Sub-group analysis
Firstly, we carried out a subgroup risk analysis stratified according to treatment settings. Our results demonstrated that risk of LVEF decline and CHF was comparable between dual HER-2 blockade and anti-HER2 monotherapy in neoadjuvant or metastatic setting (bothp >0.05, table 2). However, the addition of dual HER2 blockade to adjuvant treatment in breast cancer significantly increased the risk of developing CHF (OR 2.00, 95%CI: 1.23-3.24, p =0.005) and LVEF decline (OR1.17, 95%CI: 1.00-1.38, p =0.048, table 2).
The concomitant treatment with anti-HER-2 therapy might impact the ORs of cardiac toxicities. Our combined results demonstrated that concomitant hormonal therapy with dual HER2 blockade in breast cancer significantly increased risk of developing LVEF decline in comparison with hormonal therapy plus anti-HER2 monotherapy (OR 4.51, 95%CI:1.24-16.40, p =0.022), while no concomitant treatment or concomitant chemotherapy with dual HER-2 blockade did not increase the risk of developing LVEF decline(p =0.19 and p =0.11, respectively). As for CHF events, concomitant chemotherapy with dual HER2 blockade treatment significantly increased the risk of developing CHF when compared to anti-HER2 monotherapy plus chemotherapy (OR 1.47, 95%CI: 1.00-2.16, p =0.052), while no concomitant treatment or concomitant hormonal therapy with dual HER-2 blockade did not increase the risk of CHF (p =0.22 and p =0.59, respectively).
We also did sub-group analysis according to anti-HER-2 monotherapy. Our result showed that dual HER-2 blockade significantly increased the risk of developing LVEF decline (OR 1.49, 95%CI: 1.14-1.96, p =0.004) when compared to lapatinib, but not for CHF (OR 2.62, 95%CI: 0.90-2.94,p =0.11). In comparison with trastuzumab alone, no significantly increased risk of developing LVEF decline(p =0.37) and CHF (p =0.24, table 2) was observed in dual HER-2 blockade group.