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Heterogeneity of Triple Negative Breast Cancer: Differential response to metronomic chemotherapy in the IBCSG 22-00 trial

par Joaquin Garcia, Andrea
Président du jury Maenhaut, Carine
Promoteur Sotiriou, Christos
Publication Non publié, 2024-08-29

Thèse de doctorat

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Résumé :

Triple-negative breast cancer (TNBC) makes up about 10-20% of all breast cancers and represents a heterogenous disease characterized by a clinically aggressive disease course, with higher relapse rates and worse overall survival compared to other breast cancer types. Studies have shown that TNBC can be divided into different molecular subtypes with distinct mutational profiles, genomic alterations, and biological processes. While these subtypes are extensively described in the literature, their potential association with different treatment effects and the option to steer therapeutic strategies remains largely understudied. Various hypotheses have been developed to describe the potential benefits of treatments for each subtype; however, these molecular classifications have not yet been adopted in clinical practice. TNBC has commonly been treated with a standard chemotherapy regimen; however, in the last years, systemic immunotherapy stands as a therapeutic choice for this disease attributed to its immunogenic nature.The main objective of this thesis is to gain a deeper understanding of immunosuppressive pathways in the tumor microenvironment (TME) of TNBC, which could aid in identifying patients who might benefit from novel therapeutic strategies including immunotherapy. For this purpose, we analyzed the transcriptomics data and the clinicopathological features from the IBCSG 22-00 phase 3 trial.In the first study, we explored the association of TNBC molecular subtypes with survival outcomes and their potential interactions with low-dose cyclophosphamide and methotrexate (CM) maintenance therapy. A significant disease-free survival (DFS) benefit was observed within the immune-enriched TNBC subtypes for patients receiving low-dose CM, suggesting a positive interaction between low-dose CM and immune response. Additionally, stromal tumor-infiltrating lymphocytes (TILs) in our cohort confirm previous research suggesting that lymphocyte-predominant breast cancer (LPBCs) may benefit from this metronomic approach. Moreover, a high expression of regulatory T-cell (Tregs) signature was associated with a better prognosis in the CM arm, in line with a potential immunomodulating role of cyclophosphamide. In contrast, a worse outcome was observed in tumors with a mesenchymal (M) subtype treated with low-dose CM.In the second study, we explored the role of the JNK pathway and its immunosuppressive role in the TME across the TNBC molecular subtypes. Patients with tumors expressing an immune-enriched (IM or high TILs) phenotype along with low pJNK levels experienced a better outcome compared to those with high pJNK levels. These findings indicate that the pJNK signature can discern subgroups within inflamed tumors where immunosuppressive processes are predominant. Furthermore, we observed that high pJNK signature levels were linked to significantly higher Tregs levels and lower CD8+ T cell levels, providing additional confirmation of the pJNK gene signature's accuracy in reflecting JNK phosphorylation. Additionally, IM tumors with high pJNK levels had better outcomes when treated with low-dose CM, these survival rates were similar to those with low pJNK levels. These results further suggest the immune-modulating effect of low-dose CM chemotherapy on tumors with high Tregs in the TME.Our results highlighted the importance of TNBC heterogeneity and provided insights into the potential mechanisms behind the observed benefit of metronomic chemotherapy in immune-enriched tumors. Moreover, our findings provide a rationale for the development of treatment strategies tailored to the different molecular TNBC subtypes.