In this edition of “How I Will Treat My Next Patient,” I highlight the potential role of circulating tumor DNA (ctDNA) monitoring in patients with a history of nonmetastatic colorectal cancer (CRC) and the approval of a new targeted agent for a subset of patients with gastrointestinal stromal tumors (GISTs). Taken together, this information may guide the management of selected patients with gastrointestinal malignancies, now and in the future.
ctDNA in colorectal cancer
Dr. Alan P. Lyss
Unfortunately, among patients with CRC with standard blood monitoring, multiple, incurable metastases are the predominant finding when relapse occurs. To improve upon the detection of potentially curable recurrent disease, researchers performed a cross-sectional, observational study of routine monitoring of ctDNA in patients with stage I-III CRC. The patients were also monitored with carcinoembryonic antigen (CEA) levels and imaging in accordance with guidelines from the National Comprehensive Cancer Network (Cancer. 2020 Jan 7. doi: 10.1002/cncr.32695). The investigators used the COLVERA assay of methylated CBAT1/IKZF1 for ctDNA monitoring and the LIAISON CEA plasma test.
Among the 50 patients with recurrence and 177 without recurrence of CRC who met all blood and imaging collection criteria, ctDNA testing offered a sensitivity of 68.1%, compared with 31.9% for CEA (P = .0002), with comparable specificity (97.9% vs. 96.4%; P = 1.000). Over about a 4-year time period, ctDNA detected an additional 18 patients (38%) with recurrence who did not have an elevated plasma CEA, whereas there was only 1 case (2.1%) with an elevated plasma CEA and negative ctDNA test.
Among recurrences considered amenable to surgery with curative intent, (n = 20), ctDNA was positive in 60% of patients, compared with only 20% for CEA (P = .010). Multivariate analysis indicated that ctDNA was an independent predictor of recurrence, whereas CEA was not.
The authors concluded that the methylated BCAT1/IKZF1 ctDNA test was superior to CEA monitoring after initial treatment for potentially curable CRC.
How these results influence practice
The current study adds to the body of work showing superior sensitivity of ctDNA monitoring in the detection of recurrence in patients with solid tumors. In May 2019, this column highlighted the work of Yuxuan Wang, MD, PhD, and colleagues in 58 patients with stages I-III CRC; over a similar duration of follow-up as in the current study (JAMA Oncol. 2019;5[8]:1118-23), Dr. Wang found that 10 of 13 recurrences (77%) were detected by monitoring ctDNA levels. CEA levels were detected 63% of recurrences.
The central, critical hypothesis of these efforts is that the earlier detection of metastatic disease will lead to improved survival for patients with CRC. As the authors state in their discussion, that hypothesis remains tantalizing but unproven.
Prospective, randomized trials like the recently opened COBRA trial (NRG-GI005), which tests ctDNA assay–directed therapy in patients with stage IIA CRC, deserve our enthusiastic support. Research with similar designs will establish the value of ctDNA monitoring as a biomarker for early intervention in patients with stage IV disease and for selecting patients after primary therapy who are unlikely to have been cured and who could potentially benefit from adjuvant therapy.
Monitoring ctDNA is a research tool that could be practice changing in the near future. It has shown enough promise to justify prospective, randomized trials to determine whether its superior sensitivity translates into improved survival.