Optimal value of CA19-9 determined by KRAS-mutated circulating tumor DNA contributes to the prediction of prognosis in pancreatic cancer patients

AbstractDespite the acceptance of carbohydrate antigen 19-9 (CA19-9) as a valuable predictor for the prognosis of pancreatic ductal adenocarcinoma (PDAC), its cutoff value remains controversial. Our previous study showed a significant correlation between CA19-9 levels and the presence of KRAS-mutated ctDNA in the blood of patients with PDAC. Based on this correlation, we investigated the optimal cutoff value of CA19-9 before surgery. Continuous CA19-9 values and KRAS-mutated ctDNAs were monitored in 22 patients with unresectable PDAC who underwent chemotherapy between 2015 and 2017. Receiver operating characteristic curve analysis identified 949.7 U/mL of CA19-9 as the cutoff value corresponding to the presence of KRAS-mutated ctDNA. The median value of CA19-9 was 221.1 U/mL. Subsequently, these values were verified for their prognostic values of recurrence-free survival (RFS) and overall survival (OS) in 60 patients who underwent surgery between 2005 and 2013. Multivariate analysis revealed that 949.7 U/mL of CA19-9 was an independent risk factor for OS and RFS in these patients (P = 0.001 and P = 0.010, respectively), along with lymph node metastasis (P = 0.008 and P = 0.017), unlike the median CA19-9 level (P = 0.150 and P = 0.210). The optimal CA19-9 level contributes to the prediction of prognosis in patients with PDAC before surgery.

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Optimal Value of CA19-9 Determined by KRAS-Mutated Circulating Tumor DNA Contributes to the Prediction of Prognosis in Pancreatic Cancer Patients

10.21203/rs.3.rs-568196/v1 ◽

2021 ◽

Author(s):

Fumiaki Watanabe ◽

Koichi Suzuki ◽

Sawako Tamaki ◽

Iku Abe ◽

Yuhei Endo ◽

...

Keyword(s):

Characteristic Curve ◽

Circulating Tumor Dna ◽

Carbohydrate Antigen ◽

Ductal Adenocarcinoma ◽

Free Survival ◽

Cutoff Value ◽

Optimal Value ◽

Prediction Of Prognosis ◽

Tumor Dna ◽

Valuable Predictor

Abstract Despite the acceptance of carbohydrate antigen 19-9 (CA19-9) as a valuable predictor for the prognosis of pancreatic ductal adenocarcinoma (PDAC), controversy remains with regards to its cutoff. Our previous study showed a significant correlation between CA19-9 levels and the presence of KRAS-mutated ctDNA in the blood of patients with PDAC. Based on this correlation, we investigated the optimal cutoff value of CA19-9 before surgery. Continuous CA19-9 values and KRAS-mutated ctDNAs were monitored in 22 patients with unresectable PDAC who underwent chemotherapy between 2015 and 2017. Receiver operating characteristic curve analysis identified 949.7 U/mL of CA19-9 as the cutoff value corresponding to the presence of KRAS-mutated ctDNA. The median value of CA19-9 was 221.1 U/mL. These values were then verified for their prognostic values of recurrence-free survival (RFS) and overall survival (OS) in 60 patients who underwent surgery between 2005 and 2013. Multivariate analysis revealed that 949.7 U/mL of CA19-9 was an independent risk factor for OS and RFS in these patients (P=0.001 and P=0.010, respectively), along with lymph node metastasis (P=0.008 and P=0.017), but the median CA19-9 level was not (P=0.150 and P=0.210). The optimal CA19-9 level contributes to the prediction of prognosis in patients with PDAC before surgery.

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Sequential assessments of KRAS-mutated circulating tumor DNA in longitudinal monitoring enable the prediction of prognosis and therapeutic responses in patients with pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15712 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15712-e15712

Author(s):

Fumiaki Watanabe ◽

Koichi Suzuki ◽

Sawako Tamaki ◽

Hideki Ishikawa ◽

Nao Kakizawa ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Resection ◽

Predictive Biomarker ◽

Circulating Tumor Dna ◽

Ductal Adenocarcinoma ◽

Monitoring Methods ◽

Short Period ◽

Prediction Of Prognosis ◽

Tumor Dna ◽

Therapeutic Responses

e15712 Background: Liquid biopsy enables the detection of circulating tumor DNA (ctDNA) levels, including KRAS-mutated ctDNA, which is considered a predictive biomarker for pancreatic cancer. This study aimed to evaluate the significance of sequential KRAS ctDNA assessments in longitudinal monitoring. Methods: A total of 422 blood samples were collected from 78 patients undergoing treatments for localized and metastatic pancreatic ductal adenocarcinoma. KRAS ctDNA levels was determined by droplet digital polymerase chain reaction. Longitudinal monitoring of KRAS ctDNA was performed to assess its significance for predicting recurrence and prognosis and evaluating therapeutic responses to chemotherapy. Results: In 39 patients who underwent surgery for potentially resectable tumors, sequential assessments of KRAS ctDNA in longitudinal monitoring was significantly associated with prognosis ( P < 0.001). In 39 patients who did not undergo surgery, sequential assessments of KRAS ctDNA was a predictive factor for prognosis ( P = 0.005). Multivariate analysis revealed that detection of KRAS ctDNA in longitudinal monitoring was the only independent prognostic factor regardless of tumor resection ( P< 0.001). Longitudinal monitoring revealed the significance of sequential assessments of KRAS ctDNA within a short period. The presence of KRAS ctDNA in sequential assessments within 1 year after surgery showed significant association with prognosis irrespective of recurrence ( P< 0.001). The presence of KRAS ctDNA in sequential assessments within 6 months was significantly correlated with therapeutic responses in the first line chemotherapy ( P< 0.001). Conclusions: Our study showed for the first time that sequential assessments of KRAS ctDNA levels within a short period enabled the prediction of prognosis and therapeutic response in patients with pancreatic cancer.

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Circulating Tumor DNA as a Sensitive Marker in Patients Undergoing Irreversible Electroporation for Pancreatic Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000490874 ◽

2018 ◽

Vol 47 (4) ◽

pp. 1556-1564 ◽

Cited By ~ 11

Author(s):

Mao Lin ◽

Mohammed Alnaggar ◽

Shuzhen Liang ◽

Jibing Chen ◽

Kecheng Xu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Irreversible Electroporation ◽

Circulating Tumor Dna ◽

Carbohydrate Antigen ◽

Ductal Adenocarcinoma ◽

Diagnostic Tools ◽

Tumor Biomarker ◽

Monitoring Treatment ◽

Tumor Dna

Background/Aims: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage, resulting in extremely poor 5-year survival. Late diagnosis of PDAC is mainly due to lack of a reliable method of early detection. Carbohydrate antigen (CA) 19-9 is often used as a tumor biomarker in PDAC; however, the test lacks sensitivity and specificity. Therefore, new sensitive and minimally invasive diagnostic tools are required to detect pancreatic cancer. Methods: Here, we investigated circulating tumor DNA (ctDNA) which contained KRAS-mutated as a potential diagnostic tool for PDAC patients who underwent irreversible electroporation (IRE). We used droplet digital polymerase chain reaction (ddPCR) to detect the expression of KRAS-mutated genes in plasma samples of 65 PDAC patients who underwent IRE. Results: In these 65 cases, ctDNA was detected in 20 (29.2%) samples. The median overall survival (OS) was 11.4 months with ctDNA+ patients and 14.3 months for ctDNA- patients. ctDNA+ patients had a obviously poorer prognosis associated to overall survival (P < 0.001). Conclusion: Our results suggested that the existence of ctDNA was a predictor of survival for PDAC patients. Therefore, ctDNA may be a new sensitive biomarker for monitoring treatment outcome in PDAC.

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MSH2 promoter hypermethylation in circulating tumor DNA is a valuable predictor of disease-free survival for patients with esophageal squamous cell carcinoma

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2012.01.008 ◽

2012 ◽

Vol 38 (4) ◽

pp. 326-332 ◽

Cited By ~ 17

Author(s):

Z.Q. Ling ◽

Q. Zhao ◽

S.L. Zhou ◽

W.M. Mao

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Disease Free Survival ◽

Promoter Hypermethylation ◽

Circulating Tumor Dna ◽

Free Survival ◽

Disease Free ◽

Tumor Dna ◽

Valuable Predictor

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Circulating tumor DNA as a prognostic marker in high-risk endometrial cancer

Journal of Translational Medicine ◽

10.1186/s12967-021-02722-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Weiwei Feng ◽

Nan Jia ◽

Haining Jiao ◽

Jun Chen ◽

Yan Chen ◽

...

Keyword(s):

Endometrial Cancer ◽

High Risk ◽

Tumor Recurrence ◽

Disease Free Survival ◽

Circulating Tumor Dna ◽

Plasma Samples ◽

Free Survival ◽

Tumor Relapse ◽

Disease Free ◽

Tumor Dna

Abstract Background Currently, there is no reliable blood-based marker to track tumor recurrence in endometrial cancer (EC) patients. Liquid biopsies, specifically, circulating tumor DNA (ctDNA) analysis emerged as a way to monitor tumor metastasis. The objective of this study was to examine the feasibility of ctDNA in recurrence surveillance and prognostic evaluation of high-risk EC. Methods Tumor tissues from nine high-risk EC patients were collected during primary surgery and tumor DNA was subjected to next generation sequencing to obtain the initial mutation spectrum using a 78 cancer-associated gene panel. Baseline and serial post-operative plasma samples were collected and droplet digital PCR (ddPCR) assays for patient-specific mutations were developed to track the mutations in the ctDNA in serial plasma samples. Log-rank test was used to assess the association between detection of ctDNA before or after surgery and disease-free survival. Results Somatic mutations were identified in all of the cases. The most frequent mutated genes were PTEN, FAT4, ARID1A, TP53, ZFHX3, ATM, and FBXW7. For each patient, personalized ddPCR assays were designed for one-to-three high-frequent mutations. DdPCR analysis and tumor panel sequencing had a high level of agreement in the assessment of the mutant allele fractions in baseline tumor tissue DNA. CtDNA was detected in 67% (6 of 9) of baseline plasma samples, which was not predictive of disease-free survival (DFS). CtDNA was detected in serial post-operative plasma samples (ctDNA tracking) of 44% (4 of 9) of the patients, which predicted tumor relapse. The DFS was a median of 9 months (ctDNA detected) versus median DFS undefined (ctDNA not detected), with a hazard ratio of 17.43 (95% CI, 1.616–188.3). The sensitivity of post-operative ctDNA detection in estimating tumor relapse was 100% and specificity was 83.3%, which was superior to CA125 or HE4. Conclusions Personalized ctDNA detection was effective and stable for high-risk EC. CtDNA tracking in post-operative plasma is valuable for predicting tumor recurrence.

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Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy

JCO Precision Oncology ◽

10.1200/po.20.00321 ◽

2021 ◽

pp. 510-524

Author(s):

Jeffrey C. Thompson ◽

Erica L. Carpenter ◽

Benjamin A. Silva ◽

Jamie Rosenstein ◽

Austin L. Chien ◽

...

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Circulating Tumor Dna ◽

Variant Allele ◽

Molecular Response ◽

Next Generation ◽

Free Survival ◽

Variant Allele Fraction ◽

Tumor Dna ◽

Allele Fraction

PURPOSE Although the majority of patients with metastatic non–small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging. MATERIALS AND METHODS Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded. RESULTS Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders. CONCLUSION Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies.

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Ultra-low Input Circulating Tumor DNA Detection by MED-Amp in Early-Stage Pancreatic Cancer

10.1101/2021.03.28.437388 ◽

2021 ◽

Author(s):

Erica D Pratt ◽

David B Zhen ◽

Robert W Cowan ◽

Heather Cameron ◽

Kara Schradle ◽

...

Keyword(s):

Early Stage ◽

Locally Advanced ◽

Progression Free Survival ◽

Circulating Tumor Dna ◽

Fold Change ◽

Diagnostic Sensitivity ◽

Ductal Adenocarcinoma ◽

Kras Mutations ◽

The Relationship ◽

Tumor Dna

Purpose: The clinical utility of circulating tumor DNA (ctDNA) has been shown in advanced pancreatic ductal adenocarcinoma (PDA). However, diagnostic sensitivity of many ctDNA assays is low in resectable and locally advanced disease, where tumor burden is substantially lower. We have previously described Multiplex Enrichment using Droplet Pre-Amplification (MED-Amp), a multiplexed panel for the detection of the most common oncogenic KRAS mutations in PDA. In this study, we aimed to assess the diagnostic sensitivity of MED-Amp for detection of rare mutant alleles present in the plasma of patients with localized PDA. Experimental Design: We retrospectively analyzed ninety-eight plasma samples from 51 patients with various stages of localized disease. For comparison, we measured ctDNA levels in 20 additional patients with metastatic PDA. The MED-Amp assay was used to measure the abundance of the four most common KRAS codon 12 mutations (G12C/D/R/V). We correlated the presence and quantity of ctDNA with overall survival (OS) as well as progression-free survival (PFS). Using serial plasma draws, we also assessed the relationship between changes in ctDNA allelic frequency and progression. Results: KRAS-positive ctDNA was detected in 52.9% of localized PDA and 75% of metastatic samples tested using DNA inputs as low as 2 ng. As previously reported, the presence of KRAS mutant ctDNA was correlated with worse OS for all disease stages (p = 0.02). In patients with localized PDA high ctDNA levels also correlated with significantly worse median OS (533 days vs 1090 days) and PFS (192 days vs 787 days). We also studied a small cohort of serial plasma draws to observe the relationship between ctDNA fold change and PFS. We found 83% of patients with increased fold change in mutant KRAS experienced disease progression (n=6). In contrast, 75% (n=4) of patients with decreased fold change remained disease-free (p=0.03). Conclusions: MED-Amp is a flexible and cost-effective approach for measurement of ctDNA in patients with localized cancer. Though this study focused on KRAS mutation detection, this assay could be adapted for a number of common oncogenic alterations.

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Increased circulating tumor DNA as a noninvasive biomarker of early treatment response in patients with metastatic ovarian carcinoma: A pilot study

Tumor Biology ◽

10.1177/1010428320919198 ◽

2020 ◽

Vol 42 (5) ◽

pp. 101042832091919 ◽

Cited By ~ 1

Author(s):

Mariana Cartaxo Alves ◽

Fernando Luiz Affonso Fonseca ◽

Alayne Magalhães Trindade Domingues Yamada ◽

Lílian Arruda do Rego Barros ◽

André Lopes ◽

...

Keyword(s):

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Systemic Treatment ◽

Disease Free Survival ◽

Advanced Ovarian Cancer ◽

Early Response ◽

Circulating Tumor Dna ◽

Free Survival ◽

Disease Free ◽

Tumor Dna

Detection of circulating tumor DNA is a new noninvasive technique with potential roles in diagnostic, follow-up, and prognostic evaluation of patients with many types of solid tumors. We aimed to evaluate the role of circulating tumor DNA in the setting of metastatic ovarian carcinoma. A prospective cohort of patients with metastatic ovarian cancer who were referred to systemic therapy was enrolled. Blood samples were collected before the start of treatment and monthly thereafter for 6 months. Circulating tumor DNA was quantified by real-time quantitative reverse transcription polymerase chain reaction of different lengths of Arthrobacter luteus elements as described by Umetani et al. A total of 11 patients were included, 2 for primary disease and 9 for recurrent disease. After the first cycle of chemotherapy, patients whose circulating tumor DNA levels increased from baseline were more likely to respond to chemotherapy than those whose circulating tumor DNA levels did not increase (p = 0.035). Furthermore, patients whose circulating tumor DNA levels rose after the first cycle of chemotherapy also had improved disease-free survival compared to those whose circulating tumor DNA levels did not increase (p = 0.0074). We conclude that the increase in circulating tumor DNA values collected in peripheral blood after the first cycle of systemic treatment in patients with advanced ovarian cancer is associated with an early response to systemic treatment and correlates with superior disease-free survival in this population. Circulating tumor DNA might be a specific, noninvasive, and cost-effective new biomarker of early response to systemic treatment in these patients.

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