Liquid Biopsy for ctDNA in Peritoneal Lavage and Blood in Pancreatic Cancer

Summary

Pancreatic cancer (PC) is a deadly disease and surgical resection of the tumor is the only hope of cure. Approximately 20-25% of the PC patients are candidates for intended curative resection, but despite microscopically radical resection the majority of patients will have recurrent disease within 2 years. This indicates that most patients will harbour non-detected (i.e. occult) cancer cells at the time of resection. Studies suggest that free tumor cells in the peritoneum and in the blood are part of this occult disease burden, and that patients with such findings should not be operated but treated as having metastatic disease. However, the exact incidence of these tumor cells in an unselected cohort of patients undergoing pancreatic resection is unknown, and the potential impact on postoperative survival is also uncertain. In recent years, molecular biomarkers are increasingly being regarded as both predictive and prognostic tools for cancer patients. This study will use the most optimal available methods to investigate the incidence of biomarkers for tumor cells in the peritoneum and blood in PC patients, and to relate these findings to the final outcome of the resected patients. This project has become highly relevant since new treatment methods (i.e. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC)) may be used to eradicate free tumor cells.

A recent systematic review and meta-analysis demonstrated that PC patients with positive peritoneal cytology (Cy+) had a significant poorer survival than patients with negative peritoneal cytology (Cy-) (HR 3.18), and the authors concluded that Cy+ patients should not undergo surgery. This conclusion was supported by a significant lower overall survival and a higher peritoneal recurrence rate after resection of Cy+ patients when compared to Cy- patients. Agreement that Cy+ in resectable PDAC is a negative predictor of prognosis came from another recent meta-analysis and systematic review. However, this study also indicated that the median OS was worse in patients without than in those with resection among patients with Cy+, thereby emphasizing need of further careful assessment of indications for radical resection in Cy+ patients.

KRAS mutations have been detected in circulating tumor DNA (ctDNA) in the blood (liquid biopsies) from patients with metastatic PC, and ctDNA is considered a marker of poor prognosis. Similar, KRAS mutations were found in the plasma of one-third of patients with a resectable tumor, and ctDNA positive (ctDNA+) patients had a significantly poorer overall survival (13.6 months vs 27.6 months, p\<0.0001). Similar conclusions were drawn in recent systematic reviews and meta-analyses, while one study failed to confirm these results. The detection of KRAS mutations in cell-free DNA has also been identified as a prognostic biomarker in PC patients. If looking at studies including all stages of PC patients, the prevalence of KRAS mutations in liquid biopsies was 40.8%, and these mutations had a negative impact on overall survival with a HR of 3.16. Different ctDNA detection methods have been used, however the recent introduction of digital droplet PCR (ddPCR), a new robust PCR method for quantifying low-abundance point mutations in cell-free circulating DNA, shows promising results and offers increased sensitivity and reproducibility relative to quantitative PCR (qPCR).

The treatment of resectable, locally advanced and metastatic PC has changed significantly over the past few years. New chemotherapy regimens have improved survival in metastatic PC, and these regimens (+/- radiation therapy) are presently being tested in both resectable and locally advanced PC with promising preliminary results. In theory, these new regimens may be potentially effective against ctDNA in PC patients, whereas the effect on peritoneal lavage positive (PLF+) PC patients is more speculative due to the low intraperitoneal concentrations of systemic chemotherapy. However, the latter problem may be solved by using Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) which allows better intraperitoneal distribution, concentration and accumulation of chemotherapy, without the systemic side effects. It may be speculated that the highly sensitive ddPCR of KRAS may be a better tool for PLF+ detection when focusing on PC patients, as up to 95% of these harbour mutations in this gene. So far, only very few studies used PCR to evaluate KRAS mutations in PLF in PC patients.

Main study aims are:

1. We aim to investigate the incidence of PLF+ and KRAS ctDNA in the blood from an unselected cohort of PC patients scheduled for attempted curative surgery.
2. Secondly, we will study the prognostic impact of PLF+ and KRAS ctDNA positivity in PC patients.

Conditions

• Pancreatic Cancer
• Pancreatic Adenocarcinoma

Sponsors & Collaborators

• Martin-Luther-Universität Halle-Wittenberg

  collaborator OTHER

• University Hospital Schleswig-Holstein

  collaborator OTHER

• Karolinska Institutet

  collaborator OTHER

• Sonke Detlefsen

  lead OTHER

Principal Investigators

• Sönke Detlefsen, MD, PhD · Odense University Hospital

Eligibility

Min Age

20 Years

Max Age

100 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-08-01

Primary Completion

2023-06-30

Completion

2024-12-31

Countries

• Denmark

Study Locations