In solid cancers, after the formation and growth of the primary tumor, some more aggressive
tumor cells actively detach from it and then travel through the circulating compartment to
reach distant organs (bone marrow - liver - lung - brain…) and constitute new foci or
micro-metastases. These circulating tumor cells (CTCs) that have become disseminated tumor
cells (DTCs) flourish in their new environments and may remain dormant for many years after
the complete resection of the primary tumor. Due to events not fully elucidated, DTCs can
develop on site giving rise to macroscopic metastases but also join again the circulating
compartment in the form of CTCs, swarm, colonize other organs and cause secondary metastases.
Detecting CTCs in the blood is very relevant for assessing tumor progression but also
promising in terms of cancer disease prognosis and therapeutic follow-up. This new approach,
published for the first time in 2010 under the term liquid biopsy, is therefore defined as a
non-invasive blood test, extremely sensitive, achievable in real time and that allows the
analysis of CTCs.
Currently, the choice of targeted therapies for a given patient is made after analyzing the
primary tumor for expression and/or genomic status of specific molecular targets.
Many studies show that metastatic cells have phenotypic and genotypic characteristics
distinct from those of most of the primary tumor. This can be explained either because
metastatic cells acquire new genomic skills over time, or because a subset of metastatic
sub-clone pre-exists within the primary tumor but has escaped detection by standard tissue
biopsy techniques.
A direct analysis of CTCs could provide important additional information to prevent patients
from inappropriate, costly treatments and harmful side effects.
For several years, the AXL protein, a tyrosine kinase receptor, has emerged as a new
strategic target in oncology. Over-expression of AXL has been frequently identified in
patients with pancreatic adenocarcinoma. AXL is a member of the Tyro3-Axl-Mer family, like
its ligand protein Gas-6 (growth arrest-specific). An activation of the Gas6/AXL signaling
pathway results in the activation of several effector pathways such as RAS/RAF/MEK/ERK or
PI3K/AKT and is associated with, among other things, tumor cell growth and survival,
metastatic formation and dissemination, Epithelial-to-mesenchymal transition (EMT) or drug
resistances. It has been shown clinically that the AXL protein is a factor of poor prognosis
and resistance to reference treatments (radiotherapy, chemotherapy or targeted therapy).
Thus, many therapeutic strategies have been proposed and developed to inhibit the AXL
pathway, ranging from chemical molecules, blocking its kinase activity and therefore the
underlying signaling pathways, to nucleotide aptamers, AXL fusion proteins, and monoclonal
antibodies.
Pancreatic adenocarcinoma, the 4th leading of cancer related deaths, remains among cancers of
very poor prognosis and thus represents a major therapeutic challenge. The median overall
survival is 11.1 months after optimal treatment (FOLFIRINOX). The clinical relevance and
oncogenic potential of AXL in the progression of different types of tumors have been largely
evidenced. Indeed, 50% to 75% of pancreatic adenocarcinoma samples have overexpression of AXL
and the level of expression of AXL is correlated with clinical parameters indicating tumor
aggressiveness and poor prognosis such as frequency of distant metastases or the survival.
In this context, the LCCRH lab, which has specialized in the detection and analysis of CTCs
for 20 years, has developed a CTC-AXL detection test using the CellSearch® system. The
CellSearch® system is the only method approved by the Food and Drug Administration (FDA) for
the detection of CTC in colorectal, breast and metastatic prostate cancers. In addition, the
LCCRH holds a patent for another technology for the detection and characterization of live
and functional CTCs, called EPIDROP. The implementation of the AXL research is already done
for AXL labelling on CTCs in EPIDROP as well as the visualization of the AXL cleavage by live
CTC.
Thanks to this unique functional test of CTCs, it is easy to imagine offering an oncology
'oncogram' by testing in real time the effectiveness of drugs on CTCs and personalized
medicine to patients.
This real-time liquid biopsy proposal on functional CTCs is quite innovative in Oncology.
To date, there are no studies on the study of functional CTCs related to AXL.
Primary objective:
- Evaluate the concordance of the CTC-AXL measurement (inclusive) by the innovative EPIDROP
technique and the CellSearch technique®
Secondary objectives:
Evaluate the accuracy of the CTC-AXL measurement (inclusive) between EPIDROP and
CellSearch®
Assess the degree of agreement between CTC-AXL measurement (inclusive) by EPIDROP and
CellSearch®
Evaluate the overall survival of patients with metastatic pancreatic cancer based on the
number of circulating tumour cells carrying the AXL marker measured by EPIDROP or
CellSearch® at inclusion
Evaluate the progression-free survival of patients with metastatic pancreatic cancer
based on the number of circulating tumour cells carrying the AXL marker measured by
EPIDROP or CellSearch® at inclusion
Culture CTCs from the blood sample (EDTA 10mL)
Creation of a single liquid biopsy bio-bank for pancreatic cancer involving only plasma
storage
Study the expression of PD-L1 (at inclusion) and detect the CTC subgroup expressing
PD-L1 using EPIDROP and CellSearch® techniques;
Study the circulating immune system in this cohort of patients with metastatic
pancreatic cancer by performing immunological analysis on blood mononuclear cells;
Determine if there is a significant correlation between the detection of CTC and
CTC-PD-L1 and the circulating immune system (T cells, NK cells, B cells,
macrophages, immune checkpoints, platelets);
To assess the correlation between CTC, CTC-PD-L1 and immune cells and the clinical
outcomes (progression-free survival, overall survival) of these patients with
metastatic pancreatic cancer.