## 4 Discussion
Together, these facts may hint that the effect of exercise in preventing cardiac dysfunction, assessed by LVEF, may only be detected after long-term of AC-T, which suggests that studies designed to explore this topic need to include a long-term follow-up. Moreover, further studies are needed to conclude whether the exercise training performed during AC-T provides adaptations to protect the heart in the long-term and whether this potential cardioprotective effect would extend to prevent cardiotoxicity during trastuzumab. Regarding the setting of TC-T, we only have identified one RCT [23] and one published study protocol [38] which aimed to evaluate the effects of a high-intensity interval training (HIIT) intervention. In the unique RCT conducted during adjuvant trastuzumab, [PERSON] et al. [23] showed that an exercise intervention combining AT and RT was able to significantly alleviate the decline in LVEF and in aerobic capacity (assessed by the six min walk test) among the exercise group, a phenomenon that occurred in the control. Previously, in a single-arm trial, [PERSON] et al. [51] verified that AT did not prevent a significant decline in LVEF and this was not related to previous AC-T, trastuzumab dose and adherence to training sessions. The authors also reported that trastuzumab was discontinued in three patients (18%) before the post-intervention assessment. Asymptomatic decline in LVEF is the most common manifestation of cardiotoxicity during trastuzumab and can lead to premature interruption or discontinuation of therapy [5]. Although often considered reversible after treatment discontinuation (Type II cardiotoxicity) [5], [PERSON] et al. [52] verified that patients with versus without history of trastuzumab-related cardiotoxicity presented lower mean values of resting LVEF (56.9 \(\pm\) 5.2% vs. 62.4 \(\pm\) 4%; \(p\) < 0.001), GLS (\(-\)17.8 \(\pm\) 2.2% vs. \(-\)19.8 \(\pm\) 2.2%; \(p\) < 0.001) and VO\({}_{2}\) peak (22.9 \(\pm\) 4.4 mL/kg/min vs. 27 \(\pm\) 5.3 mL/kg/min; \(p\) < 0.001) after a mean seven-year follow-up. These novel findings suggest that the development of cardiotoxicity during trastuzumab may lead to a persistent long-term impairment on cardiac function, which extends beyond the heart, affecting the cardiorespiratory capacity, emphasizing the need to implement holistic strategies for support cardiovascular health. Previous meta-analysis [15, 47, 48] have highlighted the effectiveness of exercise training to prevent or mitigate the decline of cardiorespiratory capacity. Although widely used for monitoring cardiac function in cardio-oncology setting, LVEF has important limitations [10, 11], thus, an integrated approach which includes the assessment of other echocardiographic outcomes (parameters of diastolic function and strain imaging), and biomarkers has been recommended. Three [23, 25, 26] and two [25, 26] included trials reported, respectively, data on diastolic function (measured by E/A ratio), and NT-proBNP. For both outcomes, pooled analysis did not reveal significant changes. Regarding strain imaging outcomes, two studies analyzed longitudinal strain [23, 26] and GLS [23], but no changes were verified. In contrast, findings from a non-randomized study showed that exercise training, combining AT and RT, during AC-T, mitigated the GLS decline [53]. This is a relevant finding, that needs to be confirmed, as GLS has been suggested to early predicts subclinical cardiac dysfunction [10; 11]. The limited number of trials in this review did not allow us to analyze the role of different training types and intensity on study outcomes. In light of the literature of the cardiac rehabilitation field, continuous aerobic exercise, at moderate intensity, has been associated to improve LVEF in heart failure patients, but that benefit was not evident when RT was performed alone or combined with AT [54; 55; 56]. However, [PERSON] et al. [23] demonstrated that AT combined to RT had a favorable effect in preventing LVEF decline among women with BC receiving adjuvant trastuzumab.