Postoperative molecular residual disease detected by circulating tumor DNA (ctDNA) at 4 weeks after resection has emerged as the strongest prognostic risk factor for disease-free survival in patients with resected colorectal cancer. This finding was observed regardless of BRAF V600E status and microsatellite instability–high (MSI-H) status, according to an update of the observational GALAXY study presented at the 2023 ASCO Breakthrough meeting.¹

BRAF status and MSI-H status were also found to be significant prognostic factors, but the incorporation of ctDNA status provided added value and enhanced the ability to estimate recurrence risk. These findings may inform selection of the most appropriate therapy after resection for these patients.

Jun ­Watanabe, MD, PhD

“Combining BRAF/MSI status with ctDNA status at the 4-week postoperative molecular residual disease time point will allow us to differentiate recurrence risk after radical resection, leading to the choice of adjuvant therapy,” explained lead author Jun ­Watanabe, MD, PhD, of the Gastroenterological Center, Yokohama City University Medical Center, Japan.

Here were some of the unexpected findings:

• Among patients testing ctDNA-negative at 4 weeks, the presence of MSI-high was associated with a lower risk of relapse compared with BRAF wild-type and microsatellite stable, regardless of BRAF status.
• Among patients testing ctDNA-positive at 4 weeks, the presence of BRAF V600E was associated with a higher risk of relapse compared with BRAF wild-type and microsatellite stable, regardless of MSI status.

“We were surprised to find a strong influence of BRAF in ctDNA-positive patients and a strong influence of MSI in ctDNA-negative patients,” Dr. Watanabe told the audience.

ctDNA Analysis

Monitoring of ctDNA is being widely studied as a noninvasive tool to detect molecular residual disease and measure the effects of curative therapy for patients with colorectal cancer. A personalized tumor-informed ctDNA assay may predict the risk of recurrence in patients with resected colorectal cancer and may detect recurrences an average of 9 months before standard radiologic imaging.^2,3

The phase III CIRCULATE-Japan initiative is designed to further evaluate the clinical utility of ctDNA analysis to select more precise adjuvant therapy for patients with resectable colorectal cancer. GALAXY, the first of these trials, is a prospective large-scale nationwide registry for monitoring ctDNA in patients with stages II to IV resectable colorectal cancer. Future trials will build on GALAXY findings.

In the study, serial ctDNA analyses are conducted using the previously mentioned personalized tumor-informed assay. The initial assessment of molecular residual disease is performed 4 weeks postoperatively. Additional assessments are conducted at 3, 6, 9, 12, 18, and 24 months after surgery or until recurrence. CT scans are conducted every 6 months.

In January 2023, outcomes of the first 1,039 patients were published after a median follow-up of 16.7 months.⁴ In that analysis, postoperative ctDNA positivity was associated with a 10-fold increase in the risk of recurrence (hazard ratio [HR] = 10.00; P < .0001). The study also showed that test results could select patients most likely to benefit from adjuvant chemotherapy. The current analysis, reported at the 2023 ASCO Breakthrough meeting, included an additional 1,044 patients enrolled in GALAXY and explored outcomes based on BRAF and MSI status.

GALAXY Details

At a median follow-up of 16.3 months for 2,083 patients, 14% were ctDNA-positive at the 4-week molecular residual disease time point. At week 4, ctDNA positivity was associated with a significantly shorter disease-free survival and a 12-fold increase in recurrence risk (HR = 12.00; P < .001).

Overall, 2.9% of patients were BRAF V600E–positive and microsatellite stable; 4.8% were BRAF wild-type and MSI-H; and 5.5% were BRAF V600E–positive and MSI-H. BRAF status and microsatellite stability status remained statistically significant as prognostic markers for recurrence.

Among patients with BRAF wild-type tumors, disease-free survival outcomes were more favorable among those with MSI-H tumors than those with microsatellite-stable tumors (HR = 4.14; P = .015). Disease-free survival outcomes were also better among patients with BRAF V600E–positive and MSI-H tumors than those with BRAF wild-type and microsatellite-stable tumors (HR = 4.80; P = .007).

Despite the significance of BRAF and MSI status, in a multivariate analysis, ctDNA positivity emerged as the strongest prognostic factor. It was significantly associated with shorter disease-free survival (HR = 11.68; P < .001), with a greater magnitude of significance compared with other factors, including BRAF status and MSI status.

Future Plans

GALAXY investigators plan to accrue a total of 6,300 patients to validate their findings in a larger sample. Two randomized, phase III trials are evaluating ctDNA-guided adjuvant therapy based on ctDNA status in the GALAXY study.

The noninferiority VEGA trial is comparing postoperative surgery vs standard adjuvant therapy in patients with high-risk stage II or low-risk stage III colon cancer who are ctDNA-negative at postoperative week 4 in the GALAXY study. The double-blind, phase III ALTAIR trial is comparing trifluridine/tipiracil vs placebo in patients with resected colorectal cancer who are ctDNA-positive in the GALAXY study. 

DISCLOSURE: Dr. Watanabe has served on the speakers bureau of Johnson & Johnson, Eli Lilly, Medtronic, and Takeda; and has received institutional research Funding from AMCo, Medtronic, Stryker, and Terumo.

REFERENCES

1. Watanabe J, Oki E, Kotani D, et al: Postoperative circulating tumor DNA-based molecular residual disease in patients with BRAF V600E and MSI-H colorectal cancer: Updated results from GALAXY study in the CIRCULATE-Japan. 2023 ASCO Breakthrough. Abstract 32. Presented August 3, 2023.

2. Coombes RC, Page K, Salari R, et al: Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res 25:4255-4263, 2019.

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. Kotani D, Oki E, Nakamura Y, et al: Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Nat Med 29:127-134, 2023.