Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis

Background Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting. Methods A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents. We calculated summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) for each AE within each class of targeted agents for each trial, and pooled analysis using the random and fixed effect models. Results Sixteen studies (n = 8529 patients) were included. The addition of targeted agents to ET was associated with a significant higher risk of grade 3–4 AEs: OR 2.86 (95% CI 2.49–3.27) for CDK4/6 inhibitors, 1.88 (95% CI 1.39–2.53) for mTOR inhibitors, 2.05 (95% CI 1.63–2.58) for PI3K inhibitors, and 2.48 (95% CI 1.09–5.66) for anti-HER2 agents. The highest class-specific risks were neutropenia grade 3–4 for CDK4/6 inhibitors (OR 40.77; 95% CI 19.52–85.19), stomatitis grade 3–4 for mTOR inhibitors (OR 11.92; 95% CI 3.68–38.57), hyperglycemia grade 3–4 for PI3K inhibitors (OR 40.93; 95% CI 10.08–166.22) and diarrhea for anti-HER2 agents (OR 9.93; 95% CI 4.71–20.95). Conclusions Adding targeted agents to ET is associated with a significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used.