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

Abstract.

Several radiolabeled steroidal and nonsteroidal estradiol derivatives of which the tumoral uptake is believed to relate quantitatively to the content and binding characteristics of the α-estrogen receptor (αER) receptor in the target tissue have been synthesized and their imaging potential and clinical usefulness evaluated in vivo in humans. Due to the use of different methodologies and cut-off values for the measurement of αER positivity, the use of both quantitative positron emission tomography and semiquantitative single-photon emission tomography, and the difference in patient populations studied, direct comparison of these data is not possible. Individual data, however, fail to substantiate a direct relationship between these radiolabeled estradiol derivatives and αER status, in keeping with recent pathophysiological findings demonstrating (1) estradiol sequestration and retention through other than αER-mediated, either membrane- or non-membrane-related, mechanisms and (2) an inverse relationship between estradiol uptake and local biosynthesis through aromatization and interconversion in αER-positive tumors. Additionally, given the discovery of very high affinity αER-like binding sites (K _d, dissociation constant, <0.1 nM), and the potential for underestimation of αER K _d when using ligand binding assays, at least part of the radiolabeled estradiol derivative uptake reflects tumoral perfusion rather than the ligand-receptor binding process. However, the reduction in cellular uptake, membrane sequestration and local biosynthesis of estradiol following tamoxifen treatment in αER-responsive tumors should allow early prediction of response to therapy through rapid sequential radiolabeled estradiol scintigraphy with higher accuracy than conventional αER estimations, as supported by recent data.