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Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients receiving cardiotoxic therapies. The SAFE trial (ClinicaTrials.gov identifier: NCT2236806) is a four-arm, randomized, phase 3, double-blind, placebo-controlled study. This is a subgroup analysis focused on the impact of postoperative breast radiation therapy (RT) of the pre-specified interim analysis on the first 174 patients who had completed cardiac assessment at 12-month.

Patients were eligible for trial inclusion if they had indication to primary or postoperative systemic therapy using an anthracycline-based regimen. Cardioprotective therapy (bisoprolol, ramipril, or both drugs, as compared to placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy. The primary endpoint was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS).

At 12-month, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .005). GLS worsened by 6.0% in placebo arm and 1.5%, .6% in ramipril, and bisoprolol arms, respectively; whereas it was unchanged (.1% improvement) in ramipril plus bisoprolol arm (P < .001). Concerning differences in 3D-LVEF changes from baseline to end of treatment, bisoprolol-containing arms showed significant benefit in patients not receiving RT (P = .09), in patients receiving right-sided breast RT (P = .0001), and with lesser extent, in patients receiving left-sided RT (P = .041). No significant benefit was shown in ramipril-containing arms. Concerning differences in GLS changes from baseline to end of treatment, bisoprolol-containing arms showed significant benefit in patients not receiving RT (P = .0001) and in patients receiving right-sided breast RT (P = .0001), while no benefit was shown in patients receiving left-sided breast RT (P = .270). Ramipril-containing arms showed significant benefit in patients not receiving RT (P = .035) and in patients receiving left-sided breast RT (P = 0.14), while no benefit was shown in right-sided breast RT (P = .260).

At the interim analysis, cardioprotective pharmacological strategies in patients affected by breast cancer receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodeling. This favorable effect seems to be reduced in patients receiving postoperative left-sided breast RT, thus calling for further investigations on potentially radiation-related early subclinical heart damage.