mKRAS ctDNA Emerges as Predictor of Metastasis, Survival in PDAC

Pancreatic cancer anatomy concept: © Лилия Захарчук - stock.adobe.com

The presence of mutant KRAS (mKRAS) circulating tumor DNA (ctDNA) in plasma and peritoneal fluid was associated with increased risk of metastatic progression and worse overall survival in patients with localized pancreatic ductal adenocarcinoma (PDAC); this biomarker now allows for more informed treatment decision making in this patient population.^1,2 

The findings, which come from a study by researchers at the Mayo Clinic in Rochester, MN, showed that among patients who received baseline ctDNA mKRAS testing, plasma mKRAS–positive patients were more likely to have early postoperative recurrence or die within 6 months of resection compared with patients without plasma mKRAS at 46% vs 13%, respectively (P <.001). There was also a positive correlation between positive plasma mKRAS status and subsequent metastatic disease at 78% vs 49%, respectively (P <.001). At 20% vs 58%, respectively, plasma mKRAS­­–positive patients were also significantly less likely to be alive at follow-up.

In patients who received baseline peritoneal fluid mKRAS testing, the likelihood of having clinically positive staging at laparoscopy was much higher in peritoneal mKRAS­–positive patients (53% vs 12% in peritoneal mKRAS–negative patients; P <.001).There was also an increased likelihood of having metastatic disease at follow-up in patients with positive peritoneal mKRAS status (67% vs. 42%; P < .001). The combined likelihood of metastatic disease or death at follow-up was significantly higher in peritoneal mKRAS–positive vs –negative patients at 76% vs 53%, respectively (P <.001).

"Historically, we've known that KRAS mutations are associated with a more biologically aggressive pancreatic cancer," first study author Jennifer Leiting, MD, hepatobiliary and pancreatic surgeon within Mayo Clinic's Department of Surgery, said in an article about the study released by the Mayo Clinic.¹ "But this large study gives us a much clearer understanding of how to interpret the test results and use them to improve patient care. It allows for more accurate staging at diagnosis, leading to better treatment decisions."

Study Design and Patient Characteristics

The researchers for this single-institution study assessed data for 785 patients with nonmetastatic PDAC who underwent a full-staging work-up and baseline mKRAS testing of plasma and/or peritoneal fluid ctDNA at the Mayo Clinic from January 2018 to May 2022. Progression to metastatic disease and survival outcomes were assessed, with a median follow-up time of 16 months across all patients.

Overall, 743 (95%) of the 785 patients received baseline plasma mKRAS testing. Of these patients, 86% (n = 639) were mKRAS-negative and 14% (n = 104) were mKRAS-positive. Baseline characteristics were mostly well balanced between these 2 groups. Across both groups, the median age was 65, about 60% of patients were male, and 93% were White. A higher rate of patients in the plasma mKRAS–negative group received neoadjuvant chemotherapy prior to testing at 47% vs 16% of patients in the mKRAS-positive group. Patients who were plasma mKRAS–positive more often had a clinically positive laparoscopy (33% vs 21%; P = .032), and significantly fewer patients who tested positive for plasma mKRAS underwent resection (11% vs 34%; P < .001).

The researchers reported that over half (53%; n = 419) of the 785 patients assessed received peritoneal mKRAS testing. Of these, 29% (n = 123) were mKRAS-positive. Overall, patient characteristics were well balanced between the peritoneal mKRAS–positive and –negative groups, with a median patient age of 65 years, about 55% of patients being male, and about 94% of patients being White. The likelihood of having clinically positive staging laparoscopy was significantly higher in patients who were peritoneal mKRAS–positive (53% vs 12%; P < .001).

About half (48%) of patients received both plasma and peritoneal mKRAS testing. The researchers reported that any patient in this combined group with a positive mKRAS test, regardless of plasma or peritoneal, experienced worse outcomes.

"This is a major advancement for pancreatic ductal adenocarcinoma," said senior study author Mark Truty, MD, hepatobiliary and pancreatic surgical oncologist within Mayo Clinic's Department of Surgery.¹ "We've had this genetic testing available for a number of years, however, we did not know the significance of the results or how to interpret them. Having the KRAS status will allow the patient and their provider to make better decisions about their individual cancer treatment."

"This improved diagnostic capability offers hope for patients and their families facing this challenging disease," added Truty. "It's optimistic to see how advances in genetic testing are directly helping our patients.¹

References

1. Luckstein K.Mayo Clinic researchers identify a measurable genetic mutation as a significant predictor of metastasis and survival in pancreatic cancer. Published online March 19, 2025. Accessed March 24, 2025. https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-identify-a-measurable-genetic-mutation-as-a-significant-predictor-of-metastasis-and-survival-in-pancreatic-cancer

2. Leiting JL, Alva-Ruiz R, Yonkus JA, et al. Molecular KRAS ctDNA Predicts Metastases and Survival in Pancreatic Cancer: A Prospective Cohort Study [published online ahead of print March 11, 2025]. Ann Surg Oncol. doi: 10.1245/s10434-025-17036-y