Neoadjuvant Endocrine Therapy for Breast Cancer: Medical Perspectives 1

The indolent nature of estrogen-dependent breast cancer is the most important obstacle for development of new adjuvant endocrine treatments. Clinical trials require thousands of study participants and at least a decade of clinical investigation. How can we be sure that a new endocrine agent warrants this extraordinary level of investment? Traditionally, we have relied on advanced breast cancer trials to determine which drugs are suitable for adjuvant studies. However, with endocrine agents the high incidence of resistance in metastatic breast cancer may mask important advances in efficacy. Recent clinical results with the aromatase inhibitor letrozole suggest that neoadjuvant endocrine therapy is a highly informative additional approach to consider when planning adjuvant studies. In this report, new neoadjuvant endocrine therapy study designs are discussed that address the following issues: (a) the scientific opportunities afforded by gene microarray studies and other genetic technologies to investigate the molecular basis of estrogendependent breast cancer; (b) studies that address critical drug development questions as a prelude to adjuvant studies; and (c) the conduct of randomized trials that compare neoadjuvant chemotherapy with neoadjuvant aromatase inhibitor therapy to establish a place for neoadjuvant endocrine therapy in routine clinical practice. Neoadjuvant Endocr ine Therapy v e r s u s Neoadjuvant Chemotherapy Neoadjuvant endocrine therapy has a long and interesting clinical history. The first description of primary breast cancer treatment with an endocrine agent was in 1957 when Kennedy et al. described successful treatment of locally advanced disease with diethylstilbestrol (1). After the introduction of tamoxifen, numerous trials examined the effect of this antiestrogen on primary breast cancer, but these studies were not true neoadjuvant protocols, i.e., addressing the use of preoperative tamoxifen to improve surgical outcomes. Most randomized investigations focused on the concept of primary tamoxifen therapy for older patients. Here the clinical intent was to replace initial breast Presented at the First International Conference on Recent Advances and Future Directions in Endocrine Therapy for Breast Cancer, June 21-23, 2001, Cambridge, MA. 2 To whom requests for reprints should be addressed, at Duke University Medical Center, Box 3446, The Morris Building 25149-F, Durham, NC 27710. Phone: (919)668-0718; Fax: (919) 668-0720; E-mail: ellis053 @mc.duke.edu. surgery and radiation with long-term tamoxifen treatment, with definitive surgery and radiation reserved for patients who suffered local progression. Poor local control in these trials indicated that primary tamoxifen therapy is suitable only for the most frail and infirm patients who are unable to tolerate surgery and are unlikely to live long because of comorbid illness (see Ref. 2 for a review). The more recent studies described in this report have refocused attention on neoadjuvant endocrine treatment and particularly on aromatase inhibitors, because these agents have considerable clinical activity in this clinical setting. As one thinks about these studies, it hardly needs stressing that the biological and pharmacological basis for neoadjuvant endocrine therapy and neoadjuvant chemotherapy are very different. From a clinical perspective, perhaps the most obvious issue is that the entire adjuvant effect of neoadjuvant chemotherapy occurs during neoadjuvant treatment phase. The opposite is true for neoadjuvant endocrine therapy because the preoperative phase provides only a small fraction of the total drug exposure (because all patients receive 5 years of postoperative treatment). One consequence of this fundamental difference is that pathological complete responses are uncommon with neoadjuvant endocrine therapy, but this should not necessarily be viewed as a disadvantage as long as tumors regress sufficiently to allow an improvement in surgical outcomes. Furthermore, alternative biomarkers to pathological complete responses will need to be explored in neoadjuvant endocrine therapy trials to help us to predict the likelihood of long-term disease-free survival with the endocrine agent. Early experience with tamoxifen does suggest a relationship between clinical response in the primary tumor and the likelihood that adjuvant tamoxifen treatment will control systemic disease (3). Other, potentially more reliable, predictive biomarkers could be easily analyzed after neoadjuvant endocrine therapy including proliferation rate, radiological changes, and modulation of gene expression. Neoadjuvant Endocrine Therapy Trials with Anastrozole and Exemestane. By the mid-1990s the development of selective aromatase inhibitors had reached a stage where direct comparisons with tamoxifen were warranted. At that point several neoadjuvant endocrine therapy investigations were initiated, driven by the opportunity to obtain tumor tissue before and after treatment so that both baseline predictive markers and surrogate markers for the effectiveness of endocrine therapy could be investigated. Currently, information on the activity of neoadjuvant anastrozole and exemestane are limited to Phase II studies. The group at Edinburgh conducted a randomized double-blind study of 24 patients that examined 1 mg and 10 mg of anastrozole per day for 3 months. The average reduction in tumor volume was 89.3% (ultrasound measurements). In this study there were 15 patients who would have been expected to require a mastectomy at the outset of the study, who were subsequently able to undergo breast conservation after 3 months of treatment (4). These data encouraged initiation of a 300-patient randomized study in which tamoxifen is being compared with anastroCancer Research. on November 11, 2017. © 2001 American Association for clincancerres.aacrjournals.org Downloaded from Clinical Cancer Research 4389s