Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05257707 |
| Other study ID # |
2021-A01532-39 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 1, 2022 |
| Est. completion date |
March 2027 |
Study information
| Verified date |
September 2022 |
| Source |
Centre Hospitalier Universitaire de Besancon |
| Contact |
Jean-Luc PRETET |
| Phone |
+33.3.70.63.20.49 |
| Email |
jean_luc.pretet[@]univ-fcomte.fr |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In oncology, the search for genetic alterations or infectious agents in tumour tissues has
become a major medical challenge for diagnosis, prognosis, prediction of response to
treatment and in particular to targeted therapies, or for the biological monitoring of the
disease. Over the last ten years, the development of new molecular biology tools based on
high-throughput technologies has enabled us to revisit our conceptions of the development and
natural history of cancers. The use of these tools has also allowed the dismemberment of
numerous cancerous pathologies according to their molecular etiologies and oncogenetic
histories. These new molecular biology tools have thus contributed to the emergence of
so-called personalised or precision medicine.
Description:
It is in this context the prescription of targeted therapies is now conditioned by the
identification of specific genetic anomalies in the tumour. As such, kinase inhibitors have
been shown to be effective in patients with non-small cell lung cancer or metastatic melanoma
when mutations in epidermal growth factor receptor (EGFR) or BRAF, respectively, are
identified. Conversely, the identification of KRAS or NRAS mutation in metastatic colon
cancers predicts resistance to anti-EGFR antibody-based therapies. Under these conditions,
the prescription of these targeted therapies provides a major benefit to patients. The
efficacy of these therapies is linked to the fact that the target mutations are "driver"
mutations delivering a powerful oncogenic signal. These mutations are also an 'Achilles heel'
for the tumour cell, which becomes hypersensitive to certain tyrosine kinase inhibitors.
However, tumour escape from targeted therapies is well documented after a few months of
treatment. Here again, molecular analysis of progressing tumours has revealed intratumoural
heterogeneity with, in particular, the appearance of secondary mutations responsible, at
least in part, for the development of resistance. This is why it is important to characterise
the molecular profile of tumours both during the natural history of the disease and in
treated patients in order to offer them appropriate follow-up.
Among the 170 human papillomaviruses (HPV) described in 2013, a dozen or so so-called
high-risk or oncogenic HPVs are responsible for all cervical cancers, almost all anal
cancers, half of vulvar and vaginal cancers and certain cancers of the upper aerodigestive
tract. While HPV infection is necessary for cancer to develop, it is not sufficient and
co-factors that promote persistent infection increase the risk of developing precancerous
lesions and then cancers. Thus, the natural history of infection by these viruses is closely
linked to that of the cancer they induce. The molecular mechanisms of HPV-related
carcinogenesis/transformation are well described. It is the combined action of two viral
proteins (E6 and E7) on the two tumour repressors p53 and pRb that initially lifts the
intrinsic mechanisms of replicative senescence of the cell (which thus acquires the capacity
to divide indefinitely), and then gradually leads to its transformation. However, the
determinants that lead an infected cell to immortalise and then transform remain poorly
understood and the vast majority of infections are eliminated spontaneously within 10 to 18
months following the development of effective immune responses. It is likely that host
(immunosuppression, genetic factors), viral, and environmental (smoking, oral contraception)
co-factors will influence the carcinogenesis process. Thus, it is recognised that HPV16 is
the most carcinogenic genotype. It is the longest persisting HPV and is associated with the
highest risk of developing pre-cancer or cervical cancer. Cervical cancers associated with
HPV16 (or HPV18/45) have been shown to have a worse prognosis than those infected with other
genotypes. Conversely, in upper aerodigestive tract cancers, those induced by an HPV (this is
HPV16 in more than 95% of cases), have a better prognosis than those not induced by a virus.
Thus, genotyping a tumour to identify the type of HPV involved could be of clinical interest,
particularly depending on the location of the tumour.
The therapeutic management of patients with HPV-associated cancers most often consists of a
combination of surgery and/or radiochemotherapy (cis-platinum, 5-fluorouracil) depending on
the extent of the tumour. For anal cancers, work in Bisonne showed that the addition of a
third chemotherapy molecule (taxane) was very promising as it allowed previously unobserved
remissions. The reasons for such efficacy are not clear, nor is there a predictor of response
to treatment.
Molecular genetic analyses are carried out using various types of samples such as cells from
smears or punctures, biopsies, surgical parts and numerous fluids such as urine,
cerebrospinal fluid or blood. While the standard for molecular diagnosis today is to analyse
the tumour sample, the use of a "liquid biopsy" from a simple blood sample is widely
considered. Indeed, it has now been shown that cancers release DNA that can be detected in
the blood of patients, this is circulating tumour DNA. Thus, it is possible to diagnose or
perform biological monitoring of cancers (e.g. before/after treatment) from a liquid biopsy.
However, the study of circulating tumour DNA still faces some difficulties. Firstly, the
concentration of circulating DNA is very low, in the order of a few tens of nanograms per mL
of plasma. Furthermore, the vast majority of circulating DNA is composed of DNA released from
normal cells and the proportion of circulating tumour DNA is only 1-4% of circulating DNA.
Finally, circulating tumour DNA is generally fragmented (<200 bp). In order to overcome these
constraints, it is necessary to use highly sensitive techniques, both to measure the
concentration of circulating DNA and to search for molecular alterations characteristic of
the tumour. In this respect, circulating tumour DNA analysis brings a new dimension to the
management of cancer patients. Based on circulating tumour DNA analysis, it is possible to
direct treatment towards a targeted therapy in the absence of a tissue biopsy, to assess the
effectiveness of a treatment, to follow the evolution of the disease, and even to identify
recurrence. Circulating tumour DNA analysis also provides a snapshot of all genetic
alterations in the tumour (primary and metastatic) reflecting tumour heterogeneity, whereas
biopsy results are only representative of the site from which they were taken. For
HPV-associated cancers, viral genome detection from liquid biopsies is also largely feasible.
However, studies are still needed today to not only validate the principle of liquid biopsy
in cancers, but also to clarify its clinical utility. Recent results have shown that changes
in plasma HPV viral load predict response to treatment.
Since the sequencing of the human genome in 2001, DNA analysis techniques have progressed
enormously and the new 'next generation sequencing' (NGS) technologies allow the simultaneous
analysis of a very large number of genes (several hundred) from several dozen different
samples. These sequencing capabilities make it possible to rapidly explore a large number of
genetic anomalies at a lower cost. Data on genetic abnormalities in HPV-associated cancers
exist and it has been very recently reported that HPVs are also subject to genetic variations
during the carcinogenesis process.
Technological advances in molecular biology (high-throughput sequencing, digital PCR,
circulating tumour DNA) now make it possible to describe very precisely any genetic or
epigenetic modifications that could constitute potential biomarkers. A better description of
these genetic modifications in sequential samples during the transition between a normal
state, a precancer and a cancer as a function of time will make it possible to develop, on
the one hand, models predicting the appearance of cancers and, on the other hand, innovative
tools for diagnosis and risk stratification of developing a cancer. It will be possible to
propose early medical interventions only for those patients who need them. The study of
genetic abnormalities in patients treated for cancer will make it possible to propose
innovative tools for monitoring the disease, predicting relapse or cure or identifying new
therapeutic or vaccine targets.
This is why the investigators want to be able to collect biological samples of various kinds
(smears, biopsies, biological fluids, etc.), whether they have been taken in the context of
care or stored in declared collections (tumour libraries, for example). These samples will be
collected and stored at the Besançon University Hospital in the form of a collection (MOCA
collection) which will be associated with clinical data. The investigators will then be able
to build up homogeneous cohorts of patients from this collection from which the investigators
can study theranostic biomarkers.
