4.6 Article

IHC-based Ki67 as response biomarker to tamoxifen in breast cancer window trials enrolling premenopausal women

Journal

NPJ BREAST CANCER
Volume 7, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41523-021-00344-3

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Funding

  1. A Sister's Hope foundation
  2. Dutch Cancer Society [NKI-2014-7140]

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Window studies focusing on molecular changes in short timeframes are gaining attention. Decreased Ki67 levels in tumor cells are often used as an indicator of treatment response. The study compared pre- and postmenopausal breast cancer patients in a trial focused on endocrine therapy, finding that the decrease in Ki67 levels was smaller in premenopausal women and was directly related to post-treatment estradiol levels. These findings suggest that IHC-based Ki67 may be a suitable biomarker for evaluating tamoxifen response in premenopausal breast cancer patients, with the anti-proliferative effect size depending on estradiol levels.
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.

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