The phosphorylation of the androgen receptor (AR) at various sites has been associated with diverse functions and clinical outcomes in prostate cancer and the processes underlying phosphorylation at S81 (pAR81) and S213 (pAR213) may possibly be targeted therapeutically. In addition, inflammation upregulates AR and cancer-promoting pathways, and high CD3+ and CD8+ T-cells in the tumour microenvironment have been associated with poorer outcomes. Therefore, this study aims to assess the prognostic value of tumour markers – AR, immune cell infiltrate and proliferation – and develop a combined prognostic score.
Immunohistochemistry was performed for 243 patients with prostate cancer to assess AR, pAR81, pAR213, Ki67, CD3 and CD8. AR expression was evaluated separately based on localisation: tumour or stromal cell, nuclear or cytoplasmic, with nuclear/cytoplasmic ratio (N/C) calculated. These tumour markers were assessed with overall survival and other biomarkers.
High Ki67 (p = 0.003), CD8 (p = 0.022), CD3 (p = 0.006), and tumour cytoplasmic AR (p = 0.001) and pAR81 (p = 0.049), were associated with lower survival. Conversely, associated with higher survival were high tumour nuclear AR (p = 0.027) and N/C for AR (p = 3 × 10−4), pAR81(p = 0.032) and pAR213 (p = 0.010). In the stroma, high nuclear AR (p = 0.002), AR N/C (p = 0.041) and cytoplasmic pAR81 (p = 0.039) were associated with better survival. The Phosphorylated Androgen Receptor and Lymphocyte (PARL) score was derived by adding 1 for each of: high CD8, high tumour cytoplasmic pAR81, low tumour pAR213 N/C and low stromal nuclear AR. Patients are stratified into low (0-1), medium (2) and high (3-4) with worsening five-year survival of 88%, 79% and 50% respectively. The PARL score was a significant predictor of survival (p = 0.001), independent of Gleason score, prostate-specific antigen, perineural invasion and serum albumin.
CD3+ and CD8+ T-cell infiltration are negative prognostic markers, while the AR has different roles and prognostic values depending on localisation and phosphorylation. The PARL score could be a useful immunohistochemistry-based measure of tumour biomarkers for prognostication and adds value to current clinico-pathological markers.
NHS Greater Glasgow and Clyde.
Prostate Cancer UK Wolfson Foundation.
All authors have declared no conflicts of interest.