N Engl J Med 2022 Jun 04
Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer.
Abstract
Background
The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.
Methods
We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.
Results
Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not.
Conclusions
A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).
Related Questions
Why does NCCN still not recommend using circulating tumor DNA to guide adjuvant chemotherapy in stage II colon cancer when colon cancer experts are currently embracing the practice?
While I cannot speak to that panel itself, I can support the very rigorous process that all NCCN guidelines undergo, and I surmise that the reason why ctDNA is not yet recommended is because there is no consensus that: It is better than CEA and good quality cross-sectional imaging (see, for example,...
Are there any adverse risk factors in stage I colon cancer that would warrant ctDNA testing?
I would not check ctDNA in this setting. If there is an adverse feature of the tumor and the patient is a candidate for further treatment, I would do close surveillance imaging and CEA at the most. A recent publication of a larger cohort study of stage II to IV resected colorectal cancer suggests th...
How would you approach a stage II colon cancer with negative ctDNA but markedly elevated CEA level post-colectomy?
Thanks for the question. Highly complicated case. Few things matter here. First, what platform is used for ctDNA testing (whether tumor informed or not), and second whether this is T4 or T3 disease. It would be unusual to have high CEA but negative ctDNA in a true minimal residual disease (MRD). For...
Would you give adjuvant chemo for a mucinous stage II adenocarcinoma of the colon in the lack of other high-risk clinical pathological features?
The mucinous feature is reported to be a poor prognostic feature in colorectal cancer based on some retrospective series (e.g., Symonds and Vickery, PMID 177180, Green et al., PMID 8380140, Catalano et al., PMID 21531784, and Ott et al., PMID 29870979). However, there are some other studies suggesti...
Would you offer adjuvant chemotherapy in a patient with MSS colon cancer who only has residual mucin left, without viable cancer cells despite no pre-operative chemotherapy, in the colon and lymph nodes?
This is a very specific question, and I would simplify the question to whether we should determine adjuvant chemotherapy based on the mucin seen in the lymph node for resected colon cancer. It would be very unusual that there is mucin without viable cancer cells in the colon cancer surgical specimen...
For patients with resected colon cancer, to what extent would you adapt adjuvant chemotherapy if ctDNA results don't correspond with your initial treatment recommendation?
Data in this field is evolving quickly. We will have more answers in the upcoming months as BESPOKE, SU2C MGH, more follow-up on PEGASUS presented at ESMO a few weeks ago, as well as CIRCULATE-JAPAN and CIRCULATE-US accrue and read out.Till that, the strongest evidence would be from what happened to...
Would you offer adjuvant chemotherapy or radiation to a resected MSS T3N0 high-rectal lesion with low anterior resection without pre-op therapy?
For patients with T3N0 upper rectal cancer with no significant risk factors (R0, CRM clear, no EMVI) who undergo high quality TME surgery as suggested by an intact TME pathologic specimen, the 5-year risk of pelvic recurrence without the delivery of adjuvant radiotherapy is < 5%. I do not recommend ...
If an average-risk, physically fit, resected stage II colon cancer patient has a positive signatera result (3.2 MTM/ml), would you recommend adjuvant chemotherapy?
A Positive Tumor-informed assay like signatera is not just a prognostic or predictive marker, but more so signifies PERSISTENCE of disease. A stage-2 average risk is not average risk anymore once you have a positive ctDNA result. Maybe in the future, the TNM would be revised to say TNM-MRD (Stage-2 ...
How would positive ctDNA results after 12 cycles of adjuvant FOLFOX affect your management for patients with colon cancer?
I think the question should be, should you be testing ctDNA post adjuvant therapy? I do not want to order a test and then not know what to do with a positive result. I can imagine that this would cause fear and panic in certain patients.
What are your top takeaways in GI Cancers from ASCO 2022?
1. DYNAMIC study: I believe circulating tumor DNA (ctDNA) will dramatically improve personalized medicine for cancer patients. This study confirmed that ctDNA-based adjuvant chemo treatment significantly decreases the patients who need/are recommended for adjuvant treatment (50% reduction) without c...