4 days ago
Can a Blood Test Tell if Pancreatic Cancer Therapy Works?
A new blood test that uses artificial intelligence (AI) may offer a faster, more accurate way to determine whether pancreatic cancer treatment is working. Known as ARTEMIS-DELFI, the test detects DNA fragments shed by pancreatic tumors that circulate in blood.
In two large clinical trials of immunotherapy for metastatic pancreatic cancer, researchers successfully applied the test to identify patients with therapeutic responses. Two months after starting treatment, ARTEMIS-DELFI was better at predicting outcomes than imaging or other existing clinical and molecular markers.
'Early determination of response to therapy is crucial for patients with pancreatic or other cancers, especially when treated with immunotherapy where we do not have good biomarkers of response,' senior author Victor Velculescu, MD, PhD, codirector of the Cancer Genetics and Epigenetics Program at Johns Hopkins Kimmel Cancer Center in Baltimore told Medscape Medical News.
'We want to know as quickly as we can if the therapy is helping the patient or not. If it is not working, we want to be able to switch to another therapy,' Velculescu added in a news release.
The study was published online in Science Advances .
Real-Time Monitoring of Therapeutic Response
Pancreatic cancer, one of the deadliest cancers, often goes diagnosed at an advanced stage, with limited treatment options and a dismal prognosis.
Traditional methods for assessing treatment response — such as CT imaging and the CA19-9 tumor marker — are often unreliable, especially during immunotherapy, where pseudo-progression can obscure outcomes.
To address this challenge, Velculescu and colleagues developed two advanced liquid biopsy techniques that leverage cell-free DNA (cfDNA) for real-time, noninvasive therapeutic monitoring — ARTEMIS-DELFI (AI-driven, tumor-independent genome-wide cfDNA fragmentation profiles and repeat landscapes) and WGMAF (tumor-informed whole-genome mutant allele fraction).
Both techniques were tested in participants in the phase 2 CheckPAC trial, which evaluated nivolumab with or without ipilimumab in combination with radiation in patients with refractory metastatic pancreatic cancer.
Researchers established strong correlations between cfDNA signals and patient outcomes. With WGMAF, molecular responders to treatment had significantly longer median progression-free survival (PFS: 157 days vs 51 days; hazard ratio [HR], 0.23; P = .0053) and overall survival (OS: 319 days vs 126 days; HR, 0.29; P = .011) than nonresponders.
With ARTEMIS-DELFI, responders also had significantly longer PFS (105 days vs 53 days; HR, 0.28; P =.0024) and OS (233 days vs 172 days; HR, 0.12; P < .0001) when than nonresponders.
The researchers validated ARTEMIS-DELFI in the PACTO trial, which assessed gemcitabine/nab-paclitaxel with or without tocilizumab for advanced pancreatic cancer. Once again, ARTEMIS-DELFI scores were significant predictors of survival ( P = .048).
Both WGMAF and ARTEMIS-DELFI outperformed standard imaging and molecular markers in predicting treatment outcomes within 2 months. However, ARTEMIS-DELFI was more effective and practical, as it relies solely on DNA fragments circulating in blood.
'The 'fast-fail' ARTEMIS-DELFI approach may be particularly useful in pancreatic cancer where changing therapies quickly could be helpful in patients who do not respond to the initial therapy,' lead study author Carolyn Hruban, PhD, postdoctoral researcher at the Dana-Farber Cancer Institute in Boston, said in a news release. 'It's simpler, likely less expensive, and more broadly applicable than using tumor samples.'
Limitations and Future Directions
The researchers noted their analysis drew from a relatively small sample size – 40 patients each in CheckPAC and PACTO — with fewer evaluable by WGMAF due to tumor biopsy constraints. Some liquid biopsy timepoints did not align exactly with imaging assessments. As with most pancreatic cancer studies, there were few responders, limiting the pool of patients to analyze. Additionally, cut points for determining molecular response were derived from quantiles of observed responses rather than predefined thresholds.
The researchers plan future prospective studies to determine whether ARTEMIS-DELFI can help clinicians more efficiently identify effective therapies and improve outcomes across various cancers.
Earlier this year, the researchers reported that a variation of the cell-free fragmentation monitoring approach called DELFI-tumor fraction (DELFI-TF) was helpful in assessing colon cancer therapy response.
Velculescu and colleagues have founded a company, DELFI Diagnostics, which has developed a fragmentomics monitoring test for research purposes and eventual use within clinical care.
Nice Validation, More Work Ahead
Commenting on this research for Medscape Medical News , Karyn A. Goodman, MD, MS, professor and vice chair of clinical research, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York City, noted that 'the approach of using circulating tumor DNA to evaluate response to therapy is being evaluated for many tumor types, including pancreas cancer.'
'This study of the ARTEMIS-DELFI test is a nice validation of this approach using a different method of detecting tumor-related cfDNA that does not require a biopsy to establish the types of mutations in a particular tumor,' said Goodman, associate director of clinical research at The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City.
Goodman noted that the test does not use AI to make treatment decisions but rather to help identify the features in the cfDNA that correlate with tumor burden and treatment response.
'If the ARTEMIS-DELFI test detected a lower level of tumor-related cfDNA, this correlated with a good response to therapy and appeared to be more accurate than typical imaging tests,' observed Goodman, who wasn't involved in the study.
Although emphasizing that further prospective studies are needed, Goodman called the results 'very exciting,' as they point to a future with more noninvasive options for monitoring treatment response in pancreatic cancer.
