Role of Sodium-glucose Linked Transporter 2 (SGLT2) and Its Inhibitor Over CARdiotoxicity Induced by Anthracyclines and Breast Cancer Tumorigenesis SCARA-B

Condition(s) studied

Investigational drug(s) / intervention(s)

Anthracycline: as standard of care

Study summary

In the context of breast cancer, in case of an indication for chemotherapy, anthracycline-based protocols make it possible to improve the overall survival of patients most at risk. The frequency of anthracycline-related cardiac toxicities (ARCT) increases with the cumulative dose of anthracyclines administered and explains, at least in part, the increased risk of cardiovascular (CV) mortality in patient populations treated for breast cancer. The numerous indications for anthracycline-based protocols have made it possible to describe ARCT, among which heart failure with reduced left ventricular ejection fraction (LVEF) remains one of the most comorbid. In addition to left ventricular dysfunction, anthracyclines have been associated with endothelial dysfunction, microvascular damage and myocardial ischemia responsible for dilated cardiomyopathy.

Different approaches have attempted to better understand and prevent these ARCT. However, apart from the notion of limit cumulative doses of anthracyclines, few of them have made it possible to screen patients at risk and prevent the onset of cardiac dysfunction. The search for biological markers (Troponin I, BNP) or ultrasound markers (Longitudinal Strain) warning of subclinical cardiac damage is still struggling to assert its interest due in particular to significant inter- and intra-observer variability. Therapeutically, ACE inhibitors and beta-blockers have shown a significant improvement in the incidence rate of LVEF reduction during adjuvant treatment of breast cancer. However, despite equivalent signals in other cancers, the studies conducted to date are insufficiently powered and the role of these treatments is limited to secondary prevention or the treatment of objective heart failure. It remains necessary to determine new biological markers that can identify patients most at risk of ARCT and thus adapt our therapeutic prevention strategies. To do this, it is first necessary to better understand the pathophysiology underlying these ARCT.

The objective of this study is to determine whether expression of the receptor among endothelium and circulating cells, SGLT2, is associated with an additional risk of presenting cardiovascular toxicity following treatment with anthracycline. If this association is demonstrated, it will then be possible to better screen and prevent these cardiovascular complications.

Eligibility

Primary outcome measure(s)

• Evaluate the expression of SGLT2 — At cycles 1, 2, 3, 4 and 2-3 weeks after end of treatement.
  Measurement of protein expression (Western Blot) and mRNA (RT-qPCR) of SGLT2 within the different models studied and according to the cumulative quantity of anthracyclines received and the patient's cardiovascular history before and after epirubine infusion.
• Evaluate the expression of SGLT2 — At cycles 1, 2, 3, 4 and 2-3 weeks after end of treatement.
  Measurement of the polarization of peripheral blood mononuclear cells (PBMCs) into pro-inflammatory M1 and anti-inflammatory M2 before and after epirubine infusion.
• Evaluate the expression of SGLT2 — At cycles 1, 2, 3, 4 and 2-3 weeks after end of treatement.
  Fluorescence measurement of the level of reactive oxygen species (ROS) formation and senescence of cardiovascular cells before and after epirubine infusion.
• Evaluate the expression of SGLT2 — At cycles 1, 2, 3, 4 and 2-3 weeks after end of treatement.
  Measurement of inflammatory mediators secreted by circulating cells.Comparison with positive and negative controls that induce inflammation and ROS before and after epirubine infusion.

Trial sites (1)

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