Assessing the Full Potential of ctDNA in Colorectal Cancer

Gregory P. Botta, MD, PhD: The CIRCULATE-US study is basically an NRG Oncology NCI [National Cancer Institute]-developed protocol that has been FDA approved for the Signatera assay. It’ll be enrolling in the first half of this year. The study is going to enroll approximately 2000 patients with stage II or III colon cancer after resection. Similar to the CIRCULATE-Japan study, it’s going to follow them over time to determine if their ctDNA [circulating tumor DNA] remains negative after surgery or adjuvant therapy or whether it initiates to a positive study.

At the end of the day, the endpoints in these are molecular residual disease–negative patients and whether initiating therapy immediately vs later changes their outcomes. Meaning that after your surgery, your adjuvant therapy isn’t initially given if your ctDNA is negative. However, if it turns positive, then adjuvant therapy is given. The other is that the patients who are postsurgical who have molecular residual disease positivity are either going to be given standard of care CAPOX [capecitabine, oxaliplatin] or FOLFOX [fluorouracil, leucovorin, oxaliplatin] regimens, or an intensified adjuvant chemotherapy regimen. That’s very similar to the CIRCULATE-Japan study.

Ultimately, the big question is going to be whether the results of these studies can be combined so that we have an enlarged or enriched patient population. However, the CIRCULATE-US trial will be following in the footsteps of the CIRCULATE-Japan trial. Considering how quickly the CIRCULATE-Japan trial has enrolled and how many patients are now involved, we’d expect to see a similarly enrolled patient population in the US, and I’d expect us to be able to have very comprehensive and sensitive data with those numbers of patients.

Other very intriguing studies for the use of ctDNA are the neoadjuvant studies in which we’re determining whether a patient should go to surgery. I’m thinking about rectal cancer in particular. When we’re evaluating rectal cancer, the overwhelming standard of care leans toward total neoadjuvant therapy [TNT], in which we’re using both a chemotherapy-based regimen as well as chemoradiation. Ultimately, at the end of TNT, the idea is to move to surgical resection. However, we know that some patients have curative, complete responses, seen both radiographically as well as on flexible sigmoidoscopy. In those cases, patients are being initiated on watch-and-wait protocols in which they’re not moving forward with surgery.

That’s a big deal in the rectal world. Surgical resection of rectal cancer can lead to colostomies and sometimes permanent colostomies. We also know that (patients diagnosed with) rectal and colorectal cancer are becoming increasingly younger. It makes a significant deal for a patient in their 30s and 40s to move forward with resection of their rectal cancer and have a colostomy for the rest of their life. As such, we’re looking for tools to help us better understand the watch-and-wait protocol.

This is where ctDNA would come into play. If a patient is able to get to MRI negativity on their radiographic response after TNT and they’re able to have a flexible sigmoidoscopy that shows that there’s no disease burden, and then they have a ctDNA that shows no molecular residual disease, can we feel more confident in moving to a watch-and-wait approach? Can that ctDNA help guide that watch-and-wait approach? Can we reduce the number of MRIs that we’re getting in a year? Can we reduce the number of flexible sigmoidoscopies that we’re getting in a year? Can we show that these patients who get to ctDNA negativity should avoid surgery? Should patients who don’t get to ctDNA negativity go to surgery to help their outcomes? There are very exciting data that are going to be coming out.

Transcript edited for clarity.