Positive STAT5 Protein and Locus Amplification Status Predicts Recurrence after Radical Prostatectomy to Assist Clinical Precision Management of Prostate Cancer

Abstract

Background: A significant fraction of prostate cancer patients experience post-radical prostatectomy (RP) biochemical recurrence (BCR). New predictive markers are needed for optimizing postoperative prostate cancer management. STAT5 is an oncogene in prostate cancer that undergoes amplification in 30% of prostate cancers during progression.

Methods: We evaluated the significance of a positive status for nuclear STAT5 protein expression versus STAT5 locus amplification versus combined positive status for both in predicting BCR after RP in 300 patients.

Results: Combined positive STAT5 status was associated with a 45% disadvantage in BCR in Kaplan-Meier survival analysis in all Gleason grade patients. Patients with Gleason grade group (GG) 2 and 3 prostate cancers and combined positive status for STAT5 had a more pronounced disadvantage of 55% to 60% at 7 years after RP in univariate analysis. In multivariate analysis, including the Cancer of the Prostate Risk Assessment Postsurgical nomogram (CAPRA-S) variables, combined positive STAT5 status was independently associated with a shorter BCR-free survival in all Gleason GG patients (HR, 2.34; P = 0.014) and in intermediate Gleason GG 2 or 3 patients (HR, 3.62; P = 0.021). The combined positive STAT5 status improved the predictive value of the CAPRA-S nomogram in both ROC-AUC analysis and in decision curve analysis for BCR.

Conclusions: Combined positive status for STAT5 was independently associated with shorter disease-free survival in univariate analysis and was an independent predictor for BCR in multivariate analysis using the CAPRA-S variables in prostate cancer.

Impact: Our results highlight potential for a novel precision medicine concept based on a pivotal role of STAT5 status in improving selection of prostate cancer patients who are candidates for early adjuvant interventions to reduce the risk of recurrence.

Figure 1.

STAT5 protein levels and STAT5 locus amplification in prostate cancer tissue microarrays. A: Individual prostate cancer (PC) tissue microarray (TMA) cores were scored for nuclear STAT5a/b levels, detected by immunohistochemistry (IHC), on a scale from 0 to 3, where 0 represented negative, 1 weak, 2 moderate and 3 strong immunostaining (top panel). B: STAT5A/B FISH analysis of PC TMA cores (bottom panel). The top row shows representative sections from 5 cases showing no STAT5 locus amplification. Most cells show 2 copies of STAT5A/B (red signal). A chromosome 17 centromeric probe was used (green signal) as a control. The bottom row shows representative sections from 4 cases with STAT5 locus amplification. Arrows point to cells with STAT5 locus amplification.

Figure 2.

Univariate analysis of the combined status for both STAT5 gene locus amplification status and protein expression and progression-free survival with biochemical recurrence (BCR) as the endpoint in prostate cancers of all Gleason GG (A) vs. prostate cancers of Gleason GG 2 and 3 (B) vs. GG 4 and 5 (C). Univariate analysis of the STAT5 gene locus amplification status and progression-free survival in prostate cancers of all Gleason Grade Groups (GG) (D) vs prostate cancers of Gleason GG 2 and 3 (E) vs GG 4 and 5 (F). Univariate analysis of the STAT5 protein status and progression-free survival in prostate cancers of all Gleason Grade Groups (GG) (G) vs. prostate cancers of Gleason GG 2 and 3 (H) vs. GG 4 and 5 (I). Kaplan Meier curves, with global p-values calculated by Mantel-Haenszel tests. The STAT5 protein status detected by immunohistochemistry (IHC) and STAT5 locus amplification by fluorescence in situ hybridization (FISH). Global Mantel-Haenszel log-rank p-values were calculated comparing the difference in survival between all patient groups.

Figure 3.

Receiver-operating characteristic-area under the curve (ROC-AUC) and decision curve analyses (DCA). A: ROC-AUC and (B) DCA of CAPRA-S with and without the combined positive STAT5 status in the entire cohort, and a separate sub-analysis of Gleason GG 2 and 3 PC patients exclusively.