PTEN Loss Is Associated with Adverse Outcomes in the Setting of Salvage Radiation Therapy.

ABSTRACT

BACKGROUND: Salvage radiation therapy (SRT) is a mainstay of treatment for biochemical relapse following radical prostatectomy; however, few studies have examined genomic biomarkers in this context. OBJECTIVE: We characterized the prognostic impact of previously identified deleterious molecular phenotypes-loss of PTEN, ERG expression, and TP53 mutation-for patients undergoing SRT. DESIGN, SETTING, AND PARTICIPANTS: We leveraged an institutional database of 320 SRT patients with available tissue and follow-up. Tissue microarrays were used for genetically validated immunohistochemistry assays. INTERVENTION All men underwent SRT with or without androgen deprivation therapy OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox-proportional hazard models assessed the association of molecular phenotypes with biochemical recurrence-free (bRFS) and metastasis-free (MFS) survival after SRT. RESULTS AND LIMITATIONS: Loss of PTEN (n = 123, 43%) and ERG expression (n = 118, 39%) were common in this cohort, while p53 overexpression (signifying TP53 missense mutation) was infrequent (n = 21, 7%). In univariable analyses, any loss of PTEN portended worse bRFS (hazard ratio [HR] 1.86; 95% confidence interval 1.36-2.57) and MFS (HR 1.89; 1.21-2.94), with homogeneous PTEN loss being associated with the highest risk of MFS (HR 2.47; 1.54-3.95). Similarly, p53 overexpression predicted worse bRFS (HR 1.95; 1.14-3.32) and MFS (HR 2.79; 1.50-5.19). ERG expression was associated with worse MFS only (HR 1.6; 1.03-2.48). On the multivariable analysis adjusting for known prognostic features, homogeneous PTEN loss remained predictive of adverse bRFS (HR 1.82; 1.12-2.96) and MFS (HR 2.08; 1.06-4.86). The study is limited by its retrospective and single-institution design. CONCLUSIONS: PTEN loss by immunohistochemistry is an independent adverse prognostic factor for bRFS and MFS in prostate cancer patients treated with SRT. Future trials will determine the optimal approach to treating SRT patients with adverse molecular prognostic features. PATIENT SUMMARY: Loss of the PTEN tumor suppressor protein is associated with worse outcomes after salvage radiotherapy, independent of other clinical or pathologic patient characteristics.