Future Role of ctDNA in Pancreatic Cancer

Gregory P. Botta, MD, PhD: Cancer Research UK is evaluating the PRIMA studies. The PRIMA studies are precision pancreatic clinical studies that are evaluating biomarkers to tell if patients will do better on either a FOLFOX [leucovorin calcium (folinic acid), fluorouracil, oxaliplatin] or oxaliplatin-based treatment regimen or an Abraxane/gemcitabine–based regimen that’s based off of a patient’s homologous recombination deficiencies or lack thereof. In this scenario, the patients who are neoadjuvantly treated with either FOLFOX or gemcitabine/Abraxane will be followed for biomarker analysis to determine if the patients who were initially on the FOLFOX-based regimen did better based on their circulating tumor DNA [ctDNA] or deficient homologous recombination mutations vs a gemcitabine/Abraxane regimen.

In these studies, it will be very important for us to understand if the patient should be switched to a different therapy if we find that they’re not responding, or if a predictive biomarker, such as homologous recombination deficiency, predicts that oxaliplatin works better. There are other ways that companies are doing this based on artificial intelligence and gene sequencing analysis. At the end of the day, we’re uncertain about whether gemcitabine/Abraxane or a FOLFOX/FOLFIRINOX [leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, oxaliplatin]-based regimen is better for each individual patient. We may also find that patients treated neoadjuvantly with 1 regimen and go to surgery may be preferable to treating with another regimen in the adjuvant setting based on this evidence. These are upcoming studies that will help guide whether the ctDNA predictive biomarkers in molecular residual disease are able to help us determine whether we should make treatment decisions in our patients with pancreatic cancer.

Using ctDNA in pancreatic cancer is very early. It’s in its infancy. We’re still trying to determine what ctDNA means for our patients with pancreatic cancer. Ordering it through all stages of disease, we’ve definitely found that some patients get to ctDNA negativity. Whether that’s with surgery or adjuvant therapy, they’re getting to a point where we’re unable to detect molecular residual disease in their body. We’re following that and using that as a surveillance tool in many of our patients: those who don’t create CA 19-9 or in whom CA 19-9 is not informative. We have been able to find recurrences very early, much earlier than radiographically that anyone would be able to find regularly based on the guidelines currently for surveillance.

The question ultimately is, what do we do with that data? In some cases, I tell the patients early on that this means that it’s an early morning detection system, that there’s smoke but we need to find if there is fire. Currently, we’re not making treatment decisions based on ctDNA turning negative to positive in our patients who are on surveillance. But we’re using it as a manner of preparing for clinical trials and as a method to prepare for finding additional radiographic evidence perhaps sooner than we would order a CT scan.

Further, we find that a lot of patients who go to ctDNA negativity unfortunately don’t stay there. This gets back to the histologic and pathologic pancreatic cancer conundrum that we’ve run into, that despite our ability to treat with chemotherapeutics, despite our ability to go through resection, and despite our ability to get to a point where our patients are at some point in remission, it seems as though we’re unable to completely eradicate this disease and that there’s always some type of residual disease in the patient’s body.

The ctDNA is a marker of whether we’re detecting that in the bloodstream. However, there’s likely a source in a lot of these patients that are recurring that hasn’t yet hit the bloodstream and has either remained local or in the liver or another niche. Ultimately…ctDNA…when they become negative, they are performing very well off of therapy and feeling quite confident. However, when they become positive, we’re getting them into the clinic earlier. We are radiographically evaluating them more often and earlier, and we’re finding these recurrences earlier. Obviously the question is whether that makes a difference to our patients. That’s to be determined.

Transcript edited for clarity.