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

Stacey E.P. Joosten, Marius Wellenstein, Rutger Koornstra, Annelot van Rossum, Joyce Sanders, Vincent van der Noort, Maria C. Ferrandez, Rolf Harkes, Ingrid A.M. Mandjes, Hilde Rosing, Alwin Huitema, Jos H. Beijnen, Jelle Wesseling, Paul J. van Diest, Hugo M. Horlings (Corresponding author), Sabine C. Linn (Corresponding author), Wilbert Zwart (Corresponding author)

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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.

Original languageEnglish
Article number138
Number of pages8
Journalnpj Breast Cancer
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
The authors would like to thank Tesa Severson, NKI Core Facility Molecular Pathology and Biobank (in particular Dennis Peters) and Agendia Inc. for (assisting in) generating gene expression data, and the NKI Scientific and –trial office Administration (in particular Tony van de Velde and Lidwina Wever) for assisting in the collection of patient data. We would also like to thank patients for participating in this trial. This work was supported by grants from A Sister’s Hope foundation and the Dutch Cancer Society (NKI-2014-7140) to WZ and SCL. AstraZeneca provided fulvestrant.


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