Circulating tumor DNA (ctDNA) has demonstrated by itself as a prognostic software, but thoughts remain as to whether or not it can be utilised to tutorial the use of adjuvant chemotherapy in clients with colorectal cancer (CRC). A great deal of the uncertainty surrounds the sensitivity of ctDNA at the time when selections pertaining to adjuvant treatment are being made.
All those were some of the key details designed all through a collection of shows 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, future observational BESPOKE CRC examine, which bundled 689 people with phase II or III colorectal cancer. The demo was designed to ascertain what outcome ctDNA benefits would have on adjuvant chemotherapy therapy conclusions. In excess of a median follow-up of 24.8 months, 623 clients had ctDNA outcomes obtainable. ctDNA positivity was connected with even worse 2-year sickness-free survival (DFS) at 29.86% vs 91.59% in the stage II/III mixed team (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 Fears
Dr Kasi observed the worth of taking into consideration the patient’s watch of ctDNA. There could be some problems that these types of checks could lead to client anxiety, but he referenced a poster at ASCO GI which instructed the reverse. “It basically decreased anxiety, and 90% of the sufferers felt self-confident in the remedy they had been obtaining. They [said that] they will continue making use of the assay, and they benefit the more info,” explained Dr Kasi, who is a health care oncologist at Weill Cornell Drugs in New York City.
In the course of the Q&A just after the converse, David Ellison, MD, a health care oncology and hematology specialist at Memorial Sloan Kettering Cancer Middle, also in New York requested Dr Kasi: “Did this [positive ctDNA] examination just prompt before imaging? Was it any superior than conventional surveillance like CEA [carcinoembryonic antigen] or imaging?” he requested.
Dr Kasi responded that the details showed ctDNA positivity 6-9 months before than most cancers detection by classic imaging.
“It doesn’t always exchange the ongoing surveillance. This certain examine did not guidebook or make it as a protocol as to what to do. All the things was performed as element of common of treatment, the normal surveillance that the most cancers centre follows, he explained. “I think [ctDNA] would help enhance the ongoing treatment and in conjunction with any person who has, for illustration, an indeterminant lung nodule but also has ctDNA positivity I assume it adds confidence to the decisions that just one could be creating.”
Eujung Kim, MD, PhD, an instructor of medication at Harvard Clinical Faculty, Boston, Massachusetts, puzzled if there could be chemoresistant tumor cells remaining that are not shedding DNA. “You have to retain the biology in mind as properly make decisions in conjunction with the medical problem, as opposed to in isolation with ctDNA benefits,” Dr Kasi responded.
In the same session, Jeannie Tie, MD, explained final results from the AGITG DYNAMIC-Rectal demo, which was a randomized review to decide if ctDNA could notify adjuvant chemotherapy conclusions in locally advanced rectal most cancers. The evaluation provided 230 sufferers who had been randomized to ctDNA-informed management (n = 155), with a beneficial examination primary to adjuvant chemotherapy, or a standard arm exactly where adjuvant treatment selections ended up still left to the physician (n = 75).
Adjuvant chemotherapy use was higher in the manage 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 unique time details when you’re in fact thinking about how to use this in clinic. The 1st technology of tests are certainly promising, but I would make the argument that these are just not sensitive plenty of,” mentioned Dr Parikh.
“Landmark testing is not however delicate sufficient to deescalate treatment in a affected person wherever chemotherapy would in any other case be indicated, and surveillance screening has not still shown clinical utility. I believe our objective to really deescalate treatment would be to check out to decrease the ctDNA-unfavorable inhabitants recurrence chance to akin to phase I people, with that 5-yr DFS of 93%-95%,” Dr Parikh claimed.
Dr Parikh supplied some tips on how to use ctDNA outside of a clinical demo environment. She said that positive ctDNA success can assistance push the conclusion to initiate adjuvant chemotherapy in live performance with scientific and other factors.
“I am very confident by the details that ctDNA is prognostic, and while we still will need outcomes facts, in specific scenarios wherever I am thinking of not providing chemotherapy, a favourable take a look at might sway me in that direction,” she claimed. She gave examples such as individuals with a solitary large-chance aspect or a phase III client with marginal functionality position or an aged affected individual with minimal-danger phase III disease.
Dr Kasi has money relationships with Precision Biosensors, Elicio Therapeutics, Bayer, BostonGene, Daiichi Sankyo/AstraZeneca, Delcath Devices, Eisai, Elicio Therapeutics, Specific Sciences, Foundation Medication, Guardant Health and fitness, Illumina, Ipsen, Lilly, MSD Oncology, Natera, NeoGenomics, QED Therapeutics, SAGA Diagnostics, Seagen, SERVIER, Taiho Oncology, Taiho Pharmaceutical, Superior Accelerator Applications, Boston Scientific, and Tersera. Dr Tie, Dr Kim, Dr Ellison, and Dr Yukami did not disclose conflicts of desire. Dr Parikh has economic associations with Abbvie, Bayer, Biofidelity, CheckMate Prescribed drugs, CVS, Delcath Methods, Foundation Drugs, Guardant Wellbeing, Illumina, Lily, SAGA Diagnostics, Scarce, Seagen, Taiho Oncology, Takeda, UpToDate, and Worth Analytics Labs.
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