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Stress, adrenergic activation and breast cancer

par Caparica Bitton, Rafael
Président du jury Verhoeven, Caroline
Promoteur de Azambuja, Evandro
Publication Non publié, 2023-05-24

Thèse de doctorat

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Résumé :

Stress is defined as a group of psychological and neuro-humoral reactions occurring in the human body to maintain homeostasis in adaptation to potentially hazardous conditions. The sympathetic autonomic nervous system is one of the first and main effectors activated in response to stress, acting via catecholamines and adrenergic stimulation to mediate key aspects of the neuro-humoral stress response. Besides its physiologic effects, stress may also impact the development and progression of breast cancer, as several preclinical studies show adrenergic activation occurring in response to stress may facilitate proliferation, stimulate invasiveness, and induce treatment resistance in breast cancer cells, whereas ß-blockers can inhibit these deleterious effects of stress. Conversely, other preclinical studies suggest that adrenergic activation may inhibit breast cancer proliferation via the modulation of the tumor immune microenvironment. In this context, the effects of stress and adrenergic activation on breast cancer cells and how these impact the outcomes of patients with breast cancer need to be further studied. The main purposes of the studies presented in this thesis are to investigate if adrenergic activation – a key mediator of stress neuro-humoral response – has an impact on the outcomes of patients with breast cancer, and to depict the mechanisms by which stress and adrenergic activation exert their effects on breast cancer cells and the tumor immune microenvironment. In Section 3.1, we investigated the impact of adrenergic activation – assessed via the expression of the ß2-adrenergic receptor gene (ADRB2) – on the prognosis of patients with breast cancer from 2 publicly available datasets and explored potential mechanisms by which ADRB2 interacts with breast cancer, by correlating ADRB2 expression with gene signatures associated with key oncogenic processes, such as angiogenesis, proliferation, invasiveness, and immune activation. The median value of ADRB2 expression in each dataset was defined as a cutoff to classify patients as having “ADRB2-high” or “ADRB2-low” tumors. Initially, in a dataset of 175 patients with HER2-positive early-stage breast cancer, we observed that a high expression of ADRB2 was associated with a longer DFS. Conversely, in another dataset of 202 patients with HER2-positive early-stage breast cancer enrolled in the FinHer trial, the high ADRB2 expression had no prognostic impact. The expression of ADRB2 was negatively correlated with angiogenesis- and proliferation-related signatures, whereas it was significantly correlated with immune-signatures associated with pro-inflammatory cytokines, interferon and STAT1 pathways, immune effector-cell activation, and differentiation, suggesting that the potential effects of ADRB2 on breast cancer may occur via modulation of the tumor immune microenvironment. To further study the effects of adrenergic activation on patients with HER2-positive breast cancer, in Section 3.2 we investigated the role of ADRB2 expression as a prognostic and predictive biomarker in 1,282 patients enrolled in the phase III NCCTG-N9831 trial. The ideal cutoff for ADRB2 expression assessed as a continuous variable for the outcome survival was established based on our own dataset, with levels above cutoff defined as “high” and levels below cutoff defined as “low”. In line with findings from one of the cohorts analyzed in Section 3.1, a high expression of ADRB2 was associated with a longer DFS in this post-hoc analysis of the NCCTG-N9831 trial. Additionally, ADRB2 expression was predictive of trastuzumab benefit, since the DFS improvement yielded by the addition of trastuzumab to adjuvant chemotherapy was restricted to the subset of patients whose tumors had a high ADRB2 expression. ADRB2 expression was significantly correlated with TIL levels, and high TIL levels positively impacted the prognosis of patients whose tumors had a high ADRB2 expression, reinforcing the role of ADRB2 as a potential modulator of the tumor immune microenvironment in patients with HER2-positive breast cancer.To further study the effects of stress and adrenergic activation on breast cancer, we investigated if the use of ß-blockers (antagonists of adrenergic activation) had an impact on the outcomes of patients with early-stage breast cancer. To meet this purpose, in Section 3.3 we performed a systematic literature review and meta-analysis that included a total of 13 publications and 103,065 patients. We showed that the likelihood of presenting a RFS event was significantly lower in patients who received ß-blockers, and a trend for a beneficial effect of ß-blockers was also observed in terms of breast cancer recurrence and breast cancer-specific mortality. Interestingly, the RFS benefit of ß-blockers was more robust in patients with TNBC, which is considered the most ‘immunogenic’ breast cancer subtype, with the worse prognosis and for which new therapeutic options are most needed. No effect of ß-blockers on pCR or OS was observed. These results suggest the use of ß-blockers prevents breast cancer recurrence and can potentially benefit these patients. In conclusion, the studies presented in this thesis highlighted the compelling potential of ADRB2 to be further explored as a biomarker in patients with HER2-positive early-stage breast cancer. In a landscape where immunotherapy is gaining relevance for the treatment of patients with breast cancer, adrenergic activation arises as an interesting potential therapeutic target, based on the correlation between ADRB2, immune-related signatures and tumor-infiltrating lymphocytes observed in our studies. Finally, by demonstrating that ß-blocker use was a favorable prognostic factor in patients with early-stage breast cancer, our meta-analysis provided updated evidence to address the important question on whether ß-blockers have a protective effect on this population. We hope these findings will support prospective studies investigating the therapeutic role of ß-blockers, which are unexpensive and safe alternatives to improve the outcomes of patients with breast cancer.