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.
