Evaluation of circulating cell-free KRAS mutational status as a molecular monitoring tool in patients with pancreatic cancer

Schlick, Konstantin; Markus, Steiner; Huemer, Florian; Ratzinger, Lukas; Zaborsky, Nadja; Hufnagl, Clemens; Neureiter, Daniel; Neumayer, Bettina; Alinger-Scharinger, Beate; Steiner, Florian; Martín, Vicente; Grundbichler, Michael; Weiß, Lukas; Melchardt, Thomas; Greil, Richard; Egle, Alexander

doi:10.1016/j.pan.2021.09.004

Cited by 7 publications

(5 citation statements)

References 14 publications

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“…Several studies, including multiple meta‐analyses, support the prognostic potential of ctDNA detection in plasma, demonstrating that patients in whom ctDNA is detected have a significantly worse prognosis than those in whom it is not detected [ 11 , 12 , 13 , 14 , 15 , 16 ]. Some studies have also explored the relationship between ctDNA and imaging, showing associations between the dynamics of ctDNA and the radiological response [ 11 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. These studies are only observational and evidence of a benefit of ctDNA‐based treatment decisions is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging

et al. 2023

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a need for better tools to guide treatment selection and follow‐up. The aim of this prospective study was to investigate the prognostic value and treatment monitoring potential of longitudinal circulating tumour DNA (ctDNA) measurements in patients with advanced PDAC undergoing palliative chemotherapy. Using KRAS peptide nucleic acid clamp‐PCR, we measured ctDNA levels in plasma samples obtained at baseline and every 4 weeks during chemotherapy from 81 patients with locally advanced and metastatic PDAC. Cox proportional hazard regression showed that ctDNA detection at baseline was an independent predictor of progression‐free and overall survival. Joint modelling demonstrated that the dynamic ctDNA level was a strong predictor of time to first disease progression. Longitudinal ctDNA measurements during chemotherapy successfully revealed disease progression in 20 (67%) of 30 patients with ctDNA detected at baseline, with a median lead time of 23 days (P = 0.01) over radiological imaging. Here, we confirmed the clinical relevance of ctDNA in advanced PDAC with regard to both the prediction of clinical outcome and disease monitoring during treatment.

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Section: Introductionmentioning

confidence: 99%

Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging

et al. 2023

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“…An even more drastic risk stratification can be applied for PFS (2.5 vs. 7.7 months). Recently, the prognostic impact of the relative change of ctDNA between treatment initiation and restaging has been shown in a small cohort (n = 14) by commercial test kits ( 16 ). However, to the best of our knowledge, a cutoff for MAF dynamics with a direct impact on the outcome for patients with metastatic pancreatic cancer has not been described so far.…”

Section: Discussionmentioning

confidence: 99%

“…However, liquid biopsy allows detection rates of only 50%–65% in metastatic PDAC ( 3 , 11 , 15 ). While the prognostic value of ctDNA positivity prior to treatment has been validated for metastatic PDAC ( 13 , 16 ), there is no established cutoff value for the ctDNA change reflecting an early response to treatment. Thus, we aimed to evaluate if a patient-normalized threshold based on the dynamic change of ctDNA during systemic treatment can predict response to systemic treatment and clinical outcomes in terms of disease-free survival (DFS) and overall survival (OS).…”

Section: Introductionmentioning

confidence: 99%

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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“…A study based on 110 PDAC patients reported that those with KRAS mutations have significantly shorter PFS and OS (5.3/6.9 months ( p = 0.044) vs. 11.8/19.9 months ( p = 0.037), respectively) [ 26 ]. Another study detecting the circulating cell-free tumor-DNA (cft-DNA) of 29 PDAC patients showed that the survival of patients with detectable plasma KRAS mutations pre-treatment was significantly worse (16.8 months vs. not reached, p < 0.031) [ 27 ]. A study comparing PDAC patients treated with surgery to chemotherapy showed that the detectable plasma KRAS mutation is an independent predictor of early recurrence after surgery, while not showing a significant difference in PFS after chemotherapy [ 28 ].…”

Section: Kras Mutations In Cancersmentioning

confidence: 99%

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

Yang

Zhang

Huang

et al. 2023

JCM

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Kristen rat sarcoma (KRAS) gene is one of the most common mutated oncogenes in solid tumors. Yet, KRAS inhibitors did not follow suit with the development of targeted therapy, for the structure of KRAS has been considered as being implausible to target for decades. Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with immunotherapy. KRAS G12C inhibitors became the most recent breakthrough in targeted therapy, with Sotorasib being approved by the Food and Drug Administration (FDA) based on its significant efficacy in multiple clinical studies. However, the subtypes of the KRAS mutations are complex, and the development of inhibitors targeting non-G12C subtypes is still at a relatively early stage. In addition, the monotherapy of KRAS inhibitors has accumulated possible resistance, acquiring the exploration of combination therapies or next-generation KRAS inhibitors. Thus, other non-target, conventional therapies have also been considered as being promising. Here in this review, we went through the characteristics of KRAS mutations in cancer patients, and the prognostic effect that it poses on different therapies and advanced therapeutic strategy, as well as cutting-edge research on the mechanisms of drug resistance, tumor development, and the immune microenvironment.

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Evaluation of circulating cell-free KRAS mutational status as a molecular monitoring tool in patients with pancreatic cancer

Cited by 7 publications

References 14 publications

Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging

Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging

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

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

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