The prognostic impact of peritoneal tumour DNA in gastrointestinal and gynaecological malignancies: a systematic review

Allan, Zexi; Witts, Sasha; Tie, Jeanne; Tebbutt, Niall; Clemons, Nicholas J.; Liu, David S.

doi:10.1038/s41416-023-02424-6

Cited by 5 publications

(3 citation statements)

References 51 publications

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“…Tumour enrichment of ascites cells can be accomplished by collecting only cell spheroids (the metastatic drivers of ovarian cancer) 11 , however, we have previously shown cell-free DNA (cfDNA) to improve on spheroids as a source of concentrated and abundant tumour DNA 12 . This is in alignment with other reports demonstrating that ascites-derived cfDNA is tumour enriched 13 , even in cases where malignant cells are absent from the fluid 10,14 .…”

Section: Introductionsupporting

confidence: 92%

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer

Werner,

Powell,

Duggan

et al. 2024

Preprint

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Background The emergence of targeted therapies and predictive biomarkers is transforming the ovarian cancer treatment paradigm. However, the demand for high quality, tumour-enriched samples for biomarker profiling can be limited by access to adequate tissue samples. The use of cell-free DNA (cfDNA) in ascites presents a potential solution to this clinical challenge. Methods A unique set of sequential ascites-derived cfDNA samples (26 samples from 15 human participants) were collected from people with ovarian cancer (age range 36-82 years). cfDNA was sequenced using targeted next-generation sequencing, along with matched DNA from ascites-derived tumour cells (n=5) and archived FFPE-tissue from surgery (n=5). Results Similar tumour purity, variant detection and reference alignment were achieved with cfDNA when compared to FFPE and ascites derived tumour cell DNA, as well as improved coverage. No artefactual single-base mutation signatures were identified in cfDNA. Combined analysis of large-scale genomic alterations, loss of heterozygosity and tumour mutation burden identified 6 cases of high genomic instability (including 4 with pathogenic variants in BRCA1 and BRCA2). Copy number profiles and subclone prevalence changed between sequential ascites samples, particularly in a case study where deletions and chromothripsis in Chr17p13.1 and Chr8q resulted in changes in clinically relevant TP53 and MYC variants over time. Conclusions Ascites cfDNA successfully identified clinically actionable information, concordant to tissue biopsies, enabling opportunistic molecular profiling. These findings advocate for analysis of ascites cfDNA in lieu of accessing tumour tissue via biopsy.

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Section: Introductionsupporting

confidence: 92%

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer

Werner,

Powell,

Duggan

et al. 2024

Preprint

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“…Hidden peritoneal tumor cells can be identi ed at an early stage by analyzing free tumor DNA found in peritoneal lavage. As shown in Table 1, it has already been shown to be feasible in various GI cancers, such as colorectal or pancreatic cancer 20 . Importantly, studies have linked the detection of ptDNA to poorer survival outcomes and reduced local tumor control in patients with peritoneal metastasis from colorectal carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Peritoneal Tumor Dna in a Multimodal Treatment Setting of Locally Advanced Gastric Cancer – A Novel Study Design

Jacob,

Heiliger,

Balonov

et al. 2024

Preprint

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Background Gastric cancer is a leading cause of death from malignant diseases and has been characterized on a molecular level in recent years. In a context of precision medicine, the proposed study aims to describe the three major compartments harboring tumor cells in patients requiring multimodal therapy: peripheral blood, the abdominal cavity, and the local tumor. Unlike tumor tissues and liquid biopsies, the peritoneal space (in terms of ascites and metastatic tumor seeds) is not regularly considered in molecular diagnostics due to difficult access. This study aims to determine circulating tumor DNA in the peritoneum (ptDNA) and in the plasma (ctDNA). It will then be investigated to what extent the detection of ptDNA before and after neoadjuvant therapy correlates with ctDNA. The main goal is to evaluate the relative changes in ptDNA and ctDNA levels after systemic treatment in patients with locally advanced gastric cancer. Hypothesis: We hypothesize that ptDNA in the abdominal cavity reacts differently to chemotherapy than ctDNA in peripheral blood and therefore, peritoneal disease cannot be adequately represented by ctDNA. Patients with elevated initial ptDNA levels, especially those who do not respond to neoadjuvant therapy, might have an increased risk of peritoneal carcinomatosis and consequently require intensified systemic or local (i.e. HIPEC) treatments. Study design: ptDNA and ctDNA will be analyzed at the time of cancer diagnosis (during exploratory laparoscopy according to diagnostics guidelines) and after neoadjuvant therapy (during tumor resection). Subsequently, the determination of ptDNA in gastric cancer patients could allow the identification of a subgroup that will benefit from intensified local treatment options for peritoneal tumor seeding. Finally, the study will attempt to establish the peritoneal space as another compartment for future precision oncology diagnostics and multimodality therapy.

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“…Additionally, we draw on our own translational and clinical experiences in the field of liquid biopsies to discuss important gaps in the literature and the future directions for ptDNA as a biomarker in this disease. [9][10][11][12][13][14]…”

Section: Introductionmentioning

confidence: 99%

Peritoneal Tumor DNA as a Prognostic Biomarker in Gastric Cancer: A Systematic Review and Meta-Analysis

Allan,

Witts,

Wong

et al. 2024

JCO Precis Oncol

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PURPOSE Gastric cancers commonly spread to the peritoneum. Its presence significantly alters patient prognosis and treatment-intent; however, current methods of peritoneal staging are inaccurate. Peritoneal tumor DNA (ptDNA) is tumor-derived DNA detectable in peritoneal lavage fluid. ptDNA positivity may indicate peritoneal micrometastasis and may be more sensitive than cytology in staging the peritoneum. In this meta-analysis, we evaluated the prognostic potential of ptDNA in gastric cancer. METHODS PubMed, Embase, Scopus, and Web of Science databases were searched using PRISMA guidelines. Studies published between January 1, 1990, and April 30, 2023, containing quantitative data relating to ptDNA in gastric cancer were meta-analyzed. RESULTS Six studies were analyzed. Of the total 757 patients with gastric adenocarcinoma, 318 (42.0%) were stage I, 311 (41.0%) were stage II/III, 116 (15.3%) were stage IV, and 22 (2.9%) were undetermined. Overall, ptDNA detected cytology-positive cases with a sensitivity and specificity of 85.2% (95% CI, 66.5 to 100.0) and 91.5% (95% CI, 86.5 to 96.6), respectively. Additionally, ptDNA was detected in 54 (8.5%) of 634 cytology-negative patients. The presence of ptDNA negatively correlated with pathological stage I (relative risk [RR], 0.29 [95% CI, 0.13 to 0.66]) and positively correlated with pathological stage IV (RR, 8.61 [95% CI, 1.86 to 39.89]) disease. Importantly, ptDNA positivity predicted an increased risk of peritoneal-specific metastasis (RR, 13.81 [95% CI, 8.11 to 23.53]) and reduced 3-year progression-free (RR, 5.37 [95% CI, 1.39 to 20.74]) and overall (hazard ratio, 4.13 [95% CI, 1.51 to 11.32]) survival. CONCLUSION ptDNA carries valuable prognostic information and can detect peritoneal micrometastases in patients with gastric cancer. Its clinical utility in peritoneal staging for gastric cancer deserves further investigation.

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The prognostic impact of peritoneal tumour DNA in gastrointestinal and gynaecological malignancies: a systematic review

Cited by 5 publications

References 51 publications

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer

Peritoneal Tumor Dna in a Multimodal Treatment Setting of Locally Advanced Gastric Cancer – A Novel Study Design

Peritoneal Tumor DNA as a Prognostic Biomarker in Gastric Cancer: A Systematic Review and Meta-Analysis

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