Prognostic Role of Inhibitor of Apoptosis Protein Overexpression on Recurrence Rate in Cervical Cancer

Study Overview
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Brief Summary
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Overexpression of inhibitors of apoptosis proteins (IAPs) in patients treated for locally advanced cervical cancer with exclusive radio-chemotherapy may have a prognostic role on the local recurrence rate at 24 months.

Detailed Description
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Cervical cancer remains one of the most common cancers in women in terms of both incidence and mortality. Human Papilloma Virus carriage is a necessary condition for the development of these cancers but is not the only factor responsible for malignant transformation. Numerous molecular alterations come into play in the development of these tumours, involving the activation of oncogenes or the inactivation of tumour suppressor genes. Treatment of locally-advanced cancer is based on radiotherapy or a combination of radiotherapy and chemotherapy. Responses to anti-neoplastic treatments remain very heterogeneous from one woman to another. Predicting the response to these treatments would make it possible to envisage early therapeutic alternatives for patients identified as not very sensitive to standard treatments. IAPs (inhibitors of apoptosis proteins), which include XIAP, cIAP1 and cIAP2, are proteins involved in many cancers and capable of downregulating tumour cell apoptosis. It seems justified to investigate the role of these IAPs in resisting apoptosis-inducing anti-neoplastic treatments such as chemotherapy or radiotherapy. The aim of our study is to assess the prognostic role of overexpression of IAPs in locally advanced cervical cancer treated exclusively with radio-chemotherapy. This research seems all the more important as IAP-inhibiting molecules are currently being studied in other types of cancer (ear, nose and throat cancers) and appear to have a very encouraging radiosensitising effect. The hypothesis is that overexpression of IAPs in patients treated for locally advanced cervical cancer with exclusive radio-chemotherapy has a prognostic role on the local recurrence rate at 24 months.

Official Title
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Evaluation of the Prognostic Role of Inhibitor of Apoptosis Protein Overexpression on the 24-month Recurrence Rate in Locally Advanced Cervical Cancer

Conditions
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Cancer of Cervix, Apoptosis

Intervention / Treatment
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* Diagnostic Test: Immunohistochemistry


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients treated with the exclusive radio-chemotherapy combination for locally advanced cervical carcinoma (stage Ib-IVb according to FIGO classification). Patients aged ≥ 18 years. Patients with a minimum of 2 years post-treatment follow-up. Patients for whom the initial biopsy specimen (before treatment) is available. Patients who have not indicated that they do not wish to participate in the study. Patients affiliated to or benefiting from a health insurance scheme. Exclusion Criteria: Patients under court protection, guardianship or curatorship.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Diagnostic Test: Immunohistochemistry|Blocks containing formalin-fixed, paraffin-embedded (FFPE) biopsies will be used to analyse the expression of XIAP, cIAP1 and cIAP2 proteins by immunohistochemistry. The antibodies will be selected on the basis of the literature and their validation for this technology (Schnoell et al. 2020). The immunohistochemical techniques will be performed on an automated immunolabelling machine (DakoLink®) after antigen demasking. The specific binding of primary antibodies will be revealed by the application of Flex reagent (Dako Agilent), a dextran polymer coupled on the one hand to anti-mouse and anti-rabbit immunoglobulins, and on the other hand to a large number of horseradish peroxidase (HRP) molecules. 3,3'-Diaminobenzidine (DAB) will be used as a substrate for this enzyme to highlight the specific expression of the biomarker. The use of an automated system will ensure the reproducibility of inter-sample labelling.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prognostic role of overexpression of XIAP on the rate of local recurrence in patients treated for locally advanced cervical cancer. | Overexpression of the Inhibitor of Apoptosis Proteins XIAP will be measured to evaluate its prognostic role on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer. The H-score for XIAP will be recorded on a scale of 0 to 300 based on the intensity of carcinoma cells. | Baseline | 
| Prognostic role of overexpression of XIAP on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer. | Overexpression of the Inhibitor of Apoptosis Proteins XIAP will be measured to evaluate its prognostic role on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer. The H-score for XIAP will be recorded on a scale of 0 to 300 based on the intensity of carcinoma cells. | 24 months | 
| Prognostic role of overexpression of cIAP1 on the rate of local recurrence in patients treated for locally advanced cervical cancer. | Overexpression of Inhibitors of the Apoptosis Protein cIAP1 will be measured to evaluate its prognostic role on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer.The H-score for cIAP1 be recorded on a scale of 0 to 300 based on the intensity of carcinoma cells. | Baseline | 
| Prognostic role of overexpression of cIAP1 on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer. | Overexpression of the Inhibitor of Apoptosis Protein cIAP1 will be measured to evaluate its prognostic role on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer.The H-score for cIAP1 be recorded on a scale of 0 to 300 based on the intensity of carcinoma cells. | 24 months | 
| Prognostic role of overexpression of cIAP2 on the rate of local recurrence in patients treated for locally advanced cervical cancer. | Overexpression of the Inhibitor of Apoptosis Protein cIAP2 will be measured to evaluate its prognostic role on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer.The H-score for cIAP2 be recorded on a scale of 0 to 300 based on the intensity of carcinoma cells. | Baseline | 
| Prognostic role of overexpression of cIAP2 on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer. | Overexpression of the Inhibitor of Apoptosis Protein cIAP2 will be measured to evaluate its prognostic role on the rate of local recurrence at 24 months follow-up in patients treated for locally advanced cervical cancer. The H-score for cIAP1 be recorded on a scale of 0 to 300 based on the intensity of carcinoma cells. | 24 months | 
| Local recurrence of cervical cancer | Local recurrence of cervical cancer at 24 months follow-up according to RECIST v1.1 criteria: Yes/No. RECIST 1.1 is a standard way to measure the response of a tumor to treatment in which Complete Response = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. Partial Response = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Overall survival at 24 months follow-up in patients treated for locally advanced cervical cancer. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A. Overall survival in patients treated for locally advanced cervical cancer at baseline. | Death will be recorded as YES/NO | Baseline | 
| A. Overall survival at 24 months follow-up in patients treated for locally advanced cervical cancer. | Death will be recorded as YES/NO | 24 months | 
| B. Progression-free survival in patients treated for locally advanced cervical cancer. | The time from diagnosis to death from any cause will be recorded in months and days. | Baseline | 
| B. Progression-free survival at 24 months follow-up in patients treated for locally advanced cervical cancer. | The time from diagnosis to death from any cause will be recorded in months and days. | 24 months | 
| B. Progression-free survival in patients treated for locally advanced cervical cancer: RECIST criteria | The time between diagnosis and progression according to v1.1 of the RECIST criteria or death from any cause will be recorded in days. RECIST 1.1 is a standard way to measure the response of a tumor to treatment in which Complete Response = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. Partial Response = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Baseline | 
| B. Progression-free survival at 24 months follow-up in patients treated for locally advanced cervical cancer: RECIST criteria | The time between diagnosis and progression according to v1.1 of the RECIST criteria or death from any cause will be recorded in days. RECIST 1.1 is a standard way to measure the response of a tumor to treatment in which Complete Response = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. Partial Response = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | 24 months | 
| B. Progression-free survival in patients treated for locally advanced cervical cancer. H-score | The histochemical scoring assessment (H-SCORE) will be recorded on a scale of 0-300 | Baseline | 
| B. Progression-free survival at 24 months follow-up in patients treated for locally advanced cervical cancer: H-score | The histochemical scoring assessment (H-SCORE) will be recorded on a scale of 0-300 | 24 months | 
| C. Correlation between the Inhibitor of Apoptosis Protein XIAP expression and Programmed Death - Ligand 1 expression. | The expression level of XIAP and the expression level of PD-L1 in biopsies will be measured by immunohistochemistry. | Baseline | 
| C. Correlation between the Inhibitor of Apoptosis Protein cIAP1 expression and Programmed Death - Ligand 1 expression. | The expression level of cIAP1 and the expression level of PD-L1 in biopsies will be measured by immunohistochemistry. | Baseline | 
| C. Correlation between the Inhibitor of Apoptosis Protein cIAP2 expression and Programmed Death - Ligand 1 expression. | The expression levels of cIAP2 and expression level of PD-L1 in biopsies will be measured by immunohistochemistry. | Baseline | 
| D. Correlation between the Inhibitor of Apoptosis Protein XIAP expression and lymphocytic tumour infiltration (LTI). | The expression level of XIAP and the level of lymphocytic tumour infiltration will be measured as % in biopsies. | Baseline | 
| D. Correlation between the Inhibitor of Apoptosis Protein cIAP1 expression and lymphocytic tumour infiltration (LTI). | The expression level of cIAP1 and the level of lymphocytic tumour infiltration will be measured as % in biopsies. | Baseline | 
| D. Correlation between the Inhibitor of Apoptosis Protein cIAP2 expression and lymphocytic tumour infiltration (LTI). | The expression level of cIAP2 and the level of lymphocytic tumour infiltration will be measured as % in biopsies. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Apoptosis inhibiting proteins, Cervical cancer, Apoptosis