Ki67 and prostate specific antigen are prognostic in metastatic hormone naïve prostate cancer

Abstract

Background

For metastatic hormone naïve prostate cancer patients, androgen deprivation therapy (ADT) with escalation therapy including docetaxel and/or androgen targeting drugs is the standard therapy. However, de-escalation is preferable to avoid unnecessary side effects, especially from docetaxel, but markers to identify these patients are lacking. The purpose of the present study was to investigate the potential of PSA and Ki67 immunoreactive scores as prognostic and treatment-predictive markers.

Material and methods

Prostate biopsies from 92 patients with metastatic hormone naïve PC (PSA > 80 ng/mL or clinical metastases) were immunohistochemically evaluated for PSA and Ki67. Gene expression analysis was performed with Clariom D microarrays to identify the phenotypic profile associated with the immunohistochemistry scores of biopsies. Cox regression analysis for progression free survival after ADT adjustment for age, ISUP, and serum PSA and Kaplan-Meier analyses were performed to assess prognostic values of Ki67, PSA, and the Ki67/PSA ratio.

Results

The immunohistochemical score for PSA was the strongest prognostic factor for progression-free and overall survival after ADT. Consequently, the ratio between Ki67 and PSA displayed a stronger prognostic value than Ki67 itself. Further, mRNA expression data analysis showed an association between high Ki67/PSA ratio, cell-cycle regulation, and DNA damage repair. In an exploratory sub-analysis of 12 patients treated with early docetaxel as addition to ADT and matched controls, a high Ki67/PSA ratio showed potential to identify those who benefit from docetaxel.

Conclusion

PSA and Ki67 immunoreactive scores are prognostic in the metastatic hormone-sensitive setting, with PSA being superior. The combination of Ki67 and PSA did not give additional prognostic value. The results suggest immunohistochemical scoring of PSA to have potential to improve identification of patients responding well to ADT alone.

Keywords:

• Metastatic prostate cancer
• biomarker
• androgen deprivation therapy
• docetaxel
• prostate specific antigen

Acknowledgments

We thank Robert Buckland, Karin Larsson, Pernilla Andersson, and Susanne Gidlund for excellent technical assistance. Thanks also to Marie Lundholm, Kerstin Almroth and Lars Rönnlund help with follow up data.

Disclosure statement

A.B. and P.W. have a pending patent application (‘Methods for diagnosis and prognosis of prostate cancer’, EP2020/054681). Other authors declare no conflicts of interest

Data availability statement

The data generated in this study are not publicly available due to information that could compromise patient privacy or consent but are available upon reasonable request from the corresponding author.

Additional information

Funding

This work was supported by grants from Swedish Research Council (2022-00946) and the Swedish Cancer Society (Grant numbers 21-1856, 20-1055, 19-0053, 19-0054), Knut and Alice Wallenberg foundation (KAW 2020.0235), the research foundation of Ulla och Karl-Erik Winberg, and the Swedish Prostate Cancer Federation.