| dc.description.abstract | Introduction
Pancreatic ductal adenocarcinoma (PDAC), a particularly deadly form of pancreatic cancer (PC), continues to challenge modern medical science regarding diagnosis and treatment of the disease. The poor prognosis associated with PDAC is largely a result of its insidious pathogenesis. The symptoms of an adenocarcinoma of the pancreas in early stages are vague, if present at all, enabling it to grow and spread undetected. Related to this spread are disseminated tumor cells (DTCs), which are theorized to play an important role in metastatic growth These cells detach from the primary tumor, travel through the body’s circulatory system, and established themselves in other tissues. The presence of DTCs in BM has previously been connected to a worsened prognosis for patients with breast cancer and colorectal cancer, and for PDAC. DTCs have also been observed to lie dormant in the bone marrow (BM) in other epithelial cancers, like breast cancer, before reactivating and proliferating again in later instances. The BM has thus been thought to work as a reservoir for these potentially metastatic cells. The purpose of this study was to identify potential biomarkers for DTCs and validate the prognostic information tied to the presence of DTCs in the BM of patients with advanced PDAC.
Patients and methods
74 BM samples were collected from 49 patients with locally advanced and/or metastatic PDAC before and two months after receiving chemotherapy. Samples were also collected from a healthy control group of 30 individuals. RNA from the samples was reverse transcribed and pre-amplified prior to analysis. DTCs were detected using real-time quantitative PCR (RT-qPCR) and a range of epithelial mRNA transcripts as biomarkers. Both known and novel biomarkers were utilized. The DTC-positive threshold was established using the highest measured level in the control group. Statistical methods and univariate survival analysis were performed to investigate prognostic significance.
Results
In pre-treatment BM samples, 13/49 (26.5%) were found DTC-positive by one or more biomarkers. In BM samples obtained during treatment, 7/25 (28%) were found DTC-positive by one or more biomarkers. A statistically significant relationship between the clinical T-stage and DTC-status in BM before treatment was found (p = 0.04).
In the pre-treatment BM samples, statistically significant relationships were observed for markers KRT7 (p = 0.04) and KRT8 (p = 4E-5) between DTC-positivity and reduced overall survival (OS). SPINK1 (p = 0.06) was considered borderline significant. The observed relationship with OS for all markers combined was found to be statistically significant (p = 0.002). No significant relationship between DTC-positives during treatment and a reduced OS (p = 0.5) was found.
Conclusion
This study found that there is a negative impact on the prognosis of patients with advanced PC presenting with DTCs in BM samples collected before treatment. No negative impact on OS could be associated with BM DTC status determined during treatment. Transcripts KRT7, KRT8 and SPINK1 were confirmed as potential biomarkers for DTCs in the BM of patients with advanced PC. | |
