Need for Estradiol Assays With a Lower Functional Sensitivity in Clinical Studies Examining Postmenopausal Women Treated With Aromatase Inhibitors
Authors: Steven Pauwels, Anneleen Lintermans, Patrick Neven, Johan Verhaeghe, Ivo Jans, Jaak Billen, Dirk Vanderschueren, Pieter Vermeersch
Journal: Journal of Clinical Oncology (2012)

In their recently published study, Folkerd et al 1 found that in postmenopausal women with early estrogen receptorpositive breast cancer who are treated with aromatase inhibitors (AIs), suppressed levels of estradiol and estrone sulfate are related to body mass index.If confirmed, this observation is of great interest, not only because it would explain why treatment with an AI results in a better outcome compared with tamoxifen in lean patients but not in obese patients, 2-4 but also because it might open the way toward individualized AI treatment by adapting the dose of AIs on the basis of the plasma estradiol and estrone sulfate concentration.Although the measurement of AIs using mass spectrometry is not so difficult, the measurement of estrogens, particularly estradiol, is quite challenging.As reported by the authors, most on-treatment values for estradiol were below 3 pmol/L, which was the "conventional sensitivity" limit 1(p2978) of the assay used. 5Conventional sensitivity was defined by the authors as the 95% CI of the zero standard, 5 which corresponds more or less to the limit of blank (LoB) as defined by the Clinical and Laboratory Standards Institute.The LoB is the highest apparent analyte concentration that is expected to be found when replicates of a sample containing no analyte are tested. 6,7The limit of detection is the lowest analyte concentration likely to be reliably distinguished from the LoB and at which detection is feasible. 6,7The limit of quantitation, which is defined as the lowest concentration at which the analyte can not only be reliably detected but also measured with an acceptable degree of imprecision, is usually significantly higher (and cannot be lower) than the LoB and the limit of detection. 6,7unctional sensitivity is usually defined as the concentration that results in a coefficient of variation (CV) of 20%. 7The authors reported a between-run CV of 12% for a concentration of 37 pmol/L for their estradiol assay, 5 suggesting that the functional sensitivity of their assay is significantly higher than 3 pmol/L, given that the CV increases exponentially around the limit of quantitation.Such a functional sensitivity is insufficient to allow a reliable quantification of estradiol concentrations in individual postmenopausal women who are treated with AIs.For estrone sulfate, there is a similar problem, although to a lesser extent.The functional sensitivity is most likely also significantly higher than 15 pmol/L, given that the authors reported a CV of 11% at 130 pmol/L, but in contrast to estradiol, a majority of on-treatment values were above the conventional sensitivity defined by the authors.To examine the relation between estrogen concentration, body mass index, and outcome, and to open the way toward individualized AI treatment, clinical studies should use estrogen assays with a better functional sensitivity, particularly for estradiol.Unfortunately, the only estradiol assays that currently have a functional sensitivity of less than 3 pmol/L are labor-intensive mass spectrometry methods that require extensive sample pretreatment including liquid/liquid extraction.A simple mass spectrometry method not requiring liquid/liquid extraction, derivatization, or large volumes of serum (eg, 500 L) is therefore needed.