Onder 2.7 Gerechtshof Den Haag 31 oktober 2017

become refractory, represents an important therapeutic dilemma. However, the development of tamoxifen resistance is not necessarily associated with progression to an ER-negative phenotype. In many cases of clinical tamoxifen resistance, ER expression may be retained (1-4), implying that the resistance is due an alteration in activity of the tamoxifen/ER complex. Tamoxifen resistance in such a case could result from three possible mechanisms that, according to present knowledge, would not preclude successful treatment with an alternative hormonal therapy. First, alterations in the ER could arise, which might diminish or extinguish inhibitory responses to tamoxifen, leaving only its partial agonist effects to predominate (5-8). Second, tamoxifen resistance arising in the setting of an intact ER could be a result of altered intratumoral tamoxifen metabolism, which might produce more estrogenic metabolites locally (7.9-11). Third, available tamoxifen could be sequestered by an increase in antiestrogen binding sites not associated with ERs (12). As mentioned, in each of these three instances, substitution of a hormonal therapy different from tamoxifen might result in a clinical response. Two such alternative therapies used in this report are steroidal estrogen antagonists, such as ICI 182,780, which lack the partial agonist activity of tamoxifen, and aromatase inhibitors, which inhibit endogenous estrogen production by all tissues, depriving the ER of its ligand.

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