Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer

Abstract

Mature outcomes from adjuvant endocrine therapy trials in estrogen receptor-positive breast cancer have enabled comparisons with neoadjuvant clinical trials that have parallel randomizations of treatment in terms of the response of disseminated disease versus the local response within the breast. Imprecise end points, such as 'clinical response', have produced inconsistent results regarding the relationship between neoadjuvant and adjuvant endocrine therapy outcomes. However, the proliferation marker Ki-67, measured during neoadjuvant treatment, has predicted accurately and consistently the results of much larger studies in the adjuvant setting. In this Review, we summarize these trials and discuss the implications for the design of future adjuvant endocrine therapy trials. We conclude that there is sufficient evidence supporting the view that the degree of Ki-67 suppression is a reliable short-term surrogate for the adjuvant potential of endocrine drugs, at least in postmenopausal women. We propose that adjuvant endocrine therapy trials should only be conducted once adequately-powered neoadjuvant studies have indicated superior Ki-67 suppression in patients receiving experimental endocrine treatment versus the standard treatment.

Figure 1

Schematic representation for the ALTERNATE Trial. Postmenopausal women with clinical stage II or III ER-positive, HER2-negative breast cancer are eligible for the study. In the first phase (neoadjuvant comparison phase), patients are randomized at 1:1:1 ratio (n = 400 in each arm) to receive neoadjuvant endocrine therapy with either anastrozole (Arm A) or fulvestrant (Arm F), or the combination of anastrozole and fulvestrant (Arm A/F) for 24 weeks. Tumor biopsy for Ki-67 assessment is performed at the end of week 4 (mandatory) and then week 12 (optional, recommended if the clinical response is less than a partial response). If Ki-67 >10%, patients are recommended to switch to 12 weeks of weekly paclitaxel for the determination of the pathologic complete response rate in this population. Patients with Ki-67 <10% will continue their assigned regimen to complete 24 weeks of treatment followed by surgery and PEPI score calculation. Adjuvant chemotherapy is not recommended for patients in the PEPI-0 group. Patients will continue their assigned regimen in the adjuvant setting for another 1.5 years followed by anastrozole for 3 more years. On completion of accrual for the first phase of the trial, enrollment for the two fulvestrant arms will not be done until a decision is made that either none (if neither treatment yield a PEPI-0 rate at least 10% higher than with anastrozole) or one (the superior fulvestrant arm) of these arms will proceed to the second phase of the study for PEPI-0 validation on the fulvestrant regimen. Abbreviations: ER, estrogen receptor; PEPI, preoperative endocrine prognostic index.