Clinical and biomarker endpoint analysis in neoadjuvant endocrine therapy trials.
Neoadjuvant endocrine therapy trials for breast cancer are now a widely accepted investigational approach for oncology cooperative group and pharmaceutical company research programs. However, there remains considerable uncertainty regarding the most suitable endpoints for these studies, in part, because short-term clinical, radiological or biomarker responses have not been fully validated as surrogate endpoints that closely relate to long-term breast cancer outcome. This shortcoming must be addressed before neoadjuvant endocrine treatment can be used as a triage strategy designed to identify patients with endocrine therapy "curable" disease. In this summary, information from published studies is used as a basis to critique clinical trial designs and to suggest experimental endpoints for future validation studies. Three aspects of neoadjuvant endocrine therapy designs are considered: the determination of response; the assessment of surgical outcomes; and biomarker endpoint analysis. Data from the letrozole 024 (LET 024) trial that compared letrozole and tamoxifen is used to illustrate a combined endpoint analysis that integrates both clinical and biomarker information. In addition, the concept of a "cell cycle response" is explored as a simple post-treatment endpoint based on Ki67 analysis that might have properties similar to the pathological complete response endpoint used in neoadjuvant chemotherapy trials.
Tao
Yu
Y
Siteman Cancer Center and Washington University in St. Louis, Campus Box 8506, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Klause
Andreas
A
Vickers
Andrew
A
Bae
Kyongtae
K
Ellis
Matthew
M
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery; D002986:Clinical Trials as Topic; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D000077289:Letrozole; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000627:therapeutic use; D013629:Tamoxifen / Q000627:therapeutic use; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole