Circulating tumor DNA-guided approach safely reduces chemotherapy use in colon cancer
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CHICAGO — Circulating tumor DNA analysis safely reduced adjuvant chemotherapy use without compromising recurrence-free survival among patients with stage II colon cancer, according to results of the randomized phase 2 DYNAMIC trial.
The findings, presented during ASCO Annual Meeting and published simultaneously in The New England Journal of Medicine, showed patients with circulating tumor DNA (ctDNA)-negative disease had a lower likelihood of benefit from chemotherapy, whereas ctDNA-positive patients experienced a survival benefit from adjuvant chemotherapy.
Rationale and methods
“Most patients with stage II colon cancer are cured by their surgery to remove the cancer from the bowel, but around 20% will develop a recurrence in following years,” Jeanne Tie, MD, MBChB, FRACP, lower gastrointestinal medical oncology and trials lead at Peter MacCallum Cancer Centre in Australia, told Healio. “Treating all stage II patients with chemotherapy will reduce the risk for recurrence by about 15%, but this means that 20 patients need to be treated to benefit one patient.”
The goal of adjuvant chemotherapy is to eradicate micrometastases, she added.
“The challenge has been that these microscopic deposits of cancer cells are miniscule and are not seen at surgery or visible on radiologic images,” Tie said. “A ctDNA analysis can detect tiny amounts of DNA released by these invisible cells into the bloodstream, enabling us to identify which patients have micrometastases and, therefore, should be offered chemotherapy. Conversely when the blood test does not reveal ctDNA, the likelihood of micrometastases is very low and chemotherapy can be avoided without compromising the risk for recurrence.”
Investigators sought to assess whether ctDNA-guided treatment could reduce adjuvant chemotherapy use without compromising recurrence risk among 455 patients with resected stage II colon cancer. They randomly assigned patients to either a ctDNA-guided treatment (n = 302) or physician-guided treatment (n = 153).
Noninferiority in RFS rate at 2 years served as the primary endpoint, with adjuvant chemotherapy use as the secondary endpoint.
Median follow-up was 37 months.
Key findings
Overall, 15.3% of patients assigned to ctDNA-guided treatment received adjuvant chemotherapy compared with 27.9% of those assigned physician-guided treatment (OR = 2.14; P = .002). Researchers noted the greatest difference among patients with T4 (OR = 6.22) or poorly differentiated tumors (OR = 6.31).
Among those who received adjuvant chemotherapy, oxaliplatin-based doublet was used more frequently than fluoropyrimidine alone among those in the ctDNA-guided treatment group compared with those assigned physician-guided treatment (62.2% vs. 9.8%; P < .001).
Researchers additionally found ctDNA-guided treatment noninferior to standard management for 2-year RFS (93.5% vs. 92.4%), an absolute difference of 1.1 percentage points (95% CI, -4.1 to 6.2). They reported 3-year RFS rates of 86.4% after adjuvant chemotherapy use among ctDNA-positive patients and, among ctDNA-negative patients, 92.5% without adjuvant chemotherapy and 96.7% in a subgroup of patients with low clinical risk.
“We showed that ctDNA testing can differentiate patients with stage II colon cancer who need chemotherapy after surgery from those who have a very low risk for recurrence and can safely avoid treatment,” Tie said. “Importantly, the use of chemotherapy is substantially reduced with the use of this ctDNA-informed approach without impacting risk for recurrence.”
Looking ahead
“The ctDNA test has the potential to revolutionize the approach to chemotherapy in patients with colon cancer — preventing unnecessary chemotherapy treatment in the majority — and will accelerate the development of promising new treatment options,” Tie said. “We are currently running trials in stage III colon cancer and other cancer types, such as pancreatic cancer and ovarian cancer.”
Several recommendations arise from this trial that may be useful when considering potential clinical implementation, Clara Montagut, MD, PhD, head of the gastrointestinal cancer unit, and medical oncologist Joana Vidal, MD, both at Hospital del Mar in Barcelona, Spain, wrote in an editorial accompanying the published study in The New England Journal of Medicine.
“The trial used a ctDNA assay specifically designed for applications related to minimal residual disease with very high sensitivity, as well as serial blood samples for ctDNA analysis to decrease the risk for a false-negative result,” they wrote. “From a logistic point of view, rapid processing and a short turnaround time for ctDNA results are crucial to avoid delays in the initiation of adjuvant chemotherapy. The present trial used a tissue-based strategy in which ctDNA probes were personalized on the basis of specific mutations identified in tumor tissue. Although this strategy confers high sensitivity, tissue-agnostic strategies might also be valid while reducing the time to obtain results.”
Further advances in the technology will undoubtedly improve the performance of ctDNA testing for minimal residual disease, including the incorporation of tumor-specific methylation profiles, they added.
References:
Montagut C and Vidal J. N Eng J Med. 2022;doi:10.1056/NEJMe2204625.
Tie J, et al. Abstract LBA100. Presented at: ASCO Annual Meeting; June 3-7, 2022;
Chicago.Tie J, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2200075.
For more information:
Jeanne Tie, MD, MBChB, FRACP, can be reached at tie.j@wehi.edu.au.
Perspective
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Julie R. Gralow, MD, FACP, FASCO
This is an important and novel concept where we have very good survival and outcomes. We are now starting to look for ways to de-escalate therapy in a subgroup that we know will do well while continuing the more intensive therapy or even escalating therapy in the group we know will not do well with our conventional therapies.
These researchers were able to show that we could administer less chemotherapy but, using liquid biopsy, we could identify a group who would not benefit from chemotherapy and still have the same excellent outcomes. The other end of this is those who had the positive ctDNA for whom we still need to do better.
These results will help us guide our selection of those who will benefit from chemotherapy, who will be able to avoid it and all the toxicities associated with treatment.
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Tie J, et al. Abstract LBA100. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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