Radiolabeled estradiol derivatives to predict response to hormonal treatment in breast cancer: a review

Several radiolabeled steroidal and nonsteroidal estradiol derivatives of wh ich the tumoral uptake is believed to relate quantitatively to the content and binding characteristics of the alpha-estrofen receptor (alpha ER) recep tor in the target tissue have been synthesized and their imaging potential and clinical usefulness evaluated in vivo in humans. Due to the use of diff erent methodologies and cut-off values for the measurement of alpha ER posi tivity, the use of both quantitative positron emission tomography and semiq uantitative single-photon emission tomography, and the difference in patien t populations studied, direct comparison of these data is not possible. Ind ividual data, however, fail to substantiate a direct relationship between t hese radiolabeled estradiol derivatives and aER status, in keeping with rec ent pathophysiological findings demonstrating (1) estradiol sequestration a nd retention through other than alpha ER-mediated, either membrane- or non- membrane-related, mechanisms and (2) an inverse relationship between estrad iol uptake and local biosynthesis through aromatization and interconversion in alpha ER-positive tumors. Additionally, given the discovery of very hig h affinity alpha ER-like binding sites (K-d, dissociation constant, <0.1 nM ), and the potential for underestimation of alpha ER K-d when using ligand binding assays, at least part of the radiolabeled estradiol derivative upta ke reflects tumoral perfusion rather than the ligand-receptor binding proce ss. However, the reduction in cellular uptake, membrane sequestration and l ocal biosynthesis of estradiol following tamoxifen treatment in alpha ER-re sponsive tumors should allow early prediction of response to therapy throug h rapid sequential radiolabeled estradiol scintigraphy with higher accuracy than conventional aER estimations, as supported by recent data.