New Paper Alert! A Novel 3-Gene Expression Score Predicts Immunotherapy Response in Advanced Renal Cell Carcinoma
New Paper Alert! A Novel 3-Gene Expression Score Predicts Immunotherapy Response in Advanced Renal Cell Carcinoma
Authors: Yoel Z. Betancor, Miriam Ferreiro-Pantín, Urbano Anido-Herranz, Mar Fuentes-Losada, Luis León-Mateos, Silvia Margarita García-Acuña, Vanessa Vaamonde-Rodríguez, Beatriz García-Pinel, Víctor Cebey-López, Rosa Villaverde-Viaño, Helena Lombardía-Rodríguez, Martin Kotrulev, Natalia Fernández-Díaz, Iria Gomez-Tourino, Carlos Fernández-Baltar, Jorge García-González, Jose M. C. Tubio, Rafael López-López, Juan Ruiz-Bañobre.
Published in Frontiers in Immunology, on April 10, 2024
Introduction:
The emergence of immunotherapy, particularly PD-1 antibodies, has revolutionized the management of patients with accRCC. However, the identification of reliable biomarkers to predict patient response to immune checkpoint blockade (ICB) remains a priority. This study aimed to develop and validate a gene expression score to predict the clinical benefit of the anti-PD-1 antibody nivolumab in access patients.
Design:
This study conducted a retrospective analysis of data from the CheckMate-009, CheckMate-010, and CheckMate-025 clinical trials to develop and validate a three-gene expression score (3GES) for predicting clinical benefit to the anti-PD-1 antibody nivolumab in patients with advanced clear cell renal cell carcinoma (accRCC). The prognostic value of the 3GES was then validated in the TCGA-KIRC cohort, and its predictive value was evaluated in the CheckMate-025 trial.
What We Learned:
- A 3GES was developed by integrating the expression of three genes (HMGA1, NUP62, and ARHGAP42) that were independently associated with overall survival (OS) in a pooled cohort of 181 nivolumab-treated patients.
- The 3GES was able to segregate patients into favourable and unfavourable risk categories, with the favourable-risk group showing significantly better OS, disease control rate, and overall response rate.
- The prognostic value of the 3GES was validated in the independent TCGA-KIRC cohort.
- In the CheckMate-025 trial, the 3GES showed a significant predictive value, with favorable-risk patients benefiting significantly more from nivolumab treatment compared to everolimus, while no such benefit was observed in the unfavorable-risk group.
- The 3GES was correlated with clinical, molecular, and immune characteristics of the tumour microenvironment.
Key Highlights:
- A novel three-gene expression score (3GES) was successfully developed and validated, enhancing the prediction of responses to nivolumab therapy in patients with advanced renal cell carcinoma (accRCC).
- The 3GES effectively identifies patients likely to benefit from nivolumab, distinguishing those who will respond favorably from those better suited for the standard care with everolimus.
- The 3GES provides crucial insights by correlating with distinct clinical, molecular, and immune characteristics within the tumor microenvironment, aiding in the understanding of the underlying biology.
- This score has the potential to become a valuable biomarker for selecting accRCC patients for immune checkpoint blockade therapy, pending validation in larger prospective clinical trials.
- Risk Group Differentiation: The 3GES delineates two risk groups with markedly different outcomes:
- Favorable-Risk Group: These patients experience significantly improved overall survival, disease control, and response rates when treated with nivolumab.
- Unfavorable-Risk Group: This group does not show a significant survival benefit when treated with nivolumab compared to everolimus.
- Molecular and Immune Profiling:
- Favorable-Risk Tumors: Characterized by PBRM1 mutations, lower immune cell infiltration, and reduced expression of exhaustion markers like CTLA-4, LAG-3, and TIGIT, suggesting an active immune environment.
- Unfavorable-Risk Tumors: Higher levels of immunosuppressive elements such as cancer-associated fibroblasts indicate a less responsive immune system.
- Strategic Treatment Implications:
- For Favorable 3GES Patients: Ideal candidates for less intensive monotherapy with anti-PD-1 antibodies.
- For Unfavorable 3GES Patients: May benefit from more aggressive combination therapies targeting multiple immune checkpoints or the tumor stroma.
Key Takeaway Messages:
- Clinical Application: The three-gene expression score provides a robust tool for predicting the effectiveness of anti-PD-1 therapy in patients with advanced ccRCC. By identifying patients more likely to respond favourably to immunotherapy, clinicians can tailor treatment strategies more effectively.
- Future Research Directions: For broader application in clinical practice, further validation of the 3GES through prospective studies and alternative measurement techniques like RT-qPCR is essential. Additionally, exploring combination therapies for patients identified with an unfavourable 3GES could potentially enhance treatment outcomes.
- Impact on Personalized Medicine: This study underscores the potential of genetic profiling in enhancing the precision of cancer treatment. As personalized medicine continues to evolve, tools like the 3GES can play a pivotal role in optimizing therapeutic strategies and improving patient quality of life.
Summary by Amalya Sargsyan, MD
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