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EP-4739800-A1 - IN VITRO METHOD FOR THE PROGNOSIS OF PATIENTS SUFFERING FROM TRIPLE-NEGATIVE BREAST CANCER

EP4739800A1EP 4739800 A1EP4739800 A1EP 4739800A1EP-4739800-A1

Abstract

The present invention refers to an in vitro method for the prognosis of patients suffering from triple-negative breast cancer (TNBC).

Inventors

  • PRAT APARICIO, Aleix
  • BRASÓ MARISTANY, Fara
  • Paré Brunet, Laia

Assignees

  • Reveal Genomics S.L.

Dates

Publication Date
20260513
Application Date
20240627

Claims (20)

  1. 1. In vitro method for identifying biomarker signatures for the prognosis of patients suffering from triple-negative breast cancer, which comprises: a. Measuring the level of expression of gene CXCR6 in combination with at least a gene selected from the group consisting of: \IRF4, LAX1, POU2AF1, CD274, CD79A, TNFRSF17, PIM2, PDCD1 and/or SLAMF1 , in a biological sample obtained from the patient; b. Determining a combination score value; and c. Wherein if a deviation of the combination score value is identified, as compared with a pre-established reference value, this is indicative that the biomarker signature may be used for the prognosis of patients suffering from triplenegative breast cancer.
  2. 2. In vitro method, according to claim 1, for identifying biomarker signatures for the prognosis of patients suffering from triple-negative breast cancer treated with chemotherapy.
  3. 3. In vitro method, according to any of the previous claims, for identifying biomarker signatures for the prognosis of patients suffering from triple-negative breast cancer treated with taxane-based therapy.
  4. 4. In vitro method, according to any of the previous claims, for identifying biomarker signatures for the prognosis of patients suffering from triple-negative breast cancer treated with adjuvant or neoadjuvant taxane-based therapy.
  5. 5. In vitro method for the prognosis of patients suffering from triple-negative breast cancer, the method comprising measuring the level of expression of gene CXCR6 in combination with at least a gene selected from the group consisting of: \IRF4, LAX1, POU2AF1, CD274, CD79A, TNFRSFI7, PIM2, PDCD1 and/or SLAMFl , in a biological sample obtained from the patient.
  6. 6. In vitro method, according to claim 5, for the prognosis of patients suffering from triplenegative breast cancer, the method comprising measuring the level of expression of a gene combination selected from: CXCR6 IRF4, CXCR6 LAX1, CXCR6 POU2AF 1 , CXCR6 CD274, CXCR6 CD79A, CXCR6 TNFRSF17, CXCR6 PIM2, CXCR6 PDCD1 and/or CXCR6 SLAMF1, in a biological sample obtained from the patient.
  7. 7. In vitro method, according to any of the claims 5 or 6, for the prognosis of patients suffering from triple-negative breast cancer, which comprises: a. Measuring the level of expression of the gene combination, in a biological sample obtained from the patient; b. Determining a combination score value; and c. Wherein if a deviation of the combination score value is identified, as compared with a pre-established reference value, this is indicative of the prognosis of patients suffering from triple-negative breast cancer.
  8. 8. In vitro method, according to any of the claims 5 to 7, for the prognosis of patients suffering from triple-negative breast cancer, which comprises: a. Measuring the level of expression of the gene combination, in a biological sample obtained from the patient; b. Determining a combination score value; and c. Wherein if an increased score value is identified, as compared with a pre- established reference value, this is indicative of good prognosis.
  9. 9. In vitro method, according to any of the claims 5 to 8, for the prognosis of patients suffering from triple-negative breast cancer, which comprises: a. Measuring the level of expression of the gene combination in a biological sample obtained from the patient; b. Determining a combination score value; and c. Wherein if an increased score value is identified, as compared with a pre- established reference value, this is indicative of lack of cancer recurrence.
  10. 10. In vitro method, according to any of the claims 5 to 9, for the prognosis of patients suffering from triple-negative breast cancer which comprises: a. Measuring the level of expression of the gene combination in a biological sample obtained from the patient; b. Determining a combination score value; and c. Wherein if an increased score value is identified, as compared with a pre- established reference value, this is indicative of response to chemotherapy -based therapy.
  11. 11. In vitro method, according to any of the claims 5 to 10, for the prognosis of patients suffering from triple-negative breast cancer treated with chemotherapy.
  12. 12. In vitro method, according to any of the claims 5 to 11, for the prognosis of patients suffering from triple-negative breast cancer treated with taxane-based therapy.
  13. 13. In vitro method, according to any of the claims 5 to 12, for the prognosis of patients suffering from triple-negative breast cancer treated with adjuvant or neoadjuvant taxane-based therapy.
  14. 14. In vitro use of the gene CXCR6 in combination with at least a gene selected from the group consisting of: \IRF4, LAX1, POU2AF1, CD274, CD79A, TNFRSF17, PIM2, PDCD1 and/or SLAMFl , or of a kit comprising reagents for the assessing the level of expression of the gene combination, for identifying biomarker signatures for the prognosis of patients suffering from triple-negative breast cancer.
  15. 15. In vitro use the gene CXCR6 in combination with at least a gene selected from the group consisting of: [IRF4, LAX1, POU2AF1, CD274, CD79A, TNFRSFI7, PIM2, PDCD1 and/or SLAMFl , or of a kit comprising reagents for the assessing the level of expression of the gene combinations, for the prognosis of patients suffering from triple-negative breast cancer.
  16. 16. In vitro use, according to claim 15, of at least a gene combination selected from: CXCR6 IRF4, CXCR6 LAX1, CXCR6 POU2AF1, CXCR6 CD274, CXCR6 CD79A, CXCR6 TNFRSF17, CXCR6 PIM2, CXCR6 PDCD1 and/or CXCR6 SLAMFl, or of a kit comprising reagents for the assessing the level of expression of the gene combination, for the prognosis of patients suffering from triple-negative breast cancer.
  17. 17. In vitro use, according to any of the claims 15 or 16, for predicting recurrence.
  18. 18. In vitro use, according to any of the claims 15 to 17, for predicting response to chemotherapy-based therapy.
  19. 19. In vitro use, according to any of the claims 15 to 18, for the prognosis of patients suffering from triple-negative breast cancer treated with chemotherapy.
  20. 20. In vitro use, according to any of the claims 15 to 19, for the prognosis of patients suffering from triple-negative breast cancer treated with taxane-based therapy.

Description

IN VITRO METHOD FOR THE PROGNOSIS OF PATIENTS SUFFERING FROM TRIPLE-NEGATIVE BREAST CANCER FIELD OF THE INVENTION The present invention refers to the medical field. Particularly, the present invention refers to an in vitro method for the prognosis of patients suffering from triple-negative breast cancer (TNBC). STATE OF THE ART The implementation of biomarkers to guide therapy is crucial for the de-escalation and escalation of systemic therapy in early-stage TNBC. Currently, the identification of the key genes responsible for driving this disease, specifically the core immune TNBC genes, remains unknown. Additionally, it is unclear whether combinations of these genes can enhance their association with clinical endpoints. To effectively optimize treatment strategies, it is essential to determine which specific immune genes play a central role in TNBC. By identifying the core immune TNBC genes, researchers can gain valuable insights into the underlying molecular mechanisms driving the disease's progression and treatment response. This knowledge will enable the development of more targeted therapies that focus on modulating these key genes and their associated pathways. Furthermore, investigating the potential synergy between different immune genes may offer additional therapeutic opportunities. By studying combinations of these genes, researchers can explore whether their collective expression has a stronger association with clinical endpoints than individual gene expression. This approach could provide a more comprehensive understanding of the complex immune response in TNBC and potentially lead to the development of novel therapeutic strategies. In summary, there is an unmet medical need of finding new tools focused on the prognosis of patients suffering from TNBC. The de-escalation and escalation of systemic therapy in early- stage TNBC require the integration of biomarkers to guide treatment decisions. It remains essential to identify the core immune TNBC genes responsible for driving the disease. Additionally, exploring combinations of these genes may enhance their association with clinical endpoints and unlock new therapeutic possibilities. Ultimately, this research will contribute to more precise and personalized approaches for the management of early-stage TNBC. The present invention is precisely focused on solving this problem and it is herein provided a new tool for the prognosis of patients suffering from TNBC which helps the clinicians to design or elect therapies in this particular type of cancer. DESCRIPTION OF THE INVENTION Brief description of the invention Such as it is indicated above, de-escalation and escalation of systemic therapy in early-stage TNBC will require the implementation of biomarkers to guide therapy. To date, it is unknown which are they key genes driving this disease (i.e., the Core Immune Genes [CIG]) and if combinations of these genes can improve their association with both clinical endpoints. Consequently, the inventors of the present invention evaluated the expression of up to 185 genes on pre-treatment tumor biopsies from 3 independent publicly available datasets of early-stage TNBC: CALGB40603 (n=389) (NCT00861705), BrighTNess (n=482) (NCT02032277), and SCAN-B (n=498). Patients in CALGB40603 and BrighTNess were treated with neoadjuvant chemotherapy -based therapy (for instance taxane-based therapy) and had pathological complete response (pCR) data. Patients in CALGB40603 and SCAN-B had survival outcome data (event- free survival [EFS] or relapse-free interval [RFi]). Each individual gene was associated with each clinical endpoint within each dataset using Cox model and logistic regression analyses, adjusting for treatment arm. Genes found in common across datasets were selected as CIG, except for PDCD1, which was not available in BrighTNess. Using the CIGs, it was evaluated whether combinations of 2 genes enhance their association with each clinical endpoint using different methods: adding, subtracting, multiplying, and ratio. Likelihood ratio testing was used to evaluate the added contribution of each gene in 2 combined cohorts evaluating pCR (i.e., CALGB40603 and BrighTNess) and survival (i.e., CALGB40603 and SCAN-B). Ten CIGs related to B-cells and T-cells (i.e., IRF4, LAX1, POU2AF1, CD274, CD79A, TNFRSF17, PIM2, PDCD1, CXCR6, and SLAMFP) were associated with higher pCR rates and improved survival outcome across datasets. The correlation coefficient among the 10 CIG genes was 0.63 (moderate). Such as it is shown, for instance, in Table 6, the sum of 2 CIGs provided more prognostic information than a single gene (p<0.001). Two-gene subtraction, multiplication or ratio decreased the amount of prognostic information (p<0.001). The top 10 2-gene CIGs associated with prognosis (p<0.001) were CD274 TNFRSF17, IRF4 CD274, PDCD1 TNFRSF17, CD79A CD274, CD274 POU2AF1, CXCR6 TNFRSF17, LAX1 TNFRSF17, SLAMF1 TNFRSF17, CD 274 LAX 1 and CD79A CXCR6 (Table 6). On the other hand,