Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers

Abstract

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

Detection and localization of surgically resectable cancers with a multi-analyte blood test

“…Diagnostic sensitivity is also an issue for liquid biopsies. Available evidence indicates that patients with early-stage cancers can harbor less than one mutant template molecule per milliliter of plasma (11, 20), which is often beyond the limit of detection of previously reported technologies that assess multiple mutations simultaneously (19, 21). Yet another issue with liquid biopsies is the identification of the underlying tissue of origin.…”

“…A subsequent study suggested that the combination of four protein biomarkers with one genetic marker ( KRAS ) could enhance sensitivity for the detection of pancreatic cancers (20). We sought to generalize this approach by evaluating a panel of protein and gene markers that might be used to detect many solid tumors at a stage before the emergence of distant metastases.…”

“…Previous studies have demonstrated that a major fraction of early-stage tumors do not release detectable amounts of ctDNA, even when extremely sensitive techniques are used to identify them (11, 20). Many proteins potentially useful for early detection and diagnosis of cancer have been described in the literature (25–27).…”

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

“…A well-established example is non-small-cell lung cancer where liquid biopsy can help in guiding the choice of suitable therapeutic regimens and are already included in the portfolio of routine clinical algorithms as of to date [90,91]. Apart from these applications, in pancreatic cancer, liquid biopsy techniques are thought to carry great potential for early detection and secondary prophylaxis [92,93,94]. …”

Progress in Liquid Biopsy: A possible role of neutrophils

“…However, the amount of early tumor cells and their associated tumor bioproteins that enter the peripheral blood is extremely small. For example, recent studies have shown that the number of oncogenic mutations per milliliter of serum is often less than one copy, which is below the lower limit of current routine biopsies [2,3]. Therefore, the sensitivity of liquid biopsies limits its clinical applications.…”