Challenges of measuring accurate estradiol levels in aromatase inhibitor‐treated postmenopausal breast cancer patients on vaginal estrogen therapy

Breast cancer patients who are taking adjuvant Aromatase Inhibitor (AI) therapy typically have extremely low estradiol levels, which are undetectable by routine clinical laboratories. Thus, it becomes difficult to assess the safety of interventions such as low‐dose vaginal estrogen, which may increase estradiol levels. In this study, we aimed to assess the utility of enzyme‐linked immunosorbent assay (ELISA) to measure low estradiol concentrations in breast cancer survivors on AI therapy treated with either vaginal estrogen or lubricant for atrophic vaginitis as a part of clinical trial. The samples were tested using two independent ELISA kits. Some of the samples were also evaluated using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) for comparison. We found that while the results by ELISA were reproducible, they were not accurate when compared to LC‐MS/MS. It is possible that medications or supplements may cross‐react with the ELISA reagents and confound the assessment; however, those were often not the reason for the discrepancy. Our results highlight the need for developing novel, reliable, and clinically accessible assays to measure ultra‐low estradiol levels to improve care of breast cancer survivors. At this stage, based on our findings, we recommend using MS‐based assays for estradiol quantitation for breast cancer survivors, whenever necessary.