A “liquid biopsy” that detects circulating tumor DNA (ctDNA) after surgery for stage 2 colon cancer helps identify patients who are most likely to benefit from adjuvant chemotherapy, and also identifies those who are unlikely to benefit allowing them to skip that treatment.
The results are from the phase 2 DYNAMIC trial.
“The strategy of using ctDNA results to inform treatment almost halved the number of patients who received chemotherapy postsurgery, from 28% down to 15%,” commented first author Jeanne Tie, MD, from the Walter and Eliza Hall Institute of Medical Research at the Peter MacCallum Cancer Centre, University of Melbourne, Australia.
The overall proportion of patients who were alive and cancer-free at 3 years after ctDNA-guided treatment was 92% — the same as in patients randomized to standard management, she added.
The chance of being alive and cancer-free was 86.4% and 92.5%, respectively, in ctDNA-positive patients who received adjuvant chemotherapy and in ctDNA-negative patients who did not, she said. Conversely, the risk of recurrence is greater than 80% without treatment in ctDNA-positive patients, said Tie.
Tie reported the results here at the American Society of Clinical Oncology 2022 annual meeting, which were simultaneously published in the New England Journal of Medicine.
The study support a ctDNA-guided approach to treatment in this patient population, Tie said, noting that this approach addresses what has been a clinical dilemma: surgery can cure more than 80% of stage 2 patients, but the benefits of chemotherapy after surgery have been less clear — fewer than 1 in 20 patients will benefit, but the ability to predict which patients will benefit has been lacking.
The findings are practice-changing, commented Julie Gralow, MD, ASCO’s chief medical officer and executive vice president.
“I see this study as an important kind of new concept in cancers, where for the most part we have really very good survival and outcomes…and now we’re starting to look at ways we can deescalate therapy in a subgroup who we know are going to do well while continuing the more intensive therapy, or even escalating therapy, in the group who we know are not going to do well with our conventional therapies,” Gralow said at a press briefing where the study was highlighted.
“I do believe the results are going to help us guide our selection of who benefits from chemo and who can avoid it — and all the toxicities of it — in stage 2 colon cancer,” she added.
They may also identify patients who may need more than standard treatment. This is a group in which “we might need to think outside the box and do even more besides just thinking about adjuvant chemo,” she told Medscape Medical News in a preconference interview. “Maybe this is a group we should be thinking about adjuvant immunotherapy, for example, or adjuvant EGFR-targeted therapy, or other things that we have shown [to have benefit] in the metastatic setting.”
For the DYNAMIC trial, Tie and colleagues enrolled 455 patients with resected stage 2 colon cancer at multiple centers between August 2015 and August 2019. Of those, 302 were randomized to receive ctDNA-guided chemotherapy and 153 received standard management based on conventional criteria, including tumor stage of disease, number of lymph nodes assessed, whether the tumor had perforated the bowel wall, and other factors.
The Safe-SeqS tumor-informed personalized ctDNA assay was used to detect ctDNA in the experimental group. Patients with a ctDNA-positive result at 4 or 7 weeks after surgery received oxaliplatin-based or fluoropyrimidine chemotherapy; those who were ctDNA-negative were observed during follow-up.
Fewer patients overall in the ctDNA-guided group, compared with the standard management group, received adjuvant chemotherapy (15.3% vs 27.9%; odds ratio, 2.14).
Two-year recurrence-free survival (RFS) in the ctDNA-guided treatment group was noninferior to that in the standard management group (93.5% vs 92.4%). Three-year RFS was 86.4% in ctDNA-positive patients who received chemotherapy, 92.5% in ctDNA-negative patients without chemotherapy, and 96.7% in a clinical low-risk subgroup.
ASCO expert Cathy Eng, MD, applauded the findings, stating in a press release that “thanks to the results of this study, we may now be able to use it to better identify which patient with stage 2 colon cancer would benefit from post-surgery treatment with chemotherapy and which ones can be spared the additional treatment, without compromising relapse-free survival.”
Eng is the David H. Johnson Chair in Surgical and Medical Oncology, co-leader of the Gastrointestinal Cancer Research Program, co-director of GI oncology, and professor of medicine in hematology and oncology at Vanderbilt University, Nashville, Tennessee.
The authors note that a randomized trial is being considered in which ctDNA-positive and -negative patients would be randomized to treatment versus no treatment. This could provide more definitive evidence of treatment impact, or lack of impact, in each of the patient subsets, according to the press release.
Given the novelty of the approach used in this study, and the potential clinical implications of the results, “the authors must be congratulated,” Clara Montagut, MD, PhD, and Joana Vidal, MD, write in an accompanying editorial in the New England Journal of Medicine.
The DYNAMIC trial addresses the important issue of the role of minimal residual disease, detected as ctDNA, in “increasing the precision of adjuvant treatment of solid cancers,” explain Montagut and Vidal, both from Hospital del Mar, Institut Hospital del Mar d’Investigacions Modius, Centro de Investigación Biomedicals en Red Cáncer, Barcelona.
The trial also raises important questions, including whether select patients with high-risk pathological factors and ctDNA-negative disease might benefit from chemotherapy, whether chemotherapy prevents or just delays relapse, and which subgroup of ctDNA-positive patients might really benefit from chemotherapy and which chemotherapy scheme should be used.
“Further studies integrating assessments of minimal residual disease with standard factors or new biologic markers may help to further increase precision in this context,” they write. There are several ongoing trials similar to the DYNAMIC trial “that are assessing the escalation of chemotherapy in ctDNA-positive patients or the deescalation of chemotherapy in ctDNA-negative patients with stage 2 disease,” they note. The results from these trials are “eagerly awaited and could provide additional validation of the ctDNA-guided strategy to individualize adjuvant chemotherapy in the treatment of colon cancer.”
The DYNAMIC trial was funded by the Australian National Health and Medical Research Council, US National Institutes of Health, the Marcus Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation, the Conrad R. Hilton Foundation, the Sol Goldman Charitable Trust, John Templeton Foundation, and Eastern Health Research Foundation. Tie has reported receiving honoraria from Inivata and Servier, and serving as a consultant or advisor for AstraZeneca/MedImmune, Bristol-Myers Squibb, Haystack Oncology, Inivata, MSD Oncology, and Pierre Fabre.
ASCO 2022. Abstract LBA100. Presented June 4, 2022.
N Engl J Med. Published online June 4, 2022. Full text
Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, who writes for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at firstname.lastname@example.org or on Twitter: @SW_MedReporter.
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