Tamoxifen and Aminoglutethimide in Advanced Breast Cancer1

Tamoxifen (TAM), a standard endocrine treatment for ad vanced breast cancer, probably acts by competing for the estrogen receptor protein in the breast tumor cells. If so, resistance to TAM may be a function of the level of the available endogenous estrogen. Inhibition of estrogen synthesis by aminoglutethimide may therefore facilitate the action of the antiestrogen. To test this hypothesis, the two agents were given concurrently (a) to patients who had become resistant to TAM and (to) to patients who had never received TAM in a random ized cross-over study against TAM alone. Patients with estro gen receptor protein-negative disease were excluded. Estro gen and aminoglutethimide levels were measured serially. In the first study, four of 26 patients experienced partial responses, and four of 26, stabilization of their disease. In the randomized study, four of 11 patients on the combination and three of nine on TAM alone had responses. Two patients on the combination and three on TAM alone had stabilization of disease. In the first group, the low rate of response may be attributed to extensive prior treatment. In the randomized study, there is presently no clear advantage for one treatment, and overall, there was no statistically significant correlation be tween degree of estrogen suppression, aminoglutethimide level, and response. The findings do not exclude the possibility that these agents may act in breast cancer by mechanisms other than inhibition of estrogen receptor.