The potential role of circulating tumor DNA (ctDNA) in the further investigation of colorectal cancer patients with nonspecific findings on standard investigations.
Rachel Wong, Jeanne Tie, Margaret Lee, Joshua Cohen, Yuxuan Wang, Lu Li, Stephen Ma, Michael Christie, Suzanne Kosmider, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Peter Gibbs
Author Information
Rachel Wong: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. ORCID
Jeanne Tie: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Margaret Lee: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Joshua Cohen: Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
Yuxuan Wang: Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
Lu Li: Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
Stephen Ma: Department of Medical Oncology, Western Health, St Albans, VIC, Australia.
Michael Christie: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Suzanne Kosmider: Department of Medical Oncology, Western Health, St Albans, VIC, Australia.
Cristian Tomasetti: Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
Nickolas Papadopoulos: Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
Kenneth W Kinzler: Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
Bert Vogelstein: Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
Peter Gibbs: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Early detection of metastatic colorectal cancer, at initial diagnosis or during routine surveillance, can improve survival outcomes. Current routine investigations, including CEA and CT, have limited sensitivity and specificity. Recent studies of colorectal cancer cohorts under post surgery surveillance indicate circulating tumor DNA (ctDNA) evidence of recurrence can occur many months before clinical detection. Another possible role for ctDNA is in the further assessment of indeterminate findings on standard CEA or CT investigations. To further explore this potential, we undertook a prospective study. Further investigation, including FDG-PET imaging, was at clinician discretion, blinded to ctDNA analysis. Forty-nine patients were enrolled. Analyzed here are the 45 patients with an evaluable blood sample of whom 6 had an isolated elevated CEA, 30 had indeterminate CT findings, and 9 had both. FDG-PET scans were performed in 30 patients. Fourteen of 45 patients (31%) had detectable ctDNA. At completion of the planned 2 year follow-up, recurrence has occurred in 21 (47%) patients. Detectable ctDNA at study entry was associated with inferior relapse free survival (HR 4.85, p < 0.0001). Where FDG-PET scan was normal/equivocal (n = 15, 50%) 1 of 1 with detectable ctDNA versus 3 of 14 with undetectable ctDNA ultimately had recurrence confirmed. In summary, for colorectal cancer patients with indeterminate findings on routine investigations, ctDNA detection increases the probability that the findings indicate metastatic disease, including in a nonpredefined subset that also underwent FDG-PET imaging. Further studies of the value of ctDNA analysis during patient surveillance are warranted.
