Dataset Information

Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer.

ABSTRACT:

Purpose

The purpose of this study was to identify the clinical utility of circulating tumor DNA (ctDNA) from ascites and serial plasma samples from epithelial ovarian cancer (EOC) patients.

Materials and methods

Using targeted next-generation sequencing, we analyzed a total of 55 EOC samples including ctDNA from ascites and serial plasma and gDNA from tumor tissues. Tumor tissues and ascites were collected during debulking surgeries and plasma samples were collected before and after the surgeries. Because one EOC patient underwent secondary debulking surgery, a total of 11 tumor tissues, 33 plasma samples, and 11 ascites samples were obtained from the 10 patients.

Results

Of the 10 patients, nine (90%) contained somatic mutations in both tumor tissues and ascites ctDNA. This mutational concordance was confirmed through correlation analysis. The mutational concordance between ascites and tumor tissues was valid in recurrent/progressive ovarian cancer. TP53 was the most frequently detected gene with mutations. ctDNA from serial plasma samples identified EOC progression/recurrence at a similar time or even more rapidly than cancer antigen 125, an established serum protein tumor marker for EOC.

Conclusion

Our data suggest that ascites ctDNA can be used to identify the mutational landscape of ovarian cancer for therapeutic strategy planning.

SUBMITTER: Han MR

PROVIDER: S-EPMC7373868 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer.

Han Mi-Ryung MR Lee Sug Hyung SH Park Jung Yoon JY Hong Hyosun H Ho Jung Yoon JY Hur Soo Young SY Choi Youn Jin YJ

Cancer research and treatment 20200228 3

<h4>Purpose</h4>The purpose of this study was to identify the clinical utility of circulating tumor DNA (ctDNA) from ascites and serial plasma samples from epithelial ovarian cancer (EOC) patients.<h4>Materials and methods</h4>Using targeted next-generation sequencing, we analyzed a total of 55 EOC samples including ctDNA from ascites and serial plasma and gDNA from tumor tissues. Tumor tissues and ascites were collected during debulking surgeries and plasma samples were collected before and aft ...[more]

PMID: 32106643

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Project description:Molecular characterization of cancers is important in dictating prognostic factors and directing therapy. Next-generation sequencing of plasma circulating tumor DNA (ctDNA) offers less invasive, more convenient collection, and a more real-time representation of a tumor and its molecular heterogeneity than tissue. However, little is known about the clinical implications of ctDNA assessment in gynecologic cancer. We describe the molecular landscape identified on ctDNA, ctDNA concordance with tissue-based analysis, and factors associated with overall survival (OS) in gynecologic cancer patients with ctDNA analysis. We reviewed clinicopathologic and genomic information for 105 consecutive gynecologic cancer patients with ctDNA analysis, including 78 with tissue-based sequencing, enrolled in the Profile-Related Evidence Determining Individualized Cancer Therapy (NCT02478931) trial at the University of California San Diego Moores Cancer Center starting July 2014. Tumors included ovarian (47.6%), uterine (35.2%), cervical (12.4%), vulvovaginal (2.9%), and unknown gynecologic primary (1.9%). Most ovarian and uterine cancers (86%) were high grade. 34% (N = 17) of ovarian cancers had BRCA alterations, and 22% (N = 11) were platinum sensitive. Patients received median 2 (range 0-13) lines of therapy prior to ctDNA collection. Most (75.2%) had at least one characterized alteration on ctDNA analysis, and the majority had unique genomic profiles on ctDNA. Most common alterations were TP53 (N = 59, 56.2% of patients), PIK3CA (N = 26, 24.8%), KRAS (N = 14, 13.3%), BRAF (N = 10, 9.5%), ERBB2 (N = 8, 7.6%), and MYC (N = 8, 7.6%). Higher ctDNA maximum mutation allele frequency was associated with worse OS [hazard ratio (HR): 1.91, P = 0.03], while therapy matched to ctDNA alterations (N = 33 patients) was independently associated with improved OS (HR: 0.34, P = 0.007) compared to unmatched therapy (N = 28 patients) in multivariate analysis. Tissue and ctDNA genomic results showed high concordance unaffected by temporal or spatial factors. This study provides evidence for the utility of ctDNA in determining outcome and individualizing cancer therapy in patients with gynecologic cancer.

Project description:Circulating tumor DNA (ctDNA) is one conventional type of liquid biopsy that can be collected to dynamically monitor disease status. However, its potential clinical value and concordance with ascites samples or tumor biopsy needs to be evaluated further for patients with ovarian cancer. Therefore, the present study compared the mutation profiles among ctDNA, paired tumor tissue and ascites samples to explore their possible clinical value in ovarian cancer. Targeted next-generation sequencing was used to screen for mutations in 18 peripheral blood samples, six paired ascites samples and eight paired tumor tissues collected from patients with ovarian cancer. Functional analyses were performed using public databases. WebGestalt was used to perform Gene Ontology and pathway enrichment analyses. The cBioPortal for Cancer Genomics was used to assess therapeutic targets. Chilibot and Search Tool for the Retrieval of Interacting Genes/Proteins were used to obtain key genes and their functional interactions. Comparative analysis was performed among the three types of samples using Venn diagram. A total of 104 cancer-associated mutant genes in ctDNA samples, 95 genes in tumor tissues and 44 genes in ascites samples were found. A cluster covering 10 genes, namely NOTCH2, NOTCH3, lysine methyltransferase 2A, PTEN, androgen receptor, DNA-activated protein kinase catalytic subunit, hepatocyte nuclear factor 1 homeobox A, SRC, insulin receptor substrate 2 and SRY-box transcription factor 10, was obtained by Chilibot analysis. This gene panel may have the potential to monitor metastasis and identify therapeutic targets in ovarian cancer. Taken together, the present study focused on the mutant genes in ctDNA, ascites and tumor tissues, and suggested that the integrated information of different samples could be examined to comprehensively reflect the mutational landscape in ovarian cancer. However, procedures and protocols to interpret and utilize the integrated information obtained from various forms of liquid biopsies will require optimization prior to their use for future clinical applications.

Project description:Postoperative monitoring for patients with colorectal cancer (CRC) requires sensitive biomarkers that are associated with medical response and adjuvant therapy following surgery. Conventional tumor biomarkers [including carcinoembryonic antigen (CEA), CA19-9 and CA125] are widely used, but none of the markers provide high sensitivity or specificity. Previous studies indicated that circulating tumor DNA (ctDNA) is useful for postoperative monitoring of patients with cancer. However, the majority of previous studies involved patients with lung cancer, and therefore further studies are required which investigate patients with CRC. The present study enrolled 11 patients with CRC. All patients underwent surgery, and a number of patients were treated with postoperative chemotherapy. Tumor tissues and serial blood samples were collected from each patient, and somatic mutations of each sample were obtained using next-generation sequencing. The mutation landscape and dynamic changes in mutations for each patient were analyzed, and these results were compared with the changes of CEA levels. A number of driver genes were selected, including tumor protein P53 (TP53), APC and KRAS, to monitor the postoperative outcome of the 11 patients with CRC. Driver mutations were detected in preoperative plasma in 7 patients, with markedly decreased mutation rates detected in postoperative plasma compared with preoperative plasma. Driver mutations were not detected in 4 patients in the preoperative or postoperative plasma. In 1 patient with metastatic rectal cancer, the rate of TP53 mutation increased from 8.95 (preoperative) to 71.4% (postoperative), and a new phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α mutation emerged. This patient succumbed to mortality six months following surgery, however there were no marked changes in CEA levels during periodic detection of CEA levels. In summary, ctDNA has a high sensitivity and specificity in prediction of the prognosis of patients with CRC.

Dataset Information

Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer.

Purpose

Materials and methods

Results

Conclusion

Publications

Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer.

Similar Datasets

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