Circulating epigenetic biomarkers for detection of recurrent colorectal cancer

Erin L Symonds; Susanne K Pedersen; David Murray; Susan E Byrne; Amitesh Roy; Christos Karapetis; Paul Hollington; Philippa Rabbitt; Frederick S Jones; Lawrence LaPointe; Eva Segelov; Graeme P Young

doi:10.1002/cncr.32695

Circulating epigenetic biomarkers for detection of recurrent colorectal cancer

Cancer. 2020 Apr 1;126(7):1460-1469. doi: 10.1002/cncr.32695. Epub 2020 Jan 7.

Authors

Erin L Symonds^{1

2}, Susanne K Pedersen³, David Murray³, Susan E Byrne¹, Amitesh Roy^{1

4}, Christos Karapetis^{1

4}, Paul Hollington², Philippa Rabbitt², Frederick S Jones⁵, Lawrence LaPointe⁵, Eva Segelov^{6

7}, Graeme P Young¹

Affiliations

¹ Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, South Australia, Australia.
² Bowel Health Service, Flinders Medical Centre, Bedford Park, South Australia, Australia.
³ Clinical Genomics Pty, Ltd, North Ryde, New South Wales, Australia.
⁴ Department of Oncology, Flinders Medical Centre, Bedford Park, South Australia, Australia.
⁵ Clinical Genomics, Inc, Bridgewater, New Jersey.
⁶ Department of Medicine, School of Clinical Sciences, Monash Health, Melbourne, Victoria, Australia.
⁷ Translational Oncology Research Laboratory, Monash University, Melbourne, Victoria, Australia.

Abstract

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.

Keywords: Ikaros family zinc-finger 1 protein (IKZF1); blood test; branched-chain amino acid transaminase 1 (BCAT1); circulating tumor DNA (ctDNA); colorectal cancer; methylation; recurrence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Biomarkers, Tumor / blood*
Biomarkers, Tumor / genetics
Carcinoembryonic Antigen / blood
Circulating Tumor DNA / analysis*
Colorectal Neoplasms / blood*
Colorectal Neoplasms / diagnosis*
Epigenesis, Genetic
Female
Humans
Ikaros Transcription Factor / blood
Male
Middle Aged
Neoplasm Recurrence, Local / blood*
Neoplasm Recurrence, Local / diagnosis*
Sensitivity and Specificity
Transaminases / blood

Substances

Biomarkers, Tumor
Carcinoembryonic Antigen
Circulating Tumor DNA
IKZF1 protein, human
Ikaros Transcription Factor
BCAT1 protein, human
Transaminases