De...mentioning

confidence: 94%

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Prediction of response to systemic treatment by kinetics of circulating tumor DNA in metastatic pancreatic cancer

Kirchweger

Kupferthaler²,

Burghofer

et al. 2022

Front. Oncol.

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IntroductionPretherapeutic detectable circulating tumor DNA (ctDNA) represents a promising prognostic biomarker for predicting relapse and overall survival in patients with metastatic pancreatic cancer. However, the prognostic value of ctDNA dynamics during treatment has not been studied thus far. We aimed to investigate the correlation between the change of ctDNA levels and response to treatment in patients treated by systemic therapy.Material and methodsCtDNA detection using liquid biopsy (droplet digital PCR (ddPCR) utilizing KRAS G12/13 and, if negative, Q61 commercial test kits) was prospectively performed on patients with stage IV pancreatic cancer i) prior to initiation of systemic chemotherapy and ii) serially every 2 weeks until restaging. Detection rates, levels of ctDNA, and the course of the relative ctDNA change (ctDNA kinetics) were correlated to treatment response and clinical outcome.ResultsThe detection rate at baseline was 64.3% (45/70), and complete serial measurement records were available for 32 ctDNA-positive patients. Reduction of ctDNA levels below 57.9% of its baseline value at week 2 after treatment initiation was significantly predictive of response to treatment (area under the curve (AUC) = 0.918, sensitivity 91.67%, and specificity 100%) and was associated with prolonged overall survival (OS) (5.7 vs. 11.4 months, p = 0.006) and progression-free survival (PFS) (2.5 vs. 7.7 months, p < 0.000) regardless of treatment line. Pretherapeutic ctDNA detection was independently associated with worse OS in patients receiving a first-line regimen (7 vs. 11.3 months, p = 0.046) and regardless of treatment line (11.4 vs. 15.9 months, p = 0.045) as well as worse PFS (3.4 vs. 10.8 months, p = 0.018).ConclusionThe change in magnitude of ctDNA during systemic treatment allows the prediction of treatment response and is associated with both OS and PFS. This finding adds significant clinical potential to the already established prognostic value of ctDNA positivity in metastatic pancreatic cancer.

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Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival

Cited by 8 publications

References 48 publications

Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis

Prediction of response to systemic treatment by kinetics of circulating tumor DNA in metastatic pancreatic cancer

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