Ignite Creation Date:
2024-05-06 @ 6:01 PM
Last Modification Date:
2024-10-26 @ 2:40 PM
Study NCT ID:
NCT05511688
Status:
UNKNOWN
Last Update Posted:
2022-08-23
First Post:
2022-03-24
Brief Title:
National Cohort of Colorectal Cancers With Microsatellite Instability
Sponsor:
Federation Francophone de Cancerologie Digestive
Organization:
Federation Francophone de Cancerologie Digestive
Study Overview
Official Title:
National Cohort of Colorectal Cancers With Microsatellite Instability
Status:
UNKNOWN
Status Verified Date:
2022-08
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 andor predictive biomarkers need to be better characterized in a large cohort of MSI CRCs
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 andor 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 HR102 95IC 100-104 p0014 initial bowel obstruction HR233 95CI 129-423 p0005 vascular emboli HR227 95IC 141-363 p0001 and stage T4 HR209 95IC 128-340 p0003 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 andor 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
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 HR102 95IC 100-104 p0014 initial bowel obstruction HR233 95CI 129-423 p0005 vascular emboli HR227 95IC 141-363 p0001 and stage T4 HR209 95IC 128-340 p0003 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 andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None