Study selection
Clinical trials that met the following criteria were included for analysis : (i) prospective, randomized, controlled phase 2 or 3 trials involving breast cancer patients; (ii) random assignment of participants to dual HER2 blockade or anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab or T-DM1) with or without concomitant therapy in cancer patients regardless of treatment setting and (iii) available data regarding events or incidence of cardiac events and sample size. For trials with multiple intervention arms (for example, three-arms trials with two anti-HER2 monotherapy arms and one combined anti-HER2 therapy arm), we merged the two relevant (anti-HER2 monotherapy) arms into one group, then compared the merged group with dual HER-2 blockade group as previously reported[12]. Additionally, we used the five-item Jadad scale including randomization, double-blinding, and withdrawals as previously described to assess the quality of included trials. the final score was reported between 0 and 5[14].