Circulating tumor DNA (ctDNA) has proven itself as a prognostic tool, but questions remain as to whether it can be used to guide the use of adjuvant chemotherapy in patients with colorectal cancer (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% vs 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 vs 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.
GALAXY Study Results Updated
In an afternoon session, Hiroki Yukami, MD, PhD, presented updated results of the GALAXY study, which examined 2998 patients with stage I-IV colorectal cancer who underwent ctDNA surveillance over a median 16.14 months following surgery. ctDNA-positive status was associated with worse DFS (HR, 10.53; P < .0001) in all stages as well as in stage II/III (HR, 12.05; P < .0001). The researchers also distinguished between patients with sustained ctDNA clearance and those with transient ctDNA clearance, in which a positive test occurred after an initial negative result. Recurrences occurred in 7.1% of patients with sustained ctDNA clearance versus 85.2% of patients with transient clearance (P < .0001) and 89.4% of those with no clearance (P < .0001). "Sustained clearance indicates superior DFS compared to transient or no clearance," said Dr Yukami during his presentation.
Of 117 patients treated with adjuvant chemotherapy after testing ctDNA positive, subsequent ctDNA clearance was associated with better DFS (HR, 6.72; P < .0001). There were also better DFS outcomes among patients who saw a greater decline in ctDNA plasma levels after adjuvant chemotherapy (0%-50% versus 50%-100% reduction; HR, 2.41; P = .001).
Aparna Raj Parikh, MD, assistant professor of medicine at Harvard Medical School, served as a discussant for the GALAXY study. She acknowledged that ctDNA is the most powerful prognostic marker in oncology, but to be clinically useful it is necessary to consider its utility at the landmark time point, which is when decisions are made whether to treat with adjuvant chemotherapy. At that time point, the sensitivity of ctDNA is about 48% in the GALAXY study, which Dr Parikh said is consistent with other data.
ctDNA 'Not Sensitive Enough'
"We know that postoperative ctDNA is only capturing 40%-50% of patients with recurrences in non–stage IV patients in multiple datasets to date. I think it's really important to keep in mind the sensitivity of the different time points when you're actually thinking about how to use this in clinic. The first generation of tests are certainly promising, but I would make the argument that these are just not sensitive enough," said Dr Parikh.
"Landmark testing is not yet sensitive enough to deescalate care in a patient where chemotherapy would otherwise be indicated, and surveillance testing has not yet demonstrated clinical utility. I think our goal to actually deescalate care would be to try to lower the ctDNA-negative population recurrence risk to akin to stage I patients, with that 5-year DFS of 93%-95%," Dr Parikh said.
Dr Parikh offered some advice on how to use ctDNA outside of a clinical trial setting. She said that positive ctDNA results can help drive the decision to initiate adjuvant chemotherapy in concert with clinical and other factors.
"I'm pretty convinced by the data that ctDNA is prognostic, and though we still need outcomes data, in particular scenarios where I'm thinking of not giving chemotherapy, a positive test may sway me in that direction," she said. She gave examples such as patients with a single high-risk feature or a stage III patient with marginal performance status or an elderly patient with low-risk stage III disease.
Dr Kasi has financial relationships with Precision Biosensors, Elicio Therapeutics, Bayer, BostonGene, Daiichi Sankyo/AstraZeneca, Delcath Systems, Eisai, Elicio Therapeutics, Exact Sciences, Foundation Medicine, Guardant Health, Illumina, Ipsen, Lilly, MSD Oncology, Natera, NeoGenomics, QED Therapeutics, SAGA Diagnostics, Seagen, SERVIER, Taiho Oncology, Taiho Pharmaceutical, Advanced Accelerator Applications, Boston Scientific, and Tersera. Dr Tie, Dr Kim, Dr Ellison, and Dr Yukami did not disclose conflicts of interest. Dr Parikh has financial relationships with Abbvie, Bayer, Biofidelity, CheckMate Pharmaceuticals, CVS, Delcath Systems, Foundation Medicine, Guardant Health, Illumina, Lily, SAGA Diagnostics, Scarce, Seagen, Taiho Oncology, Takeda, UpToDate, and Value Analytics Labs.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.