Abstract PD5-02: Cardioprotective strategy for non-metastatic breast cancer patients receiving an anthracycline-based chemotherapy: subgroup analysis focused on impact of postoperative breast radiation therapy of the preplanned interim analysis of the phase 3 SAFE trial (NCT2236806)

Abstract Background: several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. The SAFE trial (ClinicaTrials.gov identifier: NCT2236806) is a four-arm, randomized, phase 3, double-blind, placebo-controlled study. The objective is to determine whether pharmacological cardioprevention could reduce subclinical heart damage in breast cancer patients treated with anthracycline-based chemotherapy. This is a subgroup analysis focused on the impact of postoperative breast radiation therapy (RT) of the recently published pre-specified interim analysis on the first 174 patients who had completed cardiac assessment at 12-month. Methods: patients were eligible for trial inclusion if they had indication to primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with prior diagnosis of cardiovascular disease were excluded. 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 in case of HER2 positive patients. 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). Results: 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). The percentage of patients showing a reduction ≥10% in 3D-LVEF was 19% in placebo arm, 11.5% in ramipril arm, 11.4% in bisoprolol arm and 6.8% in ramipril plus bisoprolol arm; 35.7% patients receiving placebo showed a ≥10% GLS worsening compared to 15.9% (ramipril), 13.6% (bisoprolol), and 13.6% (ramipril plus bisoprolol) (P = .025). 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). Conclusions: 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. Citation Format: Icro Meattini, Giuseppe Barletta, Carlotta Becherini, Luca Visani, Francesca Martella, Mario Airoldi, Domenico Amoroso, Luigi Coltelli, Chiara Bellini, Giulia Stocchi, Victoria Lorenzetti, Carolina Orsatti, Lucia Angelini, Lorenzo Livi. Cardioprotective strategy for non-metastatic breast cancer patients receiving an anthracycline-based chemotherapy: subgroup analysis focused on impact of postoperative breast radiation therapy of the preplanned interim analysis of the phase 3 SAFE trial (NCT2236806) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-02.