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ctDNA identifies CRC patients who benefit from adjuvant therapy


 

FROM GI CANCERS SYMPOSIUM 2022

SAN FRANCISCO — A blood test that measures circulating tumor DNA (ctDNA) can help to identify those patients with resectable colorectal cancer who are most likely to derive the most benefit from adjuvant chemotherapy, suggest results from a Japanese study.

The team used a personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) to measure molecular residual disease (MRD) 4 weeks after surgery.

Among patients who were ctDNA positive at 4 weeks post-op, those who received adjuvant chemotherapy had significantly longer disease-free survival (DFS) at 6 months, compared with patients who didn’t receive it.

The adjuvant chemotherapy was able to clear ctDNA in 68% of that subgroup by 24 weeks, noted study author Masahito Kotaka, MD, PhD, from the gastrointestinal cancer center, Sano Hospital, Hyogo, Japan

“Even with an extended follow-up time, ctDNA positivity at 4 weeks post-op was significantly associated with inferior disease-free survival,” he said.

“Two out of three post-op patients who were positive at 4 weeks recurred, even in stage I or low-risk stage II.”

However, he noted that “patients who were 4 weeks post-op and ctDNA negative did not derive significant benefit from adjuvant chemotherapy in high- risk stage II and III.”

Overall, the study shows that stratifying postsurgical treatment decisions using the assay can identify patients likely to benefit from adjuvant chemotherapy across all stages of the disease, explained Dr. Kotaka.

Dr. Kotaka presented the new results at the Gastrointestinal Cancers Symposium.

“ctDNA dynamics from 4-week post-op positivity to 12 weeks afterwards could become new surrogate endpoints beyond disease-free survival,” he suggested.

However, the discussant for this abstract, Rona Yaeger, MD, from Memorial Sloan Kettering Cancer Center in New York, cautioned that this is not yet ready for clinical use.

“There was a clear prognostic effect,” she said. “This was a very large sample size and validates some of the earlier studies showing that ctDNA is a very important prognostic marker.” This study “gives us a tighter confidence interval due to the large size.”

However, there are limitations, one being that it was not a randomized study so it is unknown who received adjuvant therapy, she pointed out. “Since it is not randomized, the groups are not equal.”

Summarizing, she said that ctDNA is a strong prognostic marker that identifies MRD. “But it is expensive and currently doesn’t guide our adjuvant decisions,” she said. “It is not ready yet for standard evaluation of early-stage colorectal cancer patients, and we don’t know yet if additional therapy after adjuvant therapy in ctDNA-positive patients will change outcomes.”

Study details

The new results come from the GALAXY study, which is part of a large platform in Japan, called CIRCULATE, that is evaluating the clinical utility of ctDNA in patients with resectable colorectal cancer. Aside from GALAXY, which is a prospective observational trial, CIRCULATE also includes two phase 3 randomized trials: VEGA and ALTAIR.

For their study, Dr. Kotaka and colleagues monitored ctDNA status in patients with clinical stage l to IV colorectal cancer who underwent complete surgical resection and then evaluated the association of ctDNA dynamics with a short-term clinical outcome and adjuvant therapy efficacy.

A total of 1,040 patients were included in the current analysis. They were stratified into subgroups that were either ctDNA positive (n = 183) or ctDNA negative (n = 531) 4 weeks post surgery. The cohort included 116 patients with stage I disease, 478 with stage II, 503 with stage III, and 268 patients with oligomet resectable stage IV (of whom 16% received neoadjuvant chemotherapy).

Blood samples were collected before surgery and at 4, 12, 24, 36, 48, 72, and 96 weeks following resection.

The team looked at 6-month disease-free survival rates. Among patients with high-risk stage II disease and with a positive ctDNA assay at 4 weeks post-op, those who received adjuvant chemotherapy had a 6-month DFS rate of 100% vs. 53.8% who did not receive adjuvant chemotherapy.

For stage III disease, those rates were 89.2% vs. 32.0%, and for stage IV disease, they were 72.7% vs. 28.3%.

At a median follow-up of 11.4 months, the 6- and 12-month DFS was 96.5% and 92.7% for all patients who were ctDNA negative at 4 weeks post-op. Outcomes for patients who were ctDNA positive were significantly poorer, at 62.8% and 47.5% (hazard ratio, 10.9; P <.001; sensitivity for recurrence, 63.6%).

Of the 188 patients who were MRD positive at 4 weeks post-op with available MRD status at 12 weeks, 95 received adjuvant therapy. The ctDNA clearance rate at 12 weeks was significantly higher in the adjuvant therapy group vs. no adjuvant therapy; 57% vs. 8% in stage I-IV (P < .001), and 58% vs. 11% (4/37) in stage II–III (P < .001).

Additionally, the ctDNA clearance rate at 24 weeks was also significantly higher in adjuvant vs. no adjuvant therapy arms; 26% vs. 0% in patients with stage I-IV disease (P = .003), and 33% vs. 0% in patients with stage II-III disease (P = .03).

Cumulative clearance of ctDNA at 6 months post-op was significantly higher in the adjuvant vs. no adjuvant therapy arms (67% vs. 7% by 24 weeks; cumulative HR, 17.1; P < .001). For patients MRD positive at 4 weeks, the 6-month DFS was also significantly higher in adjuvant vs. no adjuvant therapy arms; 84% vs 34% (HR, 0.15; P < .001), which was observed across all stages.

Upon multivariate analysis, the highest risk of recurrence for patients with stage II-III cancer correlated with ctDNA-positive vs. ctDNA-negative status (HR, 15.3; P <. 001), mutant vs. wild-type RAS (HR, 1.8; P = .04), or mutant vs. wild-type BRAF (HR, 5.2; P < .001).

The group is continuing with its research into a ctDNA-guided adjuvant strategy. More data will be available soon from the ongoing randomized VEGA and ALTAIR studies and will be presented at future conference, Dr. Kotaka commented.

CIRCULATE‐Japan receives financial supports from the Japan Agency for Medical Research and Development and from Taiho Pharmaceutical, through Alpha‐A. Dr. Kotaka reported relationships with Chugai, Lilly Japan, Taiho, Takeda, and Yakult Honsha. Dr. Yaeger reported relationships with Array BioPharma, Boehringer Ingelheim, Mirati Therapeutics, Natera, and Pfizer.

A version of this article first appeared on Medscape.com.

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