## 4 Discussion  
Exercise training has been suggested as a potential approach to mitigate cancer treatment-related cardiotoxicity [41; 42]. There are several reviews that describe the potential protective mechanisms of exercise against cardiotoxicity, but most of these only provide narrative synthesis [43; 44], data from animal studies [45; 46] or are limited to cardiorespiratory fitness outcomes [47; 48]. The present systematic review adds to existing literature by providing the first report of pooled data from RCTs that analyzed the impact of exercise on cardiac function outcomes and circulating biomarkers among women with BC receiving AC-T or TC-T, and a systematic compilation of ongoing trials which are researching this subject. This work demonstrated that exercise appears to have a beneficial effect to mitigating LVEF decline in women with BC receiving AC-T or TC-T, and this effect was significant for interventions with \(\geq\)36 exercise sessions. Although this new finding supports the rationale of exercise as a promising approach for preventing cardiac dysfunction, this result should be interpreted cautiously, because it was based on a limited number of RCTs which involved a small sample size, considerable methodological bias, different exercise interventions, and short-term follow-up. Anthracycline-related cardiotoxicity is often characterized by a continuous progressive decline in LVEF, which predisposes for the development of overt heart failure [9]. Three included trials compared the effects of aerobic exercise versus usual care in LVEF among women with BC receiving AC-T [24; 25; 26]. Two of those studies reported a null effect [24; 25], while [PERSON] [26] found a significant efficacy of exercise (MD: \(4.26\%\); \(95\%\) CI: \(0.49\) to \(8.03\)). This discrepancy is likely to be explained by differences in sample size, protocol of exercise intervention, and, perhaps above all, due to the fact that [PERSON] [26] has presented data following six months of AC-T exposure, which represented a longer follow-up compared to the other two studies. More recently, in a non-randomized trial, [PERSON] et al. [49] tested the effects of an exercise intervention (eight to twelve weeks), combining AT and RT, on cardiac function of 28 women with BC receiving AC-T. The authors found a significant  
Figure 4: Forest plot showing the effect of exercise intervention compared to control on longitudinal strain. efficacy of exercise to mitigating cardiorespiratory fitness impairment (VO\({}_{2}\) peak), but the results regarding LVEF were congruent with the findings from [PERSON] et al. [24] and [PERSON] et al. [25] and no significant changes were verified after a short-term AC-T exposure. However, in a long-term follow-up analysis (12 months after AC-T) involving 17 participants (61%) from the initial cohort, [PERSON] et al. [50] observed that compared to baseline, LVEF did not change significantly in the exercise group (MD: \(-\)3.1%; 95% CI: \(-\)8.4, to 2.1), whereas it statistically decreased in control (MD: \(-\)6.9%; 95% CI: \(-\)11.1 to \(-\)2.0). Moreover, two participants from the control group were diagnosed with asymptomatic cardiotoxicity. Although a possible cardioprotective effect of exercise can be hypothesized, it is plausible that these differences may also be justified by the fact that the control group has presented: older age (58 \(\pm\) 8 years vs. 46 \(\pm\) 9 years; \(p\) = 0.012); higher body mass index (28.1 \(\pm\) 5.5 kg/m\({}^{2}\) vs. 24 \(\pm\) 3.3 kg/m\({}^{2}\); \(p\) = 0.07) and a larger rate of patients undergoing trastuzumab (63% vs. 22%; \(p\) = 0.15); which are recognized factors to further compound the risk for cardiotoxicity. Furthermore, one included trial reported data on LVEF decline from a long-term follow-up (12 months after AC-T), verifying a significant attenuation in the exercise group compared to control (MD: 3.80%; 95% CI: 0.49 to 7.11) [26].