ABSTRACT
I. ABSTRACT It took many years for the effectiveness of adjuvant endocrine therapy to become apparent because of the indolent nature of estrogen-dependent breast cancer. This fact is the most important obstacle to the development of new adjuvant endocrine treatments. Clinical trials require thousands of participants and at least a decade of clinical investigation. How can we be sure that a new endocrine strategy really warrants this extraordinary level of investment? The success of a recent neoadjuvant trial that compared the selective aromatase inhibitor letrozole with tamoxifen suggests that this treatment approach may provide an answer. The Letrozole 024 trial established that 4 months of neoadjuvant letrozole, in postmenopausal women with confirmed hormone receptor-positive breast cancer, ineligible for breast conserving surgery, was associated with a 60% clinical response rate and a 48% rate of conversion to breast-conserving surgery. For tamoxifen, on the other hand, the corresponding figures were 41 and 36% respectively. The superior efficacy of letrozole was particularly marked for tumors that coexpress estrogen receptors (ER) and ErbB1
and/or ErbB2, supporting the notion that tumors with this immunophenotype are relatively tamoxifen-resistant yet estrogen-dependent. Future neoadjuvant endocrine therapy designs could focus on a number of objectives, for example: (a) nonrandomized trials to focus on gene microarray studies and other genetic technologies to investigate the molecular basis of estrogen-dependent growth; (b) randomized trials to address critical drug development questions in earlystage disease as a prelude to adjuvant studies; and (c) randomized trials that compare neoadjuvant chemotherapy with neoadjuvant aromatase inhibitor therapy to establish a place for neoadjuvant endocrine therapy in routine clinical practice.
