Window studies are gaining
traction to assess (molecular) changes in short timeframes. Decreased
tumor cell positivity for the proliferation marker Ki67 is often used as a proxy for treatment response. Immunohistochemistry (IHC)-based Ki67 on tissue from neo-adjuvant trials was previously reported to be predictive for long-term response to endocrine
therapy for
breast cancer in postmenopausal women, but none of these trials enrolled premenopausal women. Nonetheless, the marker is being used on this subpopulation. We compared pathologist assessed IHC-based Ki67 in samples from pre- and postmenopausal women in a neo-adjuvant, endocrine
therapy focused trial (NCT00738777), randomized between
tamoxifen,
anastrozole, or
fulvestrant. These results were compared with (1) IHC-based Ki67 scoring by AI, (2) mitotic figures, (3)
mRNA-based Ki67, (4) five independent gene expression signatures capturing proliferation, and (5) blood levels for
tamoxifen and its metabolites as well as
estradiol. Upon
tamoxifen, IHC-based Ki67 levels were decreased in both pre- and postmenopausal
breast cancer patients, which was confirmed using
mRNA-based cell proliferation markers. The magnitude of decrease of Ki67 IHC was smaller in pre- versus postmenopausal women. We found a direct relationship between post-treatment
estradiol levels and the magnitude of the Ki67 decrease in
tumors. These data suggest IHC-based Ki67 may be an appropriate
biomarker for
tamoxifen response in premenopausal
breast cancer patients, but anti-proliferative effect size depends on
estradiol levels.