Discussion
To our best knowledge, this meta-analysis is the largest and most comprehensive meta-analysis to assess the risk of cardiac toxicities associated with dual HER2 blockade versus anti-HER2 monotherapy. A total of 16,375 patients from 15 randomized controlled trials were included for analysis. Our pooled results indicate that the overall incidence rate of LVEF decline and CHF in dual HER-2 blockade are 4.6% and 0.9%, which is higher than that of anti-HER-2 monotherapy (3.2% and 0.7%, respectively). Importantly, the present study for the first time demonstrates that dual HER-2 blockade therapy in breast cancer patients increases 19% risk of developing LVEF decline and 45% risk of developing CHF when compared to anti-HER2 monotherapy. It should be noted that patients with inadequate cardiac function would be excluded from treatment and close cardiac monitoring has been performed during the administration of anti-HER-2 agents, both of them would significantly reduced the incidence of cardiac toxicities. Although the overall incidence of cardiac toxicities is very low, a slight but significant risk of developing cardiac toxicities has been observed in dual HER-2 blockade when compared to anti-HER-2 monotherapy.
Sub-group analysis showed that addition of dual HER-2 blockade to adjuvant treatment in breast cancer significantly increased the risk of developing LVEF decline (p =0.031) and CHF (p= 0.049), but not for neoadjuvant or metastatic settings. Additionally, cardiac toxicities associated with specific anti-HER-2 agents might be difference, which might be attributable to the unique epitopes of HER2 recognized by each antibody and differential effects on downstream signaling pathways[38]. The cardiac toxicities associated with trastuzumab seems higher than that of lapatinib. In a previous publication based on 29,000 breast cancer, the authors found that incidence severe cardiac toxicities with trastuzumab was 3.0%(95%CI: 2.41-3.64)[39], while the overall cardiac toxicities associated with lapatinib was 3.0%[40]. We therefore perform sub-group analysis based on anti-HER-2 agents, and find that dual HER-2 blockade in breast cancer patients significantly increased the risk of developing LVEF decline (p =0.004) when compared to lapatinib alone, but not for CHF (p =0.11, respectively). No significant difference of cardiac toxicities is found between dual HER-2 blockade and trastuzumab. Additionally, the concomitant hormonal treatment with dual HER-2 blockade in breast cancer significantly increases the risk of developing LVEF decline in comparison with hormonal therapy plus anti-HER2 monotherapy (p =0.022), while concomitant chemotherapy with dual HER2 blockade treatment also significantly increases the risk of developing CHF when compared to anti-HER2 monotherapy plus chemotherapy (p =0.052). Based on our finding, dual HER-2 blockade therapy in breast cancer is associated with a small but statistically significant risk of developing LVEF decline and CHF when compared with anti-HER2 monotherapy. In comparison with anti-HER-2 monotherapy, addition of dual HER-2 blockade to neoadjuvant or metastatic settings for breast cancer is safe in terms of cardiac toxicities, but not for adjuvant setting. Physicians should pay more attention to cardiac toxicities during the administration of dual HER-2 treatment when concomitant hormonal/chemotherapy treatment.
The molecular mechanisms related to cardiac toxicities induced by anti-HER2 agents, either alone or in combination, remains unknown. One potential explanation for the mechanism is the inhibition of NRG-1/HER2 signaling pathway by using anti-HER-2 agents[41]. In multiple vitro studies have demonstrated that the NRG-1/ErbB2 signaling pathway plays an important role in controlling cardiomyocytes proliferation, survival and myofibril disarray in cardiomyocytes[38].
The main strengths of this study are that clinical trials are identified by a systematic literature review with the largest and comprehensive meta-analysis to investigate the cardiac toxicities associated with dual HER-2 blockade versus anti-HER-2 monotherapy. The quality of this evidence is high because all of the included trials are prospective randomized controlled trials. However, several limitations are needed to be concerned. First of all, patients enrolled in prospective trials generally need to have adequate cardiac function, and close cardiac monitoring is implemented for all treated patients, which might underestimate the incidence of cardiac toxicities in common oncology practice. Secondly, this is a meta-analysis of published data, and lack of individual patient data prevents us from adjusting the cardiac toxicities according to previous treatment and patient variables. For example, the cardiac safety of dual HER-2 blockade in breast cancer patients with preexisting cardiovascular risk factors remains undetermined. Finally, these studies are conducted at various international institutions by different investigators and may have potential bias in reporting the types of cardiac events. In addition, the primary endpoints of the these included studies are aimed to investigate the survival benefit of anti-HER2 therapy in cancer patients, but not for cardiac toxicities related dual HER-2 blockade. Thus, the frequency of cardiac toxicities might be underreported in clinical trials.