Rona Yaeger, MD

Rona Yaeger, MD, Associate Attending Physician at Memorial Sloan Kettering Cancer Center, New York, discussed the results of the GALAXY trial,¹ first putting them into context with previous studies. As she pointed out, the finding of an 11-fold increase in risk of recurrence in patients who remained positive for circulating tumor DNA (ctDNA) after surgery is in line with several important prior studies in which postoperative ctDNA positivity was associated with a 7- to 18-fold increased risk of recurrence or death.^2-4

These studies showed a “clear” and “strong” prognostic effect for ctDNA that has been validated by the results of -GALAXY, Dr. Yaeger commented. However, GALAXY is particularly noteworthy, she added, in that the sample size (more than 1,000 patients) is “an order of magnitude larger than the other studies” and therefore has tighter confidence intervals. The clear separation of the curves and large hazard ratios (9.4, 8.8) in the small cohort of patients with high-risk pathologic stage II or III disease confirm the high-risk status of this group, although, encouragingly, this poor prognosis is “not set,” according to the findings, as such patients who received adjuvant chemotherapy had better outcomes. In this regard, GALAXY went further than previous studies in examining the benefit of intervention.

Dr. Yaeger said the impact of chemotherapy in patients with stage III disease may have been muddled by the puzzling fact that many had not already received chemotherapy, which is standard treatment for this stage. “It’s possible there are other reasons that could have affected survival,” she suggested.

Dr. Yaeger further noted that the overlapping disease-free survival curves for the ctDNA-negative cohort, regardless of chemotherapy, “are reassuring” and bolster the aim of ongoing prospective studies to determine the effect of withholding chemotherapy in this subgroup. She cautioned, however, that small effects in this good-prognosis group could be missed; the duration of follow-up is short; and the no-chemotherapy group included more patients with stage II disease, whose more-favorable prognosis could have contributed to the overlapping curves.

Dr. Yaeger concluded with her recommendations for using ctDNA analysis based on current data: “Analysis of ctDNA is a strong prognostic marker that identifies molecular residual disease. However, it is expensive and does not currently guide our adjuvant therapy decisions. It’s not ready yet for standard evaluation in patients with early-stage colorectal cancer, and we don’t know yet whether additional therapy after standard adjuvant therapy in patients who test positive for ctDNA will change outcomes.”

Future Studies That Might Guide Clinical Practice

Looking ahead, Dr. Yaeger stated that the results of ongoing prospective trials may someday help guide clinical practice. Some of these studies include the following:

• VEGA (ctDNA-negative) and ALTAIR (ctDNA-positive) intervention trials of CIRCULATE-JAPAN
• CIRCULATE US: Patients with stage II and III disease will be evaluated for treatment de-escalation or escalation, depending on ctDNA status. De-escalation will compare a doublet with observation; escalation will compare a chemotherapy doublet with a triplet.
• NRG GI-005 (COBRA): Active surveillance vs treatment based on assay-directed therapy will be evaluated in patients with stage IIa disease.
• SUC ACT3: This trial will evaluate chemotherapy consolidation vs observation in patients with stage III disease who completed standard therapy but remain positive for ctDNA. Matched therapy will be evaluated in biomarker-directed cohorts. 

DISCLOSURE: Dr. Yaeger has served as a consultant or advisor to Array BioPharma, Mirati Therapeutics, Natera, and Pfizer; and had received institutional research support from Array BioPharma, Boehringer Ingelheim, Mirati Therapeutics, and Pfizer.

REFERENCES

1. Kotaka M, Shirasu H, Watanabe J, 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. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 9. Presented January 20, 2022.

2. Tie J, Wang Y, Tomasetti C, et al: Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 8:346ra92, 2016.

3. Reinert T, Henriksen TV, Christensen E, et al: Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol 5:1124-1131, 2019.

4. Parikh AR, Van Seventer EE, Siravegna G, et al: Minimal residual disease detection using a plasma-only circulating tumor DNA assay in patients with colorectal cancer. Clin Cancer Res 27:5586-5594, 2021.