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.