Efficacy and safety of PI3K/Akt/mTOR inhibitors combined with trastuzumab therapy for HER2-positive breast cancer: a meta-analysis

OBJECTIVE: Activation of the PI3K/AKT/mTOR pathway in patients with HER2-positive breast cancer is associated with acquired resistance to trastuzumab. This randomized controlled trial (RCTs) meta-analysis was designed to evaluate the clinical efficacy and safety of PI3K/Akt/mTOR inhibitors in combination with trastuzumab in HER2-positive breast cancer. MATERIALS AND METHODS: We searched on Web of Knowledge, PubMed, Embase, Co-chrane, CNKI, and ClinicalTrials.Gov for RCTs comparing PI3K/Akt/mTOR inhibitors plus trastuzumab vs. standard trastuzumab treatments. Pooled estimates of progression-free survival (PFS), pathologic complete response (pCR), and incidence of adverse events were determined. RESULTS: 5 studies out of 610 were found to be eligible and were included in our analysis (n=1,548 participants). PI3K/Akt/mTOR inhibi-tors combination with trastuzumab treatments resulted in a statistically significant increase in PFS compared with conventional trastuzumab therapy (HR 0.82; 95% CI: 0.76-0.90; p < 0.00001). The new combination treatment was more effec-tive on hormone receptor-negative patients (HR 0.73; 95% CI: 0.58-0.93; p=0.010). In addition, the combination of PI3K/Akt/mTOR inhibitors with trastuzumab slightly increased the risk of some adverse events, such as neutropenia, leukopenia, fatigue, and anemia. CONCLUSIONS: The combination treatments of PI3K/Akt/mTOR inhibitors and trastuzumab for PI3K/Akt/mTOR inhibitors combined with trastuzumab treatments for patients with HER2-posi-tive breast cancer can improve median progression-free survival while increasing the incidence of adverse events. It is still controversial based on the current evidence. Due to the limited number and quality of included studies, more high-quality studies are needed for further analysis.