IHC-based Ki67 as response biomarker to tamoxifen in breast cancer window trials enrolling premenopausal women.
Stacey E P JoostenMarius WellensteinRutger KoornstraAnnelot van RossumJoyce SandersVincent van der NoortMaria C FerrandezRolf HarkesIngrid A M MandjesHilde RosingAlwin HuitemaJos H BeijnenJelle WesselingPaul J van DiestHugo Mark HorlingsSabine C LinnWilbert ZwartPublished in: NPJ breast cancer (2021)
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.
Keyphrases
- postmenopausal women
- bone mineral density
- neoadjuvant chemotherapy
- estrogen receptor
- gene expression
- cell proliferation
- breast cancer cells
- positive breast cancer
- breast cancer risk
- early stage
- polycystic ovary syndrome
- stem cells
- squamous cell carcinoma
- signaling pathway
- adipose tissue
- cell cycle
- binding protein
- body composition
- dna methylation
- young adults
- single molecule
- mesenchymal stem cells
- bone marrow
- pregnancy outcomes
- single cell
- open label
- pi k akt
- data analysis
- combination therapy