Markers of steroid receptor, kinase signalling pathways and Ki-67 expression in relation to tamoxifen sensitivity and resistance

Campbell, Christine; Mathew, John; Ellis, Ian O.; Bradbury, Ian; Borgquist, Signe; Elebro, Karin; Green, Andrew R.; Finlay, Pauline; Gee, Julia M. W.; Robertson, John F. R.

Abstract

Background: It remains clinically important to identify ER positive breast cancers likely to respond to tamoxifen (TAM) and so we aimed to select a group of biomarkers able to predict response. We also assessed whether data from different sample types [tumor microarrays (TMAs) and core biopsies] or tumor sites could be combined for biomarker studies.

Methods: A total of 123 endocrine treatment naïve patients with known ER and HER2 status treated with TAM had paraffin-embedded tumor tissue available either as TMAs (n=102) or core biopsies (n=21). TMA cores were collected from three different tumor sites, two central and one peripheral. Ten biomarkers were evaluated by immunohistochemistry, for % positivity and/or H-Score, comprising: ER, HER2, Ki-67, phosphorylated forms of ER (Ser118), IGF1R, PRAS40, Akt & MAPK (ERK1/2), and PTEN & androgen receptor expression (AR). Each tumor was analysed for Akt1 E17K somatic mutation using BEAMing technology. Patient outcome was assessed by clinical benefit (CB) rate & survival analyses [time to progression (TTP) and time to death (TTD)].

Results: There was no significant difference in % positivity or H-Score between central & peripheral tumor sites for all biomarkers examined. After False Discovery Rate (FDR) correction differences (P less than 0.05) were observed between the two central samples only for HER2 & pER118 and pPRAS40. However, differences in biomarker expression were common between core biopsies and TMAs. Only 2/123 (1.6%) tumors had Akt1 E17K mutations. Univariate and multivariate analyses identified that lower levels of PTEN and higher levels of Ki-67 (% positivity) were predictive of poor outcome (TTP & TTD) following TAM. Higher ER. lower Ki-67 and AR/ER ratio less than 2 predicted increased CB rate.

Conclusions: There were few differences in marker expression between TMAs from different intra-tumoral sites. More marked differences between TMAs and core biopsies suggest caution if combining such datasets. Loss of PTEN, a key regulator of the PI3K/Akt pathway, was the only RTK/kinase signaling biomarker related to poorer clinical outcome. PTEN along with ER & lower Ki-67 proved the most predictive markers for better outcome (TTP & TTD and/or CBR) following TAM treatment.

Citation

Campbell, C., Mathew, J., Ellis, I. O., Bradbury, I., Borgquist, S., Elebro, K., Green, A. R., Finlay, P., Gee, J. M. W., & Robertson, J. F. R. (2020). Markers of steroid receptor, kinase signalling pathways and Ki-67 expression in relation to tamoxifen sensitivity and resistance. Translational Breast Cancer Research, 1, Article 29. https://doi.org/10.21037/tbcr-20-31

• Journal Article Type: Article
• Acceptance Date: Sep 14, 2020
• Online Publication Date: Oct 31, 2020
• Publication Date: Oct 31, 2020
• Deposit Date: Jun 22, 2021
• Publicly Available Date: Jun 22, 2021
• Journal: Translational Breast Cancer Research
• Electronic ISSN: 2218-6778
• Publisher: AME Publishing Company
• Peer Reviewed: Peer Reviewed
• Volume: 1
• Article Number: 29
• DOI: https://doi.org/10.21037/tbcr-20-31
• Public URL: https://nottingham-repository.worktribe.com/output/5718695
• Publisher URL: https://tbcr.amegroups.com/article/view/45812/html