One can hypothesize from the preceding discussion that, in the clinical setting, long-term estrogen deprivation could shift the estrogen dose-response curve of a tumor to the left and increase the sensitivity to estrogen therapy. In considering this hypothesis, a case from the author's clinic is of note.
A 62-year-old patient was diagnosed with estrogen receptor-positive stage I breast cancer and was given adjuvant tamoxifen. The patient developed metastatic disease 2 years later, which was treated for more than 1 year with a third-generation nonsteroidal AI and then with a steroidal AI without response. On subsequent progression, the patient elected another endocrine trial. The patient received high-dose estrogen and achieved almost complete clearing of pleural metastasis, which has been maintained for longer than 1 year.
It is plausible that the year-long treatment with AIs represents the clinical equivalent of long-term estrogen deprivation seen in the laboratory. The third-generation AIs such as letrozole and anastrozole are potent, and they have been found to substantially suppress total-body aromatization (>99.1% and 97.3%, respectively) and plasma E2 levels (87.8% and 84.9%, respectively) [15
The clinical observations combined with the laboratory data noted earlier support further study of high-dose estrogen following maximal estrogen deprivation in appropriately selected patients.
Song et al
. studied LTED and wild-type MCF-7 cells with regard to the potential mechanism of action of high-dose estrogen [16
]. Apoptosis was induced by high concentrations (≥ 0.1 nM) of E2 in LTED cells, with a sevenfold increase over vehicle-treated controls and a concomitant 60% decrease in growth, but not in wild-type MCF-7 cells. The authors presented data showing that only LTED cells expressed Fas protein, and they suggested that high-dose estrogen may induce tumor regressions in postmenopausal women through activation of Fas-mediated apoptosis.
Clinical responses to a wide range of estrogen doses have been seen in breast cancer. Responses to DES in a double-blind, randomized clinical trial were observed over a 3-log range from 1.5 to 1500 mg daily [17
]. Substantial tumor regressions have been seen with even relatively minor modifications in estrogen levels, as in withdrawal of physiologic estrogen replacement [18
]. Howell addressed the issue of a shifting estrogen dose-response curve in a patient's tumor [19
] and discussed potential strategies of preventing resistance such as fixed alternating endocrine therapies and stepwise modifications of estrogen levels.