Assessments of circulating tumor DNA (ctDNA) can detect minimal residual disease (MRD) and help stratify colorectal cancer (CRC) patients into high and low risk of recurrence after resection, and it may also guide adjuvant chemotherapy.
Timely detection of recurrence and identification of CRC patients at high risk of recurrence after surgery and after completion of adjuvant therapy remain major challenges. From 20 percent to 30 percent of these patients relapse.
"If we could identify MRD, we could enable a better recurrent risk assessment. Earlier detection of recurrence could increase the proportion of patients that we treat with curative intent after the recurrence, thereby hopefully improving the survival of this entire patient group. We believe that ctDNA is a promising marker for MRD detection," said Tenna V. Henriksen, a PhD candidate at Aarhus University in Denmark, at the 2021 ASCO Gastrointestinal Cancers Symposium (Abstract 11).
Identifying High Risk
In a prospective, multicenter study, researchers set out to determine whether serial postsurgical ctDNA analysis could identify the patients at high risk of recurrence, provide an assessment of adjuvant therapy efficacy, and detect relapse earlier than standard-of-care radiological imaging. The study included 265 stage I-III CRC patients, the largest cohort assessed for ctDNA to date, Henriksen noted. All patients had the tumor resected and a subset of 166 patients was additionally treated with adjuvant chemotherapy.
The patients were recruited from surgical centers in Denmark and Spain. Blood samples were collected before and directly after surgery, and in some patients every 3 months after surgery for up to 3 years. These patients were also monitored by CT scans at 12 and 36 months after surgery. "The CT scans form the clinical basis for which we compared our ctDNA data from blood samples," said Henriksen.
Examining blood samples that were drawn within 2 months after surgery and before the start of neoadjuvant chemotherapy, the researchers were able to stratify patients into high and low risk of recurrence.
"When we look at the current rates, we can also see that there is a very low recurrence rate amongst the ctDNA-negative patients compared to the higher recurrence rate in the ctDNA-positive patients," explained Henriksen.
Not all ctDNA-positive patients experienced disease recurrence. "In fact, the four patients who did not experience disease recurrence but were ctDNA-positive all received adjuvant chemotherapy," she said. "This indicates that the outcome here was modified by the adjuvant chemotherapy, and that perhaps these patients were cured for any type of residual disease that was left after the surgery by adjuvant chemotherapy. Hopefully this could indicate that there is a benefit for ctDNA-positive patients in some cases to receive adjuvant chemotherapy."
The researchers also looked into stratifying patients into high and low risk of recurrence at the end of treatment. "Again, we can see a very good stratification into high and low risk of recurrence, and low recurrence rates in the ctDNA-negative patients versus the ctDNA-positive patients with even higher recurrence rates that we saw before," stated Henriksen.
"If we include longitudinal samples drawn every 3 months after surgery, we can shift a portion of the ctDNA-negative patients to being ctDNA-positive at a later time point, simply by including more sampling. We saw the recurrence rates in the ctDNA-negative patients drop to about 3 percent, which is very low. This indicates that serial sampling has a benefit over just single time-point sampling."
They also found that ctDNA had a median lead time of about 8 months compared to clinical CT scans. In addition, a multivariable analysis showed that ctDNA was a stronger biomarker compared to an already established biomarker, carcinoembryonic antigen (CEA), at least in terms of relapse-free survival.
Detecting Recurrences Earlier
In conclusion, Henriksen said: "We saw the patients with ctDNA detected immediately after surgery had a very high risk of recurrence. Also, we could see that longitudinal monitoring increased the predictive power of ctDNA and that we had a lead time of 8 months before radiological detection of recurrence using ctDNA. And finally, we could see that longitudinal testing with ctDNA outperformed CEA in recurrence-free survival prediction."
Before ctDNA is implemented in clinics, it needs to be tested in randomized trials. She noted that two Danish trials of ctDNA-guided clinical management have begun, IMPROVE-IT and IMPROVE-IT 2. Henrisksen suggested that patients could be stratified according to ctDNA-ctDNA-positive patients would receive adjuvant treatment, but ctDNA-negative patients would not.
"Currently, all stage III patients receive adjuvant chemotherapy, but it's estimated that 60 percent of them were cured by surgery alone. These patients were in a sense overtreated with adjuvant chemotherapy. If you stratified them according to their real risk with ctDNA in mind, maybe you could spare some patients the toxic side effects of adjuvant chemotherapy," she noted.
She also suggested that using ctDNA could improve radiological surveillance. "Currently, we scan patients at 12 and 36 months-according to the Danish guidelines, at least-and only 20 percent of detected recurrences are offered curative intent treatment. If you switch to a ctDNA-based system, sampling ctDNA maybe every 3 months, and if they become ctDNA-positive you switch them over to an intensified radiological surveillance, [then] we could detect recurrences sooner because we have the lead time of ctDNA of around 8 months and thereby shift a larger proportion of patients into receiving curative intent treatment," Henriksen concluded.
Mark L. Fuerst is a contributing writer.