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EP-4650460-B1 - METHODS FOR CLASSIFYING, DETERMINING A TREATMENT AND PREDICTING THE PROGNOSIS OF A GASTRIC ADENOCARCINOMA, AND THE KIT FOR USE THEREOF

EP4650460B1EP 4650460 B1EP4650460 B1EP 4650460B1EP-4650460-B1

Inventors

  • MONTAL ROURA, Robert

Dates

Publication Date
20260513
Application Date
20240514

Claims (10)

  1. An in vitro method for determining the class of a tumor from an individual with gastric adenocarcinoma, the method comprising: - determining the level of gene expression of a gene signature in a tumor sample from said individual, wherein the gene signature comprises: - a first subgroup of five genes consisting of CD74, CD5, HLA-E, CD3E, and ITGAL; and - a second subgroup of five genes consisting of CCL20, BLM, ADORA2A, RPL23, and GLS; wherein the tumor is classified as being or not of the inflamed class.
  2. The in vitro method of claim 1, wherein the gene signature consists of the genes from the two subgroups: CD74, CD5, HLA-E, CD3E, ITGAL, CCL20, BLM, ADORA2A, RPL23 and GLS.
  3. The in vitro method according to any one of claims 1 or 2, wherein: - the tumor is classified as tumor of the inflamed class when the expression level of the five genes from the first subgroup are over-expressed compared to a reference value; and when the expression level of the five genes of the second subgroup are infra-expressed compared to a reference value; - and the tumor is not classified as tumor of the inflamed class when the expression level of the five genes from the first subgroup are not over-expressed compared to the reference value; and the expression level of the five genes of the second subgroup are not infra-expressed compared to the reference value.
  4. An in vitro method for classifying an individual afflicted with gastric adenocarcinoma, comprising: - determining the class of a tumor from the individual according to any one of claims 1 to 3; wherein the individual is classified as having or not a gastric adenocarcinoma of the inflamed class based on the class of the tumor.
  5. An in vitro method for predicting the prognosis of an individual afflicted with gastric adenocarcinoma, comprising: - determining the class of a tumor from the individual according to any one of claims 1 to 3; and - determining the prognosis of said individual based on the class of the tumor.
  6. An in vitro method for defining a treatment work-up schedule and estimating a treatment response to an Immune Checkpoint Inhibitor (ICI) for an individual afflicted with gastric adenocarcinoma, comprising: - classifying the individual as having or not a gastric adenocarcinoma of the inflamed class by means of the method defined in claim 4; and - determining the estimation of the response to an ICI treatment; wherein an ICI treatment is scheduled for the individual if the tumor is classified as the inflamed class.
  7. A kit comprising reagents adequate for determining the expression level of the group of genes consisting of CD74, CD5, HLA-E, CD3E, ITGAL, CCL20, BLM, ADORA2A, RPL23 and GLS; wherein the reagents are selected from the group consisting of primers, probes, aptamers and antibodies.
  8. Use of a kit according to claim 7 for: - determining the class of a tumor from an individual with gastric adenocarcinoma as being or not of the inflamed class; - classifying an individual with gastric adenocarcinoma as having or not a gastric adenocarcinoma of the inflamed class; - predicting the prognosis of an individual afflicted with gastric adenocarcinoma, or - selecting an ICI treatment for - an individual afflicted with gastric adenocarcinoma of the inflamed class, or - an individual which is likely to benefit from ICI treatment.
  9. Use of a kit according to claim 8, wherein the ICI treatment is combined with a treatment selected from the group consisting of radiotherapy, chemotherapy, target therapy, and any combination thereof.
  10. A computer-implemented method for predicting the prognosis of an individual afflicted with gastric adenocarcinoma, and/or for defining a treatment work-up schedule for the individual, the method comprising analyzing the data collected through the in vitro method disclosed in any one of claim 1 or 2 by comparing the expression level of the genes with a reference level for each gene; and providing the predicting the prognosis, in such a way that: - the tumor is classified as tumor of the inflamed class when the expression level of the five genes from the first subgroup are over-expressed compared to a reference value; and when the expression level of the five genes of the second subgroup are infra-expressed compared to a reference value; - and the tumor is not classified as tumor of the inflamed class when the expression level of the five genes from the first subgroup are not over-expressed compared to the reference value; and the expression level of the five genes of the second subgroup are not infra-expressed compared to the reference value.

Description

TECHNICAL FIELD The invention refers to the field of medicine, specifically to the personalized medicine. More specifically, the invention refers to methods for identifying the class of gastric adenocarcinoma, as well as methods of diagnosis based on said assessment, and the method for predicting responsiveness or non-responsiveness to a treatment for patients with gastric adenocarcinoma. The invention also refers to the kit for carrying out said methods. BACKGROUND OF THE INVENTION Gastric cancer (GC) is the fourth leading cause of cancer death with approximately 800,000 deaths, and more than one million of new cases per year. Although the pathogenesis of GC remains unclear, chronic gastritis is believed to participate in cellular changes, leading to malignant transformation. Adenocarcinoma is the most common histologic type of GC and accounts for approximately 85 to 90% of all cancers of the stomach. Gastric adenocarcinoma (GAC) is further classified into intestinal, and diffuse histologic subtypes and into chromosomal unstable, genome stable, microsatellite unstable and Epstein-Barr positive molecular subtypes (TCGA classification). Despite improvements in prevention, early diagnosis, and multidisciplinary therapies, GC is usually diagnosed at advanced stages leading to poor prognosis. In advanced clinical stages, cytotoxic chemotherapy is still the cornerstone of treatment, with a median overall survival of~12 months for patients treated with conventional chemotherapy. Intratumoral and intertumoral heterogeneity are prominent features of GC that partly contribute to its poor prognosis. However, histological classification alone is insufficient to effectively stratify patients for individualized treatment and improve patients' clinical outcomes. Therefore, cutting-edge diagnostic techniques and drugs are of fundamental importance for better characterizing molecular profiles and identifying potential novel therapeutic targets for GC patients. For patients with advanced and metastatic GC, targeted therapy represents a promising treatment option. This approach comprises the identification of molecular targets in cancer cells and the development of drugs capable of blocking or inhibiting these targets. Trastuzumab, a monoclonal antibody targeting Human Epidermal Receptor 2 (HER2), was the first approved targeted therapy for GC, and since its approval has contributed to improve the overall survival in patients with metastatic HER2-positive GC when it is added to chemotherapy. Anti-vascular endothelial growth factor (VEGF) therapy is another example of targeted therapy that, in combination with chemotherapy, has demonstrated enhanced survival rates compared to chemotherapy alone. Due to its improved efficacy outcome, monoclonal VEGFR-2-targeting antibody ramucirumab has been recommended as the standard treatment for advanced GC in the second-line setting. In recent years, immunotherapy has showed promising outcomes, particularly for patients with advanced, recurrent, or metastatic GC. Among the many alternatives, one of the most commonly utilized is the use of Immune Checkpoint Inhibitors (ICIs), such as anti-Programmed death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1). By blocking related immune checkpoint signaling pathways, ICls can restore the anti-tumor immune responses of immune cells. The good survival outcomes obtained in clinical trials measuring the efficacy of anti-PD-1/PD-L1, validated the use of chemotherapy plus nivolumab/pembrolizumab as a standard of care option in the first-line for advanced/metastatic tumors with an overexpression of PDL-1. Due to its significant association between its level of expression and the benefit derived of immune checkpoint inhibition in GC, PD-L1 expression has been increasingly utilized for the selection of patients most likely to respond to ICI treatment. Nevertheless, this biomarker shows several issues that need to be considered in the therapeutic decision, such as such as spatial and temporal heterogeneity, interobserver variability, immunohistochemistry assay, and influence by chemotherapy or radiation therapy. Therefore, the significance of PD-L1 as a predictive biomarker for GC still needs further study, and a real need to identify patients who will truly benefit from ICI intervention in the GC space still remains. Despite of the beneficial therapeutic effects presented by ICls, only a limited subset of patients shows complete response to PD-1 therapy, and some of the patients who show a response eventually develop resistance to immunotherapy. While the mechanisms of acquired resistance remain to be fully elucidated, there are actionable strategies that are emerging as alternate to anti-PD-1 blockade to modulate immune cell activity to overcome resistance to existing approved immunotherapies. Treatment with anti-Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) agents has been shown to have a synergistic effect with anti-PD-1 blockade, and this co