Trial Title:
National Cohort of Colorectal Cancers With Microsatellite Instability
NCT ID:
NCT05511688
Condition:
Colorectal Cancer
Microsatellite Instability
Conditions: Official terms:
Colorectal Neoplasms
Microsatellite Instability
Study type:
Observational
Overall status:
Unknown status
Study design:
Time perspective:
Prospective
Summary:
The three main pathways of colorectal carcinogenesis are chromosomal instability,
microsatellite instability (MSI) (15% of colorectal cancers =CRCs) and CpG island
methylator phenotype (CIMP). MSI CRCs are associated with a better prognosis after
curative surgery than CRCs without microsatellite instability (MSS). In contrast, MSI
CRCs do not appear to benefit from adjuvant 5-FU chemotherapy, unlike patients with MSS
CRCs. Nevertheless, the benefit of adjuvant chemotherapy with FOLFOX seems to be
retained. The identification of prognostic markers in this subgroup of patients is
therefore essential to decide on adjuvant chemotherapy, the efficacy of which is
currently debated in MSI CRC.
To date, there are very few data concerning metastatic MSI CRC. Metastatic forms are rare
(about 5% of metastatic CRCs), but are thought to be associated with chemoresistance and
poor prognosis. Nevertheless, data are very sparse and there are no data regarding the
use of modern chemotherapies and targeted therapies in metastatic MSI CRC. Thus, it is
important to characterize the chemosensitivity of metastatic forms.
Clinical predictors of recurrence after curative CRC surgery are known but have only been
studied in MSI CRC retrospectively. Similarly, many molecular and immunohistochemical
factors, prognostic or predictive of response to adjuvant chemotherapy, have been
recently identified in CRC (KRAS, BRAF, TP53, PI3KCA mutations, CIMP phenotype, SMAD4,
immune response...). Most of these markers have been studied in all CRCs, but not
specifically in the MSI CRC subgroup. All these prognostic and/or predictive biomarkers
need to be better characterized in a large cohort of MSI CRCs.
Detailed description:
Colorectal cancers with microsatellite instability The 3 main pathways of colorectal
carcinogenesis are chromosomal instability (75% of CRCs), microsatellite instability (15%
of CRCs) and CpG island hypermethylation or CIMP (CpG island methylator phenotype) (25%
of CRCs).
Microsatellite instability (MSI) or RER+ (replication errors) phenotype is related to an
acquired or inherited inactivation of the MMR (mismatch repair) system of DNA mismatch
repair. In MSI CRCs associated with Lynch syndrome or HNPCC (hereditary nonpolyposis
colorectal cancer) (3% of CRCs), there is a germline mutation in one of the genes of the
MMR system, essentially MLH1 or MSH2, more rarely MSH6 or PMS2. In sporadic MSI cancers,
frequently observed in the elderly, the loss of function of the MMR system is linked to a
biallelic hypermethylation of the CpG islands of the MLH1 gene promoter causing its
inactivation. Molecular individualization of CRCs has allowed the identification of tumor
subgroups, such as MSI CRCs, that are more homogeneous in terms of their progression
pathway, but the impact in terms of prognosis and treatment sensitivity remains to be
clarified.
Prognosis and chemosensitivity of colorectal cancers with microsatellite instability MSI
CRCs are associated with a better prognosis after curative surgery than CRCs without
microsatellite instability (MSS) . In contrast, retrospective analyses of randomized
trials indicate that patients with MSI CRC do not appear to benefit from adjuvant
5-FU-based chemotherapy in contrast to patients with MSS CRC. Nevertheless, the benefit
of adjuvant chemotherapy with FOLFOX seems to be retained . The identification of
prognostic markers in this subgroup of patients is therefore essential to decide on
adjuvant chemotherapy, the efficacy of which is currently debated in MSI CRC.
To date, there are very few data concerning metastatic MSI CRC. Metastatic forms are rare
(about 5% of metastatic CRCs), but are thought to be associated with chemoresistance and
poor prognosis . Nevertheless, data are very sparse and there are no data regarding the
use of modern chemotherapies and targeted therapies in metastatic MSI CRC. Thus, it is
important to characterize the chemosensitivity of metastatic forms in order to offer the
best treatment to patients.
Recent data show significant efficacy of immune checkpoint inhibitors in MSI CRC,
including anti-PD1. Indeed, these tumors present a high number of mutations generating
immunogenic neo-antigens. Thus, escape from anti-tumor immunity is a major mechanism of
progression of MSI CRCs .
Prognostic and predictive factors of response to chemotherapy in colorectal cancer with
microsatellite instability The clinical predictive factors for recurrence after curative
CRC surgery are known (lymph node involvement, T4 stage, VELIPI criteria (vascular
emboli, perineural sheaths, and lymphatic emboli), poorly differentiated tumor, analysis
of fewer than 12 nodes, tumor perforation, and overt bowel obstruction). These criteria
have only been studied in MSI CRCs retrospectively. A large French retrospective study of
MSI CRCs included 521 MSI CRCs. Four independent predictors of recurrence-free survival
were identified, age (HR=1.02; 95%IC 1.00-1.04, p=0.014), initial bowel obstruction
(HR=2.33; 95%CI 1.29-4.23, p=0.005), vascular emboli (HR=2.27; 95%IC 1.41-3.63, p<0.001),
and stage T4 (HR=2.09; 95%IC 1.28-3.40, p=0.003). It should be noted that, unlike MSS
CRCs, the prognostic impact of lymph node involvement appears to be small. This work is
nevertheless limited by missing data (5-30%), biases related to retrospective analysis
and the absence of exploitable molecular analyses (notably KRAS and BRAF mutation). These
data can be validated prospectively from the COLOMIN 2 cohort.
In stage III MSI CRC, adjuvant chemotherapy with FOLFOX is recommended. On the other
hand, in stage II MSI CRC, simple surveillance is recommended given the good prognosis .
Nevertheless, in case of vascular emboli and/or T4 stage in MSI stage II CRC, the risk of
recurrence becomes clinically significant (more than 20% at 2 years) and therefore raises
the question of adjuvant treatment on a case-by-case basis. Indeed, in high-risk stage II
MSI CRC, FOLFOX seems to provide a benefit in terms of recurrence-free survival compared
with surgery alone . The COLOMIN 2 cohort will allow prospective confirmation of the
chemosensitivity of these tumors to oxaliplatin.
Many molecular and immunohistochemical factors, prognostic or predictive of response to
adjuvant chemotherapy, have been recently identified in CRC (KRAS, BRAF, TP53, PI3KCA
mutations, CIMP phenotype, SMAD4, immune response...). These markers have been mostly
studied in all CRCs, but not specifically in the subgroup of MSI CRCs. All these
molecular and immunohistochemical factors need to be better characterized in a large
cohort of MSI CRCs in order to determine their exact frequencies, their associations with
each other, their prognostic and predictive values of response to chemotherapy. The
constitution of a biological collection in COLOMIN 2 will allow the analysis of different
biomarkers. For example, the BRAF mutation (V600E) is associated with a poor prognosis in
CRC. Nevertheless, its prognostic impact remains debated in MSI CRC, whereas more than
50% of MSI CRC are BRAF mutated. COLOMIN 2 will assess the prognostic impact of BRAF
mutation in MSI CRC.
Criteria for eligibility:
Study pop:
Patients with MSI colrectal cancers (stage I to IV)
Sampling method:
Non-Probability Sample
Criteria:
Inclusion Criteria:
- Patient with MSI colorectal cancer defined either by molecular biology (more than
30% of microsatellites tested unstable) or by immunohistochemistry (loss of
expression of at least one MMR protein: MLH1, MSH2, MSH6, PMS2)
- Histologically proven colorectal cancer diagnosed on or after January 1 of the
cohort start date
- Stage I, II, III (non-metastatic) or IV (metastatic)
Exclusion Criteria:
- Colorectal cancer MSS
- Contraindication due to psychological, social, or geographical reasons that may
hinder patient follow-up
- Opposition of the patient to registration in the cohort
- Stage 0 (Tumor in situ, N0, M0)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Chu Poitiers
Address:
City:
Poitiers
Zip:
86021
Country:
France
Facility:
Name:
CH
Address:
City:
Abbeville
Country:
France
Facility:
Name:
Chu - Hôpital Sud
Address:
City:
Amiens
Country:
France
Facility:
Name:
Chu - Hôpital Hôtel Dieu
Address:
City:
Angers
Country:
France
Facility:
Name:
CH
Address:
City:
Angoulême
Country:
France
Facility:
Name:
Ch - Hôpital Victor Dupouy
Address:
City:
Argenteuil
Country:
France
Facility:
Name:
Ch - Ght Unyon Auxerre
Address:
City:
Auxerre
Country:
France
Facility:
Name:
Ch - Hôpital Henri Duffaut
Address:
City:
Avignon
Country:
France
Facility:
Name:
Privé - Institut Du Cancer Avignon Provence
Address:
City:
Avignon
Country:
France
Facility:
Name:
Chu - Hôpital Jean Minjoz
Address:
City:
Besançon
Country:
France
Facility:
Name:
Privé- Centre Pierre Curie
Address:
City:
Beuvry
Country:
France
Facility:
Name:
Privé - Clinique Tivoli
Address:
City:
Bordeaux
Country:
France
Facility:
Name:
Privé - Polyclinique Bordeaux Nord
Address:
City:
Bordeaux
Country:
France
Facility:
Name:
Ch - Centre Hospitalier de Bézier
Address:
City:
Béziers
Country:
France
Start date:
March 22, 2017
Completion date:
October 2022
Lead sponsor:
Agency:
Federation Francophone de Cancerologie Digestive
Agency class:
Other
Source:
Federation Francophone de Cancerologie Digestive
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05511688
