Aromatase inhibitors: rationale for use following antiestrogen therapy

One third of breast cancers are hormone dependent and regress on blockade of estrogen biosynthesis or receptor-mediated action. Several hormonal approaches are available to accomplish these goals, including use of the antiestrogen tamoxifen and administration of inhibitors of aromatase, the rate-limiting enzyme for estrogen biosynthesis in postmenopausal women. Empirical observations demonstrate that women who respond to an initial hormonal therapy may experience secondary or tertiary tumor regressions when given additional endocrine-based therapies. The mechanistic basis for sequential responses to hormonal therapies is incompletely understood at the present time. In this report, we synthesize information from multiple sources to raise a hypothesis that could explain secondary hormonal responses in patients with breast cancer. The hypothesis postulates that tumor cells adapt to a deprivation in estrogenic stimulation by developing hypersensitivity to the residual levels of estrogen present. The process of hypersensitivity could result either from an absolute lowering of estrogen levels as induced by surgical oophorectomy or from interference of the estrogen response pathway by antiestrogens. This hypothesis, if correct, would explain why women respond to aromatase inhibitors secondarily after experiencing tumor regression following oophorectomy or tamoxifen therapy. This report summarizes studies documenting the development of enhanced estradiol sensitivity in cells grown in culture. This process is dynamic and reproducible on serial estrogen deprivation and re-exposure. We postulate that enhanced sensitivity to precursors of estradiol could also be induced by estrogen deprivation. With this adaptive mechanism, tumors would synthesize greater amounts of estrogen locally in the tumor after a period of estrogen deprivation. Enhancement of the amount or activity of the enzyme aromatase is one possible means of tumor adaptation. As a tool to evaluate this possibility, a new nude mouse model for postmenopausal breast cancer has been developed. In this model, the major source of tumor estrogen is that locally produced through conversion of androstenedione to estrone through the aromatase pathway. Studies using this model demonstrate higher antitumor potency of aromatase inhibitors than tamoxifen and have implications regarding combination therapy with both aromatase inhibitors and antiestrogens. This model will serve as a basis for future studies of the potential regulation of intratumoral aromatase.