The 2022 Gastrointestinal Cancer Symposium was conducted in both a hybrid in-person and virtual setting. In this year’s meeting, one of the prominent topics was regarding circulating tumor DNA (ctDNA), which was highlighted through both a panel presentation and the first glimpse of observational results from a large ctDNA trial from Japan.
With the increasing global incidence of CRC in younger individuals (<50 years), identifying novel methods for reducing morbidity and mortality related to CRC remain vital. Circulating tumor DNA (ctDNA) shows promise in this setting. ctDNA is released from tumor cells into the bloodstream and generally accounts for <1% of an individual’s total circulating free DNA (cfDNA). However, with improved assay sensitivity, the ability to detect and apply ctDNA is increasing within the field of oncology, particularly in CRC. Due to its rapidly evolving research in CRC, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute presented a framework for the development and integration into both research and clinical practice. Discussions regarding ctDNA played a prominent role in this year’s ASCO Gastrointestinal Symposium.
While traditional tissue biopsy samples are limited by technique and tissue heterogeneity, ctDNA allows for a non-invasive and serial option for monitoring a patient’s genomic profile. The proportion of patients in whom ctDNA can be detected has been shown to be associated with tumor volume. In patients with CRC, it can range from 50% in earlier stage disease to nearly 90% in patients with metastatic disease. Previous data has also shown a lead time of several months between ctDNA positivity and radiographic evidence of disease recurrence.
During the “Emerging of Roles of ctDNA on the Horizon of Gastrointestinal Cancers” session, the landscape of ctDNA assays, potential applications, and future directions of ctDNA research were presented by the panelists. Dr. Naureen Starling from The Royal Marden NHS Foundation discussed several ongoing early detection studies and the multitude of ctDNA assays available. However, sensitivities for many of these assays remain low in the stage 1 setting, so larger studies will be needed. Next, Dr. Scott Kopetz from the MD Anderson Cancer Center discussed data from his group regarding the role of ctDNA in the post-operative setting to monitor recurrence. ctDNA has almost 100% positive predictive value as well as sensitivity of ~50-70% based on current available trials with some assays able to now detect a variant allele frequency of 0.01%. Evaluation of ctDNA status after completion of curative intent therapies may be able to identify patients with minimal residual disease (MRD) who may be at increased risk to recur after definitive therapy. Dr. Kopetz described the NRG-GI005 (COBRA; NCT04068103) study led by Dr. Van Morris of the MD Anderson Cancer Center, a Phase II randomized trial of Stage IIA colon cancer patients, who are randomized to ctDNA assay-directed therapy vs. standard of care (active surveillance) with retrospective evaluation of ctDNA. Dr. Kopetz also described the NRG-GI008 (CIRCULATE-US; NCT#: pending) study led by Dr. Arvind Dasari of the MD Anderson Cancer Center and Dr. Christopher Lieu of the University of Colorado Cancer Center. This is a Phase II/III study randomizing Stage III colorectal cancer patients who are ctDNA negative 6–8 weeks postoperatively to standard-of-care (SOC) adjuvant chemotherapy versus observation with serial ctDNA monitoring until ctDNA is positive, at which time both groups are randomized to SOC versus intensified chemotherapy regimen of mFOLFIRINOX (5-fluorouracil, oxaliplatin, leuocovorin, irinotecan). CIRCULATE-US is part of an international collaboration with the goal of tailoring adjuvant chemotherapy through an international effort.
Part of this collaboration is the CIRCULATE-Japan trial (jRCT1031200006), which is ctDNA-guided adaptive platform trial. The much awaited data from the GALAXY study, which is part of CIRCULATE-Japan, was presented by Dr. Masahito Kotaka from the Sano Hospital, Japan at this year’s ASCO [1]. This observational study is the largest ctDNA study to date, with 1,365 patients enrolled and validated prior studies of ctDNA as MRD. Data from this observational study showed that post-operative ctDNA positivity was associated with inferior disease-free survival, and serial ctDNA testing up to 12-months post-operative was significantly different for patients who were able to clear ctDNA with a disease-free survival (DFS) hazard ratio (HR) of 15.8. Regarding the effect of adjuvant therapy in the GALAXY study, when stratified by ctDNA status, the DFS hazard ratio was 9.4 (95% CI 1.1-79.1, p=0.04) for high-risk Stage II patients and DFS HR was 8.8 (95% CI 3.9-19.5, p=<0.001) for Stage III patients. The wide confidence intervals, small N, and observational methodology suggest that this data remains hypothesis-generating, and larger and randomized trials will be needed to assess the impact of these results. Randomized data from the two-phase III trials (VEGA and ALTAIR) from CIRCULATE-Japan will hope to answer these questions.
Dr. Arvind Dasari then went on to describe ctDNA application in the metastatic setting with regards to tumor profiling, tracking clonal dynamics, and understanding response to systemic therapy in CRC. The COLOMATE trial (NCT03765736) led by Dr. John Strickler at Duke University seeks to explore this question with a basket-study randomizing patient with molecularly targeted therapies guided by ctDNA. Dr. Dasari also described potential pitfalls with ctDNA including false positives related to clonal hematopoiesis of indeterminate potential (CHIP), somatic mutations that may occur with age, as well as false negatives with inadequate ctDNA fraction or sample quality.
As the potential uses of ctDNA continue to grow across a multitude of cancers, the ability to translate this to the clinic in an evidence-based manner remains critical and we need to await the results of well-designed, randomized control trials prior to real world application. Two commercial ctDNA assays (Guardant™, Natera™) are currently covered by Medicare as well as most insurance companies for colorectal cancers and will hopefully expand coverage to other gastrointestinal malignancies. This will improve the ability to enroll a geographically and socioeconomically diverse patient population to ongoing clinical trials.
For now, while the data on ctDNA presented at this year’s meeting was very promising, we will have to wait for data from the many ongoing randomized trials in the US and internationally, which will ultimately guide how best to use ctDNA in the future. The continued support and enrollment of patients in these trials utilizing ctDNA will help optimize and personalize treatment for patients with colorectal cancers.
References:
1. Kotaka, M., et al., Association of circulating tumor DNA dynamics with clinical outcomes in the adjuvant setting for patients with colorectal cancer from an observational GALAXY study in CIRCULATE-Japan. Journal of Clinical Oncology, 2022. 40(4_suppl): p. 9-9.
Dr. Eluri has no conflicts of interest to report.
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