Circulating tumor DNA: a noninvasive biomarker for tracking ovarian cancer

AbstractOvarian cancer is the fifth leading cause of cancer-related mortality in women worldwide. Despite the development of technologies over decades to improve the diagnosis and treatment of patients with ovarian cancer, the survival rate remains dismal, mainly because most patients are diagnosed at a late stage. Traditional treatment methods and biomarkers such as cancer antigen-125 as a cancer screening tool lack specificity and cannot offer personalized combinatorial therapy schemes. Circulating tumor DNA (ctDNA) is a promising biomarker for ovarian cancer and can be detected using a noninvasive liquid biopsy. A wide variety of ctDNA applications are being elucidated in multiple studies for tracking ovarian carcinoma during diagnostic and prognostic evaluations of patients and are being integrated into clinical trials to evaluate the disease. Furthermore, ctDNA analysis may be used in combination with multiple “omic” techniques to analyze proteins, epigenetics, RNA, nucleosomes, exosomes, and associated immune markers to promote early detection. However, several technical and biological hurdles impede the application of ctDNA analysis. Certain intrinsic features of ctDNA that may enhance its utility as a biomarker are problematic for its detection, including ctDNA lengths, copy number variations, and methylation. Before the development of ctDNA assays for integration in the clinic, such issues are required to be resolved since these assays have substantial potential as a test for cancer screening. This review focuses on studies concerning the potential clinical applications of ctDNA in ovarian cancer diagnosis and discusses our perspective on the clinical research aimed to treat this daunting form of cancer.

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Circulating tumor DNA analysis to reveal genomic profiles for epithelial ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5543 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5543-5543

Author(s):

Yang Xiang ◽

Shan Zhu ◽

Weiran Wang ◽

Dongyan Cao ◽

Xi-Run Wan ◽

...

Keyword(s):

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Epithelial Ovarian Cancer ◽

Circulating Tumor Dna ◽

Stage Iii ◽

Signal Pathways ◽

Low Grade ◽

Serous Ovarian Carcinoma ◽

Ctdna Analysis ◽

Tumor Dna

5543 Background: Circulating tumor DNA (ctDNA) analysis in epithelial ovarian cancer (EOC) was previously reported, however with limited samples or limited genes. Here, we reported an analysis of ctDNA in EOC cohort using targeted sequencing with a 1021-gene panel. Methods: Patients with EOC were enrolled, and treatment-naïve tumor tissues and blood samples were collected. We utilized a 1021-gene NGS panel in matched tissue DNA and ctDNA to identify somatic mutations with white blood cell DNA as a germline control. Results: Mutations were identified in all of the 65 tissues and in 53 (81.5%) ctDNA. The median ctDNA mutation allelic frequency was 2.5%, ranging from 0.1% to 36.2%. A median of 66.7% (12.5%-100.0%) of tissue derived mutations were observed in ctDNA. Besides, there were 91 ctDNA private mutations, including TP53 gene mutations. The most frequently mutated genes were TP53 (55.4%), PIK3CA (13.8%) and ARID1A (12.3%) in ctDNA analysis, which were consistent with tissue analysis (60.0%, 26.2% and 20.0% of tissues with TP53, PIK3CA and ARID1A mutations, respectively). Mutations of TP53 (37/42) in high-grade serous ovarian carcinoma (HGSOC), PIK3CA (10/11) and ARID1A (8/11) in ovarian clear cell carcinoma, BRAF (4/5) in low-grade serous ovarian carcinoma and PIK3CA (3/5), ARID1A (2/5) and PTEN (2/5) in endometrioid carcinoma were observed as the most commonly genetic aberrations in ctDNA in different sub-types of EOC, which located in different signal pathways and suggested different pathogenesis. In total, 90.5% (38/42) of HGSOC were ctDNA positive, comparing with 65.2% (15/23) of other EOC subtypes (p = 0.012). In addition, 56.5% (13/23) of stage I~II EOC were ctDNA positive, comparing with 94.7% (36/38) of stage III (p = 0.002). No association between ctDNA positivity and other clinic characteristics was observed, including pathological differentiation, CA125, lesion density (solid vs. cystic-solid and cystic). Multivariable analysis suggested FIGO stage III (p = 0.008) as an independent predictor of ctDNA detection. Conclusions: In summary, genomic characterization of EOC may offer insights into tumorigenesis and identify potential therapeutic targets in this disease.

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

Cancer Research and Treatment ◽

10.4143/crt.2019.700 ◽

2020 ◽

Vol 52 (3) ◽

pp. 779-788 ◽

Cited By ~ 1

Author(s):

Mi-Ryung Han ◽

Sug Hyung Lee ◽

Jung Yoon Park ◽

Hyosun Hong ◽

Jung Yoon Ho ◽

...

Keyword(s):

Ovarian Cancer ◽

Circulating Tumor Dna ◽

Plasma Samples ◽

Cancer Antigen 125 ◽

Similar Time ◽

Targeted Next Generation Sequencing ◽

Tumor Tissues ◽

Before And After ◽

Strategy Planning ◽

Tumor Dna

PurposeThe 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 MethodsUsing 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. <i>TP53</i> 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.ConclusionOur data suggest that ascites ctDNA can be used to identify the mutational landscape of ovarian cancer for therapeutic strategy planning.

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756P Efficacy of circulating tumor DNA (ctDNA) analysis in the early detection of ovarian cancer progression

Annals of Oncology ◽

10.1016/j.annonc.2021.08.1198 ◽

2021 ◽

Vol 32 ◽

pp. S746

Author(s):

J. Heo ◽

Y.N. Kim ◽

J.Y. Lee ◽

S.T. Lee ◽

S. Shin ◽

...

Keyword(s):

Ovarian Cancer ◽

Early Detection ◽

Cancer Progression ◽

Circulating Tumor Dna ◽

Ctdna Analysis ◽

Tumor Dna

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Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Nature Communications ◽

10.1038/s41467-020-20493-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Gillian Vandekerkhove ◽

Jean-Michel Lavoie ◽

Matti Annala ◽

Andrew J. Murtha ◽

Nora Sundahl ◽

...

Keyword(s):

Tumor Tissue ◽

Treatment Options ◽

Circulating Tumor Dna ◽

Molecular Stratification ◽

Clinical Biomarkers ◽

Surgery Patient ◽

Metastatic Urothelial Carcinoma ◽

Ctdna Analysis ◽

Clinical Genomic ◽

Tumor Dna

AbstractMolecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

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Epithelial ovarian cancer and the use of circulating tumor DNA: A systematic review

Gynecologic Oncology ◽

10.1016/j.ygyno.2021.04.020 ◽

2021 ◽

Author(s):

Christine Fribert Thusgaard ◽

Malene Korsholm ◽

Kristina Magaard Koldby ◽

Torben A. Kruse ◽

Mads Thomassen ◽

...

Keyword(s):

Systematic Review ◽

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Circulating Tumor Dna ◽

Tumor Dna

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Prognostic value of baseline and 3 months postoperative circulating tumor DNA (ctDNA) in ovarian cancer patients

10.3802/jgo.2021.32.s1.o14 ◽

2021 ◽

Author(s):

Yoo-Na Kim ◽

Jinho Heo ◽

Jung-Yun Lee ◽

Seung-Tae Lee ◽

Saeam Shin ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Prognostic Value ◽

Circulating Tumor Dna ◽

Tumor Dna

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Circulating tumor DNA (ctDNA) in patients with advanced adrenocortical carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4585 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4585-4585

Author(s):

Bassel Nazha ◽

Hiba I. Dada ◽

Leylah Drusbosky ◽

Jacqueline T Brown ◽

Deepak Ravindranathan ◽

...

Keyword(s):

Adrenocortical Carcinoma ◽

Treatment Options ◽

Genomic Data ◽

Circulating Tumor Dna ◽

Copy Number Variations ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Entire Cohort ◽

Genomic Landscape ◽

Ctdna Analysis

4585 Background: Adrenocortical Carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited treatments in the advanced setting. Molecular pathways with tumor suppressor genes (e.g. TP53, CDKN2A) and oncogenes (e.g. CTNNB1 and RAS) are implicated in oncogenesis. To our knowledge, the genomic landscape of ctDNA alterations for ACC has not been described in a large cohort. We report plasma-based ctDNA alterations in patients with advanced ACC. Methods: We retrospectively evaluated genomic data from 102 patients with ACC who had ctDNA testing between 12/2016 – 10/2020 using Guardant360 (Guardant Health, CA). ctDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes. We evaluated the frequency of genomic alterations, the landscape of co-occurring mutations, and pathogenic or likely pathogenic alterations with potential targeted therapies. The prevalence of alterations identified in ctDNA were compared to those detected in tissue using a publicly available database (cBioPortal). Results: The median age was 54 years (range 24-81), and 55% of patients were male. Among the entire cohort, 84 pts (82.4%) had ≥1 somatic alteration detected. Mutations were most frequently detected in TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%). The frequencies detected in ctDNA were similar to the results detected in tissue. Pathogenic and/or likely pathogenic mutations in therapeutically relevant alterations were observed in 36 patients (35%), including EGFR, BRAF, MET, CDKN2A, and CDK4/6 (Table 1). The most frequently co-occurring mutations were EGFR + TP53 (14%), EGFR + MET (11%), BRAF + MET (10%). Conclusions: Blood-based ctDNA profiling in advanced ACC provided comprehensive genomic data in most patients, with a similar profile to tumor tissue analyses. Over one third of patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options for this aggressive malignancy.[Table: see text]

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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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