(CRC). Much of the uncertainty surrounds the sensitivity of ctDNA at the time when decisions regarding adjuvant therapy are being made.
Those were some of the key points made during a series of presentations and discussions on ctDNA at the ASCO Gastrointestinal Cancers Symposium.
In a morning session, Pashtoon Murtaza Kasi, MD, presented the first interim results from the multicenter, prospective observational BESPOKE CRC study, which included 689 patients with stage II or III colorectal cancer. The trial was designed to determine what effect ctDNA results would have on adjuvant chemotherapy treatment decisions. Over a median follow-up of 24.8 months, 623 patients had ctDNA results available. ctDNA positivity was associated with worse 2-year disease-free survival (DFS) at 29.86% versus 91.59% in the stage II/III combined group (hazard ratio [HR], 12.1; P < .0001) and in stage II (HR, 18.8; P < .0001) and stage III (HR, 9.9; P < .0001) analyzed separately.
In ctDNA-positive patients, adjuvant chemotherapy was associated with longer DFS than in those who did not undergo adjuvant chemotherapy (HR, 3.06; P = .0025), but there was no difference in DFS between ctDNA-negative patients who received adjuvant chemotherapy and those who didn’t. Patients who achieved ctDNA clearance had a longer median DFS (24.2 versus 13.8 months; HR, 0.4; P = .045).
Patient Anxiety Concerns
Dr. Kasi noted the importance of considering the patient’s view of ctDNA. There may be some concerns that such tests could cause patient anxiety, but he referenced a poster at ASCO GI which suggested the opposite. “It actually reduced anxiety, and 90% of the patients felt confident in the treatment they were receiving. They [said that] they will continue using the assay, and they value the additional information,” said Dr. Kasi, who is a medical oncologist at Weill Cornell Medicine in New York City.
During the Q&A after the talk, David Ellison, MD, a medical oncology and hematology specialist at Memorial Sloan Kettering Cancer Center, also in New York asked Dr. Kasi: “Did this [positive ctDNA] test just prompt earlier imaging? Was it any better than conventional surveillance like CEA (carcinoembryonic antigen) or imaging?” he asked.
Dr. Kasi responded that the data showed ctDNA positivity 6-9 months earlier than cancer detection through traditional imaging.
“It doesn’t necessarily replace the ongoing surveillance. This particular study did not guide or make it as a protocol as to what to do. Everything was done as part of standard of care, the usual surveillance that the cancer center follows, he said. “I think [ctDNA] would help complement the ongoing care and in conjunction with somebody who has, for example, an indeterminant lung nodule, but also has ctDNA positivity, I think it adds confidence to the decisions that one might be making.”
Eujung Kim, MD, PhD, an instructor of medicine at Harvard Medical School, Boston, Massachusetts, wondered if there might be chemoresistant tumor cells remaining that are not shedding DNA. “You have to keep the biology in mind as well make decisions in conjunction with the clinical situation, as opposed to in isolation with ctDNA results,” Dr. Kasi responded.
In the same session, Jeannie Tie, MD, described results from the AGITG DYNAMIC-Rectal trial, which was a randomized study to determine if ctDNA could inform adjuvant chemotherapy decisions in locally advanced rectal cancer. The analysis included 230 patients who were randomized to ctDNA-informed management (n = 155), with a positive test leading to adjuvant chemotherapy, or a standard arm where adjuvant therapy decisions were left to the physician (n = 75).
Adjuvant chemotherapy use was higher in the control arm (77% versus 46%; P < .001). Lymphovascular invasion was more common in the control arm (odds ratio [OR], 3.06; P = .023), and recurrence-free survival was higher in patients who remained ctDNA negative (HR, 0.29; P < .001) despite all ctDNA-positive patients and only 23% of ctDNA-negative patients undergoing chemotherapy.
The sites of relapses were also different, with 78% occurring in patients who were ctDNA negative after surgery occurring only in the lung, versus just 1% of metastases solely in the lung among those who were ctDNA positive.
In ctDNA-positive patients, 50% of relapses were only in the liver and 19% were in the liver and lung.
Over 36 months, 16% of ctDNA-negative patients developed distant relapses and 2.8% developed locoregional relapses, versus 36% and 7.1% in the ctDNA-positive group.
“Regrettably, we could not conclude about the noninferiority of [using ctDNA to guide adjuvant therapy decisions] due to the premature study closure and small sample size. We confirmed the significantly lower risk of recurrence in post-op ctDNA-negative patients compared to ctDNA-positive patients, as well as the differential pattern of relapse where lung metastases predominate in ctDNA-negative patients, while liver metastases were the dominant side of relapse in ctDNA-positive patients,” said Dr. Tie, who is a medical oncologist at the Peter MacCallum Cancer Centre, Victoria, Australia.