Department of Oncology, Akershus University Hospital (AHUS), Lørenskog, Norway; Department of Breast and Endocrine Surgery, Akershus University Hospital, Lørenskog, Norway.
Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
J Steroid Biochem Mol Biol. 2020 Jun;200:105641. doi: 10.1016/j.jsbmb.2020.105641. Epub 2020 Mar 6.
The aromatase inhibitors (AIs), letrozole (Femar®/Femara®) and exemestane (Aromasin®), are widely used to treat estrogen receptor (ER) positive breast cancer in postmenopausal patients. In the setting of metastatic breast cancer, these drugs may be used after another causing new responses in selected patients after progressing on the first choice. The precise explanation for this "lack of cross resistance" is still missing. NEOLETEXE is a neoadjuvant, randomized, open-label, cross-over trial. Postmenopausal patients with ER-positive, HER-2 negative, locally advanced breast cancer were enrolled. All patients were randomized to treatment starting with either letrozole or exemestane for at least 2 months followed by another 2 months on the alternative AI. The total estrogenic activities in blood samples were determined using the AroER tri-screen assay developed in the Chen laboratory. Using this highly sensitive assay, estrogenic activity was detected at three time points for all patients. Importantly, a significantly higher total estrogenic activity was found during therapy with exemestane compared to letrozole in 21 out of 26 patients. When letrozole was included in the AroER tri-screen assay, the estrogenic activities in most samples collected during exemestane treatment were further reduced, suggesting that low levels of androgens remained in specimens obtained after exemestane treatment. Our results suggest the AroER tri-screen to be a very sensitive method to estimate the overall estrogen-mediated activity in human samples even during therapy with highly potent aromatase inhibitors. In the present study, serum estrogen activity was significantly higher during exemestane therapy when compared to letrozole therapy.
芳香酶抑制剂（AIs），来曲唑（Femar®/Femara®）和依西美坦（Aromasin®），广泛用于治疗绝经后患者的雌激素受体（ER）阳性乳腺癌。在转移性乳腺癌的情况下，这些药物可能在另一种药物进展后用于选择的患者，在第一种药物后产生新的反应。这种“缺乏交叉耐药性”的确切解释仍然缺失。NEOLETEXE 是一项新辅助、随机、开放标签、交叉试验。招募了绝经后、ER 阳性、HER-2 阴性、局部晚期乳腺癌患者。所有患者均随机接受来曲唑或依西美坦治疗至少 2 个月，然后再接受另一种 AI 治疗 2 个月。使用陈实验室开发的 AroER 三联筛选测定法测定血样中的总雌激素活性。使用这种高度敏感的测定法，在所有患者的三个时间点均检测到雌激素活性。重要的是，在 26 名患者中的 21 名患者中，与来曲唑相比，依西美坦治疗期间总雌激素活性显著更高。当将来曲唑纳入 AroER 三联筛选测定法时，在依西美坦治疗期间采集的大多数样本中的雌激素活性进一步降低，表明在依西美坦治疗后获得的标本中仍存在低水平的雄激素。我们的结果表明，AroER 三联筛选是一种非常敏感的方法，可以估计人类样本中的整体雌激素介导活性，即使在使用高效芳香酶抑制剂治疗时也是如此。在本研究中，与来曲唑治疗相比，依西美坦治疗期间血清雌激素活性显著升高。
