Circulating Tumour DNA to Guide Treatment of Gastrointestinal Malignancies

To, Yat Hang; Lee, Belinda; Wong, Hui‐Li; Gibbs, Peter; Tie, Jeanne

doi:10.1159/000509657

Cited by 4 publications

(6 citation statements)

References 53 publications

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“…Liquid biopsy could provide essential benefits for adjuvant and palliative treatment decision making, but low detection rates in nonmetastatic UGI cancers hinders this. Positive ctDNA after neoadjuvant treatment can identify patients with significantly increased risk of relapse (HR: 18.7), distant metastases (HR: 32.1), and cancer-associated death (HR: 23.1), but identifying how this issue should be addressed for significant survival benefit is a key question for further studies[ 7 ]. Moreover, liquid biopsy may become integrated into treatment response prediction, especially of immunotherapy, in advanced UGI cancers[ 83 ].…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, detection rates of UGI cancers are low in the early stages (approximately 20%) and reporting studies, thus, have low case numbers[ 19 ]. However, potential targets for molecular tracking are: HOXD10 (higher methylation rates in more advanced disease); ZIC1, RUNX3, and TP53 (53%); or receptor tyrosine kinases, including KRAS (15%), FGFR2, EGFR (17%), ERBB2, PIK3CA (13%), or HER2 (17%)[ 7 , 20 , 21 ]. NGS of metastatic UGI cancer in small case studies revealed detection rates of up to 87.5%[ 21 ].…”

Section: Upper Gi Cancermentioning

confidence: 99%

“…The 3-year PFS was 33% vs 87% after chemoradiotherapy (HR: 6.6, P < 0.001) and was 13.0 ( P < 0.001) after resection, which allowed for stratification of patients with very high and very low risk of relapse[ 65 ]. Based on those findings, several ongoing prospective international studies are evaluating the potential additional clinical benefit from postoperative ctDNA positivity in CRC to identify patients at high risk of recurrence[ 7 ].…”

Section: Crcmentioning

confidence: 99%

“…That is being tested in the DYNAMIC (ACTRN-12615000381583), COBRA (NCT04068103), and CIRCULATE AIO-KRK/PRODIGE 70 (NCT04089631/NCT04120701) trials. Whether stratifying stage III CRC patients by ctDNA results can guide decision making for intensification or de-escalation of adjuvant treatment or surveillance is being tested in the DYNAMIC-III (ACTRN-12617001566325) study[ 7 , 67 - 69 ]. Postoperative ctDNA detection has proven to be a strong indicator of distant recurrence, with a median lead time of 10 mo compared with conventional modalities such as computed tomography (commonly known as CT) and plasma-derived biomarkers like carcinoembryonic antigen (CEA)[ 70 ].…”

Section: Crcmentioning

confidence: 99%

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Circulating tumor DNA for diagnosis, prognosis and treatment of gastrointestinal malignancies

Kirchweger¹,

Wundsam²,

Rumpold³

2022

WJCO

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Minimally invasive detection of circulating tumor DNA (ctDNA) in peripheral blood or other body fluids of patients with gastrointestinal malignancies via liquid biopsy has emerged as a promising biomarker. This is urgently needed, as conventional imaging and plasma protein-derived biomarkers lack sensitivity and specificity in prognosis, early detection of relapse or treatment monitoring. This review summarizes the potential role of liquid biopsy in diagnosis, prognosis and treatment monitoring of gastrointestinal malignancies, including upper gastrointestinal, liver, bile duct, pancreatic and colorectal cancer. CtDNA can now be part of the clinical routine as a promising, highly sensitive and specific biomarker with a broad range of applicability. Liquid-biopsy based postoperative relapse prediction could lead to improved survival by intensification of adjuvant treatment in patients identified to be at risk of early recurrence. Moreover, ctDNA allows monitoring of antineoplastic treatment success, with identification of potentially developed resistance or therapeutic targets during the course of treatment. It may also assist in early change of chemotherapy in metastatic gastrointestinal malignancies prior to imaging findings of relapse. Nevertheless, clinical utility is dependent on the tumor’s entity and burden.

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Section: Discussionmentioning

confidence: 99%

Section: Upper Gi Cancermentioning

confidence: 99%

Section: Crcmentioning

confidence: 99%

Section: Crcmentioning

confidence: 99%

See 2 more Smart Citations

Circulating tumor DNA for diagnosis, prognosis and treatment of gastrointestinal malignancies

Kirchweger¹,

Wundsam²,

Rumpold³

2022

WJCO

View full text Add to dashboard Cite

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“…One of the commonest platforms used is the polymerase chain reaction (PCR)-based assays, which include droplet digital PCR (ddPCR), quantitative real-time (RT-qPCR) and ‘Beads, Emulsion, Amplification and Magnetics’ (BEAMing) PCR ( 8 , 9 ). Another type of platform is to apply Next-Generation Sequencing (NGS) on a target panel of genomic alterations, examples of which include the Tagged-Amplicon deep sequencing (TAm-seq), Safe-sequencing System (Safe-SeqS) and CAncer Personalized Profiling by deep sequencing (CAPP-Seq) ( 8 , 10 ). Such NGS-based assays are highly sensitive with a Limit of Detection (LOD) of variant allelic frequencies (VAF) as low as 0.01%, and specific in detecting various mutations including indels, rearrangements and copy number alterations (CNAs) in GI cancers.…”

Section: Overview Of Ctdna As a Biomarker In Gastrointestinal Cancersmentioning

confidence: 99%

Clinical applications of circulating tumor-derived DNA in the management of gastrointestinal cancers – current evidence and future directions

Lam

Johnson²,

Lam³

et al. 2022

Front. Oncol.

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Advances in Next Generation Sequencing (NGS) technologies have enabled the accurate detection and quantification of circulating tumor-derived (ct)DNA in most gastrointestinal (GI) cancers. The prognostic and predictive utility of ctDNA in patiets with different stages of colorectal (CRC), gastro-esophageal (GEC) and pancreaticobiliary cancers (PBC) are currently under active investigation. The most mature clinical data to date are derived from studies in the prognostic utility of personalized ctDNA-based NGS assays in the detection of minimal residual disease (MRD) and early recurrence after surgery in CRC and other GI cancers. These findings are being validated in several prospective studies which are designed to test if ctDNA could outperform conventional approaches in guiding adjuvant chemotherapy, and in post-operative surveillance in some GI cancers. Several adaptive studies using ctDNA as a screening platform are also being used to identify patients with actionable genomic alterations for clinical trials of targeted therapies. In the palliative setting, ctDNA monitoring during treatment has shown promise in the detection and tracking of clonal variants associated with acquired resistance to targeted therapies and immune-checkpoint inhibitors (ICI). Moreover, ctDNA may help to guide the therapeutic re-challenge of targeted therapies in patients who have prior exposure to such treatment. This review will examine the most updated research findings on ctDNA as a biomarker in CRC, GEC and PBCs. It aims to provide insights into how the unique strengths of this biomarker could be optimally leveraged in improving the management of these GI cancers.

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Circulating Tumor DNA is Unreliable to Detect Somatic Gene Alterations in Gastrointestinal Peritoneal Carcinomatosis

Sullivan

et al. 2022

Ann Surg Oncol

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Introduction Tumor agnostic circulating tumor DNA (ctDNA) is routinely used to guide treatment decisions in gastrointestinal (GI) cancers, especially metastatic cancers. The amount of ctDNA detected in plasma is affected by stage, tumor burden, and tumor vascularization. We hypothesized that peritoneal carcinomatosis (PC) is associated with lower ctDNA levels than other metastatic sites in GI cancers due to the plasma–peritoneal barrier. Methods We conducted a retrospective analysis of patients with stage II–IV GI cancers treated at our institution between 2015 and 2020 with available panel-based ctDNA results (Guardant 360TM). ctDNA analysis was performed on early and pretreatment samples. We compared the reported maximum variant allele frequency (mVAF) of somatic mutations across metastatic sites. Results Of the 279 patients with GI cancers (colorectal, upper GI, pancreaticobiliary), 212 had stage IV disease (PC: n = 61; visceral metastases: n = 138; other metastases: n = 13). Mean mVAF increased with increasing stages of disease (stage II: 3.6 ± 7; stage III: 6.4 ± 10; stage IV: 28.0 ± 51; p < 0.01). Among patients with stage IV disease, PC was associated with lower ctDNA levels independent of primary tumor site (PC only: 12.1%; PC+ visceral metastases: 26.8%; and visceral metastases only: 35.0%; p < 0.01). In a subset of patients (n = 27, matched pair analysis of genomic alterations (GAs) showed fewer GAs were detected in plasma compared with tissue. Conclusions PC of GI origin is associated with significantly lower ctDNA levels compared with visceral metastasis. Caution is warranted when interpreting ctDNA results from patients with PC due to lower sensitivity for detecting actionable mutations.

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Circulating Tumour DNA to Guide Treatment of Gastrointestinal Malignancies

Cited by 4 publications

References 53 publications

Circulating tumor DNA for diagnosis, prognosis and treatment of gastrointestinal malignancies

Circulating tumor DNA for diagnosis, prognosis and treatment of gastrointestinal malignancies

Clinical applications of circulating tumor-derived DNA in the management of gastrointestinal cancers – current evidence and future directions

Circulating Tumor DNA is Unreliable to Detect Somatic Gene Alterations in Gastrointestinal Peritoneal Carcinomatosis

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