Circulating tumor DNA detection may predict treatment outcomes in colorectal cancer
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Key takeaways:
- Patients who are ctDNA positive during the MRD window have significantly inferior DFS.
- Both ctDNA-based detection of MRD and ctDNA dynamics in response to adjuvant therapy are prognostic of patient outcomes.
Circulating tumor DNA-based detection of molecular residual disease appeared to be highly prognostic of patient outcomes, according to data presented at ASCO Gastrointestinal Cancers Symposium.
Researchers also found circulating tumor DNA (ctDNA) dynamics in response to adjuvant chemotherapy to also be a key predictor of patient outcomes.
“Our data demonstrate the prognostic value and predictive capabilities of circulating tumor DNA detection analyzed in (approximately) 3,000 patients at 24 months,” Hiroki Yukami, MD, PhD, member of Osaka Medical and Pharmaceutical University in Japan, said during a presentation. “The importance of circulating tumor DNA quantification by [mean tumor molecules/mL] is also shown.”
Background and methodology
Prior data analysis from the observational GALAXY study showed postsurgical detection of molecular residual disease (MRD) to be a prognostic indicator of patient outcomes, as well as a significant risk factor for recurrence, regardless of BRAF V600E mutation status.
Researchers conducted an updated analysis and correlation of ctDNA dynamics with outcomes among patients with radically resected stage II to stage IV colorectal cancer from the same study.
They used a personalized, tumor-informed assay for detection and quantification of ctDNA in serial plasma samples collected at 1-, 3-, 6-, 9-, 12-, 18- and 24-month time periods after surgery until disease recurrence. Study investigators also conducted CT scans of the chest, abdomen, and pelvic regions every 6 months.
Study participants underwent either treatment with adjuvant chemotherapy or observation following curative-intent surgery.
DFS served as the study’s primary endpoint, defined as the time between the date of surgery and date of detection of relapse/death due to any cause.
Of the 5,781 patients with colorectal cancer enrolled in the GALAXY study, 2,998 met the inclusion criteria for data analysis.
Researchers noted a median follow-up of 16.14 months (range, 0.23-42.14).
Results
Of the 2,860 patients for which researchers had ctDNA analysis during the postoperative MRD window, 275 (14.8%) showed ctDNA-positive results and 1,783 (85.2%) tested as ctDNA-negative.
Researchers observed that patients with stage II to stage II colorectal cancer who tested ctDNA-positive during the MRD window had significantly inferior DFS compared with ctDNA-negative patients (33.5% vs. 89.3%; HR = 12.05; 95% CI, 9.46-15.34)
Within the MRD-positive subgroup, landmark analysis of ctDNA dynamics from first MRD detection to the 3-month time point showed that patients who remained ctDNA-positive had more than 5-times the likelihood to experience disease recurrence compared with those who had ctDNA clearance (HR = 5.4; 95% CI, 3.58-7.67).
Of the 309 MRD-positive patients, 181 received adjuvant therapy, 132 (72.9%) of which had subsequent ctDNA clearance.
Researchers noted that patients with sustained clearance had better outcomes compared with those with transient ctDNA clearance (HR = 32.57; 95% CI, 9.94-106.76).
They also reported significantly longer DFS among patients who were MRD-positive, received adjuvant therapy, and experienced a 50% or greater decrease in ctDNA levels at 6 months compared with those who had less than a 50% decrease (HR = 2.41; 95% CI, 1.42-4.09).
Next steps
The results provide several markers for oncologists to look for in treating this patient population, according to study investigators.
“Stage I to IV patients with ctDNA detected post surgery have significantly lower DFS at 24 months than ctDNA negative patients,” Yukami said, adding that “ctDNA status during surveillance is significantly associated with DFS.
The results also suggest that a reduction in ctDNA concentration at 6 months is a useful predictor of treatment outcomes, according to Yukami.
“ctDNA-guided adjuvant strategies will further be established by ongoing randomized interventional VEGA and ALTAIR clinical trials that are part of CIRCULATE-Japan,” Yukami said.
Perspective
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Brett L. Ecker, MD
Surgical resection is potentially curative for the management of colorectal cancer (CRC). However, the recurrence rate following surgery may be as high as 30% for patients with American Joint Commission on Cancer (AJCC) pathologic stage II to stage III CRC and 80% for patients with resected AJCC stage IV CRC. The benefit of adjuvant chemotherapy for selected populations with CRC is well-established, with demonstrated efficacy to improve recurrence rates and survival. Traditionally, we have used clinical and pathologic characteristics to pick those patients most likely to recur and have used cytotoxic chemotherapy for these patients, although only a subset may benefit.
The latest data from CIRCULATE-JAPAN, the largest prospective study of ctDNA in patients with resected CRC, continues to modernize our understanding of recurrence and the use of adjuvant chemotherapy to minimize cancer recurrence. Originally published last year in Nature Medicine, the authors shared mature data at ASCO GI. These data confirmed that ctDNA-negative patients with CRC have a very low risk for recurrence — 92% at 2 years, in contrast to 30% 2-year DFS in the MRD-positive subset. Beyond prognostication, ctDNA status was predictive of adjuvant chemotherapy efficacy. ctDNA-negative patients had excellent prognosis regardless of use of adjuvant chemotherapy. In contrast, chemotherapy was selectively associated with improved recurrence-free survival in ctDNA-positive patients. Lastly, the investigators shared novel data from their surveillance cohort of patients with sequential ctDNA testing. Not surprisingly, patients with transient ctDNA clearance suffered delayed recurrence; no recurrences were observed for those with sustained ctDNA clearance.
Together, these data lend support to a model of recurrence whereby micrometastatic cells that are actively replicating and shedding DNA lead to clinical recurrence, and establish the Signatera ctDNA platform as a reliable biomarker to accurately identify this preclinical recurrent state. Ongoing randomized studies in this population (ie, VEGA and ALTAIR clinical trials) will define if chemotherapy for patients with ctDNA-positive only disease can “jump start” treatment to prevent a clinical recurrence from even forming.
Rutgers Robert Wood Johnson Medical School
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Yukami H, et al. Abstract 6. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 18-20, 2024; San Francisco.
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