NEW YORK – A recently published study has added new data to a growing body of evidence that minimal residual disease testing after initial colorectal cancer surgery is a strong and independent source of prognostic information.
With long-term clinical follow-up data and a large cohort, the results from the CIRCULATE-Japan trial also strengthen the rationale for physicians to consider using MRD — in this case Natera's Signatera assays — to inform decisions on which patients need adjuvant chemotherapy and which may be better off forgoing it.
Natera Chief Medical Officer Alexey Aleshin said that this accumulating evidence offers a new opportunity to fundamentally shift how early-stage colorectal cancers are staged. If defining tumors based on their MRD status offers better prediction of outcome than classifying them by clinical features, terms like stage II or III or IV become less useful in deciding how a patient should be treated.
Published last week in Nature Medicine, the study assessed 1,039 patients in the GALAXY arm of CIRCULATE-Japan, one of the largest and most comprehensive prospective studies of MRD testing in resectable colorectal cancer.
Investigators had shared an earlier readout at prior scientific meetings, but the publication extends the study's median clinical follow-up significantly, to 16.74 months on average.
In a multivariate analysis including all current clinicopathological risk factors, the researchers found that post-surgical MRD status was the most significant prognostic marker.
Signatera's prognostic value has stood out in prior studies. Less clear has been whether that prognostic power translates to specific prediction of chemotherapy benefit.
The CIRCULATE-Japan investigators analyzed chemotherapy benefit directly, assessing disease-free survival in both MRD-positive and MRD-negative patients and comparing patients treated with chemo or spared it.
Overall, the authors reported that post-surgical MRD status was predictive of chemotherapy benefit. Patients who were MRD-positive at four weeks after surgery (18 percent of the cohort) derived significant benefit from adjuvant chemotherapy.
MRD-negative patients (82 percent of the trial population) did not see significant benefit from chemo.
"Until now, oncologists did not have adequate tools to determine which colorectal cancer patients are likely to benefit from adjuvant systemic therapy," the study's principal investigator Takayuki Yoshino, an oncologist at Japan's National Cancer Center Hospital East, said in a statement.
"This study provides strong evidence that Signatera MRD-positive patients will benefit significantly from adjuvant therapy, while MRD-negative patients may be safely observed, regardless of clinical or pathological stage," he added.
According to Aleshin, the takeaway for clinicians right now is clearer for MRD-positive patients than for MRD-negative.
"In every subgroup analyzed, even when adjusting for known confounding factors like age and performance status, patients who were positive and were treated with adjuvant chemotherapy had a markedly improved outcome … with the risk of long-term disease-free survival being improved by around 6.59 times for patients who received adjuvant chemotherapy versus not," he said.
Although recommendations suggest that clinically high-risk patients be offered adjuvant chemotherapy, results from CIRCULATE and other studies have made a strong case that not all risk is being captured by current staging methods. A stage II patient, whose physician might otherwise recommend against chemo, could be MRD positive, with a strong likelihood that the treatment would benefit them.
As such, Aleshin said it seems clear that implementation of MRD in this manner, to escalate more patients to chemo, could have a meaningful impact on patient outcomes.
"Currently, for lower-risk stage II disease, many patients are not getting adjuvant chemotherapy per the practice guidelines. Yet in studies like [this] we've seen that the rates of MRD for stage II disease are in the order of double digits — 10-plus percent," Aleshin said.
Regardless of stage, many patients are also undertreated because they have comorbidities or they may not want to receive chemotherapy. "Having that information that someone is ctDNA-positive and at an extremely high risk of recurrence may allow the treating physician to better tailor treatment to that individual when that decision might have been more difficult before," he added.
Natera hopes that data from the new study may tip the scales in favor of new guidelines officially recommending MRD testing in surgically treated colon cancer.
Aleshin said that Japan has already updated its CRC guidelines to recommend MRD testing post-surgery, but the field is still waiting for a planned update to the National Comprehensive Cancer Center's US recommendations. It's unclear what that update will be, and the current study was published after the guidelines body had its latest meeting so it likely wouldn't be part of the data considered.
Meanwhile, much of the excitement around MRD tests like Signatera has been related to their potential to do the opposite — de-escalate treatment in patients who are MRD-negative but who would have likely been recommended adjuvant chemo based on their stage and clinical presentation.
For escalating treatment, Aleshin said the current data, while not from a randomized trial, holds a lot of persuasive power. Considering the evidence — the magnitude of benefit MRD-positive patients gained from chemotherapy in the CIRCULATE trial — doctors might even deem a randomized trial unethical, or at least hesitate to enroll patients lest they end up in a control arm.
But because of the fear of undertreating patients, MRD-based de-escalation is likely to require randomized data for the clinic to embrace it.
Aleshin said that the current Japan trial has a randomized protocol, called Vega, that is assessing the definitive question of whether MRD-negative patients can, regardless of stage, forgo chemotherapy completely.
He said that arm is recruiting "really well," and the hope is that it will readout in the next 18 to 24 months.
Meanwhile, the similar CIRCULATE-US trial is now open, with "many, many sites already actively accruing," Aleshin added. Investigators are also discussing the possibility of combining data from both trials to more definitively answer the question of MRD actionability.
Aleshin also highlighted that the Japan study echoed prior findings that dynamic changes in MRD status match closely with patients' evolving treatment response. MRD-positive individuals in the trial who were treated with chemo and cleared their ctDNA at a subsequent testing time point had superior disease-free survival compared to those who had lingering ctDNA.
Beyond the single post-surgery MRD testing time point, which is where MRD's prognostic power lies, Aleshin said that Natera is also focused heavily on opportunities for intervention based on longer-term ctDNA monitoring.
Early data with pharma partners has suggested that there could be an opportunity to treat patients on molecular recurrence, something Aleshin said could change the landscape of early cancer treatment, if proved successful. In anticipation of that future, Natera executives recently shared that the company is working to bring the Signatera platform through US Food and Drug Administration review, creating a clear pathway to companion diagnostic labeling if and when drugs are approved in this setting.