For Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer, Targeted Therapy Plus Endocrine Therapy Was Highly Ranked in Meta-Analysis

The most common subtype of metastatic breast cancer (MBC), hormone receptor-positive (HR+), ERBB2-negative (ERBB2−) MBC, is considered incurable. Evaluating the expanding number of treatment options for this type of breast cancer can be daunting because few regimens have been compared directly in randomized clinical trials (RCTs). 

To rank these treatment regimens for hormone receptor-positive, ERBB2-negative metastatic breast cancer by their comparative effectiveness, researchers at Vanderbilt University and other institutions throughout North America conducted an information theoretic network meta-analysis (IT-NMA; JAMA Network Open. 2022;5(4):e224361. doi.10.1001/jamanetworkopen.2022.4361). This type of analysis is a graph theory-based approach to the ranking of treatment regimens that considers effect sizes and when the evidence was generated. This IT-NMA examined 203 RCTs that together included almost 64,000 patients and utilized 252 different regimens, and the analysis yielded 151 rankings. 

As a result, the analysis highly ranked combinations of endocrine therapy and targeted therapy, particularly cyclin-dependent kinase 4 and 5 inhibitors. For example, letrozole plus palbociclib received the highest ranking, and letrozole plus ribociclib received the third-highest ranking. In contrast, monotherapies such as anastrozole or letrozole that compared unfavorably with novel agents or combinations in recent RCTs received low rankings, and many regimens received a ranking of indeterminant. 

“Meta-analysis integrates findings from multiple trials and can considerably increase statistical power and resolve disparate findings among studies. Network meta-analysis (NMA) is a ranking technique that combines direct and indirect evidence within a network of clinical trials,” wrote Jeremy Warner, MD, MS, Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, and colleagues. “In this network meta-analysis study, combination therapies appeared to be associated with better outcomes than monotherapies in the treatment of HR-positive, ERBB2-negative MBC.”

Regimens were ranked on the basis of clinical trial variables that included their primary endpoint, enrollment number per trial arm, P value, effect size, years of enrollment, and year of publication of the study report.

To identify relevant RCTs to provide the data for their analysis, the researchers consulted HemOnc.org, an online source of information on treatment regimens used in hematology and oncology. The researchers included all primary and subsequent reports of RCTs of first-line, systemic treatment for HR+, ERBB2−, MBC referenced on HemOnc.org and published between 1974 and 2019. In sourcing their data, they also included additional RCTs evaluated by a previous traditional NMA of HR+, ERBB2−, MBC treatments. Separate observers independently extracted the RCTs from HemOnc.org and the traditional NMA. 

In general, the study followed the Preferred Reporting Items for Systematic Review and Meta-analyses reporting guideline for NMAs. However, the study did not assess the risk of bias within individual studies and inconsistency in the treatment network. 

“Our findings demonstrate that IT-NMA is a promising method for direct and indirect comparisons to rank cancer treatment regimens and their evolution over time,” Dr. Warner and team concluded, adding, “Given the successful ranking of regimens for HR-positive, ERBB2-negative MBC, we plan to use IT-NMA to rank regimens for other common and extensively studied cancers.”