A cross‐sectional study comparing a blood test for methylated <i><scp>BCAT</scp>1 and <scp>IKZF</scp>1</i> tumor‐derived <scp>DNA</scp> with <scp>CEA</scp> for detection of recurrent colorectal cancer

Young, Graeme P.; Pedersen, Susanne K.; Mansfield, Scott; Murray, David H.; Baker, Rohan T.; Rabbitt, Philippa; Byrne, Susan E; Bambacas, Libby; Hollington, Paul; Symonds, Erin L.

doi:10.1002/cam4.868

Cited by 90 publications

(93 citation statements)

References 38 publications

(49 reference statements)

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“…Venous blood was collected (2 × 9‐mL K3‐EDTA vacutainers), prepared, and stored as previously described . All procedures were performed by hospital‐accredited specialists and met site‐specific standards.…”

Section: Methodsmentioning

confidence: 99%

“…One such ctDNA test is COLVERA, which detects hypermethylated regions within branched‐chain amino acid transaminase 1 ( BCAT1 ) and Ikaros family zinc‐finger 1 protein ( IKZF1 ) . Furthermore, an initial evaluation of these biomarkers when they were assessed in a qualitative manner showed that this methylated ctDNA test could be up to twice as sensitive for detecting recurrent CRC in comparison with CEA …”

Section: Introductionmentioning

confidence: 99%

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Circulating epigenetic biomarkers for detection of recurrent colorectal cancer

Symonds

Pedersen²,

Murray³

et al. 2020

Cancer

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Background The sensitive detection of recurrent colorectal cancer (CRC) by the measurement of circulating tumor DNA (ctDNA) might improve the chance of a cure. This study compared a quantitative methylated ctDNA test with carcinoembryonic antigen (CEA) in the setting of surveillance for recurrence. Methods Blood samples collected either during surveillance or within 12 months of the confirmation of recurrence were assayed for ctDNA (methylated branched‐chain amino acid transaminase 1 [BCAT1]/Ikaros family zinc‐finger 1 protein [IKZF1]) and CEA. The optimal ctDNA threshold was determined by receiver operating characteristic analysis, and the test performance for the detection of recurrence was compared with CEA (5 ng/mL threshold). Results The study cohort comprised 144 eligible patients and included 50 recurrence events. The sensitivity of the methylated ctDNA test for recurrence was 66.0% (95% confidence interval [CI], 57.1%‐69.3%), which was significantly higher than the sensitivity of CEA (31.9%; 95% CI, 22.8%‐36.6%; P < .001). The sensitivity for resectable recurrence (n = 20) was also higher (ctDNA, 60.0%; CEA, 20.0%; P = .01). The specificity did not differ between the tests (ctDNA, 97.9%; 95% CI, 93.2%‐99.6%; CEA, 96.4%; 95% CI, 91.4%‐99.0%). When adjustments were made for other predictors of the presence of recurrence, a positive ctDNA test was an independent predictor (odds ratio, 155.7; 95% CI, 17.9‐1360.6; P < .001), whereas CEA was not (odds ratio, 2.5; 95% CI, 0.3‐20.6; P = .407). Conclusions The quantitative ctDNA test showed superior sensitivity in comparison with CEA without a difference in the specificity for detecting recurrent CRC. Longitudinal studies are warranted to further assess the utility (specifically the survival benefit) of methylated BCAT1/IKZF1 ctDNA in the surveillance of patients with CRC.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Circulating epigenetic biomarkers for detection of recurrent colorectal cancer

Symonds

Pedersen²,

Murray³

et al. 2020

Cancer

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“…[61][62][63][64][65][66][67][68][69] For example, an approach using a BCAT1 and IKZF1 methylation assay identified approximately 70% of CRC. [75][76][77] Detection of tumor recurrence, minimal residual disease, and prognosis value Surgery alone cures a large fraction of patients with localized CRC. However, there are currently no effective means to identify which patients have residual disease that will result in recurrence.…”

Section: Cancer Diagnosis and Screeningmentioning

confidence: 99%

Future perspectives of circulating tumor DNA in colorectal cancer

et al. 2017

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Tumor biopsy is currently the gold standard for diagnosis and in determining cell signaling pathways involved in the development of treatment resistance. However, there are major challenges with this technique, including the need for serial sampling to monitor treatment resistance, which is invasive and also has the potential for selection bias due to intra-tumoral and inter-tumoral heterogeneity. These challenges highlight the need for more effective methods for obtaining Tumor samples. Liquid biopsy analyzes genetic material or tumor cells shed into the blood from the primary tumor and metastatic sites and consequently provides a comprehensive, real-time picture of the tumor burden in an individual patient. Indeed, liquid biopsy has the potential to revolutionize cancer management. Here, we review recent studies on the potential clinical applications of liquid biopsy using circulating tumor DNA in colorectal cancer, including screening, diagnosis, detection of minimal residual disease after surgery, detection of recurrence, prognosis, predicting treatment response, monitoring tumor burden or response during treatment, and tracking resistance. We also discuss recent data demonstrating the utility of detecting KRAS-mutated circulating tumor DNA, both at diagnosis to determine an appropriate treatment strategy and during anti-epidermal growth factor receptor therapy to predict treatment resistance. The future integration of liquid biopsy into clinical practice is discussed, together with alternative approaches and key questions that need to be answered in future clinical studies before this technology can be implemented and used routinely.

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“…As most patients with CRC are asymptomatic or have non-specific symptoms in the early stages, it is vital to find a safe, acceptable, sensitive, specific, and cost-effective test that detects the early stage of the disease [5]. …”

Section: Introductionmentioning

confidence: 99%

“…Blood-based markers in current use, such as carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9, are for surveillance and for monitoring response to treatment but have a low sensitivity and specificity ranging from 40 to 70% and 73 to 90%, respectively, making them unsuitable as screening or diagnostic markers [5, 10] A more recently proposed marker, which is commercially available, is methylated septin 9. This is a molecular-based blood test whose reported accuracy in the literature has been variable.…”

Section: Introductionmentioning

confidence: 99%

Systematic review of blood diagnostic markers in colorectal cancer

et al. 2018

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The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for diagnostic blood markers for primary human colorectal cancer over the last 5 years was performed. The primary outcome was to assess the diagnostic ability of these markers in diagnosing colorectal cancer. The secondary outcome was to see whether the marker was compared to other markers. The tertiary outcome was to assess diagnostic ability in early versus late CRC, including stage IV disease. We identified 51 studies (29 prospective, 14 retrospective, and 8 meta-analyses). The markers were divided in broadly four groups: nucleic acids (RNA/DNA/messenger RNA/microRNAs), cytokines, antibodies, and proteins. The most promising circulating markers identified among the nucleid acids were NEAT_v2 non-coding RNA, SDC2 methylated DNA, and SEPT9 methylated DNA. The most promising cytokine to detect CRC was interleukin 8, and the most promising circulating proteins were CA11-19 glycoprotein and DC-SIGN/DC-SIGNR. Sensitivities of these markers for detecting primary colorectal carcinoma ranged from 70 to 98% and specificities from 84 to 98.7%. The best studied blood marker was SEPT9 methylated DNA, which showed great variability with sensitivities ranging from 48.2 to 95.6% and specificities from 80 to 98.9%, making its clinical applicability challenging. If combined with fecal immunochemical test (FIT), the sensitivity improved from 78 to 94% in detecting CRC. Methylated SEPT9, methylated SDC2, and -SIGN/DC-SIGNR protein had better sensitivity and specificity than CEA or CA 19-9. With the exception of SEPT9 which is currently being implemented as a screening test for CRC all other markers lacked reproducibility and standardization and were studied in relatively small population samples.

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A cross‐sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor‐derived DNA with CEA for detection of recurrent colorectal cancer

Cited by 90 publications

References 38 publications

Circulating epigenetic biomarkers for detection of recurrent colorectal cancer

Circulating epigenetic biomarkers for detection of recurrent colorectal cancer

Future perspectives of circulating tumor DNA in colorectal cancer

Systematic review of blood diagnostic markers in colorectal cancer

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