Risk Stratification of Prostate Cancer Through Quantitative Assessment of PTEN Loss (qPTEN)

Tamara Jamaspishvili, MD, PhD; Palak G. Patel, PhD; Yi Niu, PhD; Thiago Vidotto, PhD; Isabelle Caven; Rachel Livergant, BSc; Winnie Fu; Atsunari Kawashima, MD, PhD; Nathan How, MD; John B. Okello, PhD; Liana B. Guedes, MD; Veronique Ouellet, PhD; Clarissa Picanço, PhD; Madhuri Koti, PhD; Rodolfo B. Reis, MD; Fred Saad, MD; Anne-Marie Mes-Masson, PhD; Tamara L. Lotan, MD; Jeremy A. Squire, PhD; Yingwei P. Peng, PhD; D. Robert Siemens, MD; David M. Berman, MD, PhD

Disclosures

J Natl Cancer Inst. 2020;112(11):1098-1104. 

In This Article

Abstract and Introduction

Abstract

Background: Phosphatase and tensin homolog (PTEN) loss has long been associated with adverse findings in early prostate cancer. Studies to date have yet to employ quantitative methods (qPTEN) for measuring of prognostically relevant amounts of PTEN loss in postsurgical settings and demonstrate its clinical application.

Methods: PTEN protein levels were measured by immunohistochemistry in radical prostatectomy samples from training (n = 410) and validation (n = 272) cohorts. PTEN loss was quantified per cancer cell and per tissue microarray core. Thresholds for identifying clinically relevant PTEN loss were determined using log-rank statistics in the training cohort. Univariate (Kaplan-Meier) and multivariate (Cox proportional hazards) analyses on various subpopulations were performed to assess biochemical recurrence-free survival (BRFS) and were independently validated. All statistical tests were two-sided.

Results: PTEN loss in more than 65% cancer cells was most clinically relevant and had statistically significant association with reduced BRFS in training (hazard ratio [HR] = 2.48, 95% confidence interval [CI] = 1.59 to 3.87; P < .001) and validation cohorts (HR = 4.22, 95% CI = 2.01 to 8.83; P < .001). The qPTEN scoring method identified patients who recurred within 5.4 years after surgery (P < .001). In men with favorable risk of biochemical recurrence (Cancer of the Prostate Risk Assessment – Postsurgical scores <5 and no adverse pathological features), qPTEN identified a subset of patients with shorter BRFS (HR = 5.52, 95% CI = 2.36 to 12.90; P < .001) who may be considered for intensified monitoring and/or adjuvant therapy.

Conclusions: Compared with previous qualitative approaches, qPTEN improves risk stratification of postradical prostatectomy patients and may be considered as a complementary tool to guide disease management after surgery.

Introduction

Among single gene biomarkers, loss of phosphatase and tensin homolog (PTEN) in prostate cancer is the most consistently associated with adverse events, including risk of upgrading at prostatectomy, disease recurrence after surgery, and progression to metastasis and death.[1–3] Along with its prognostic significance, well-established assays for PTEN assessment make it an attractive candidate biomarker for risk stratification to guide disease management.[2]

PTEN gene deletion is usually a subclonal event that produces molecular heterogeneity in primary prostate cancers, making it critical to assess with single-cell resolution.[4–6] Because PTEN protein loss is highly concordant with gene deletion, PTEN status can be readily obtained by immunohistochemistry (IHC), which accurately reflects genomic loss and has been extensively validated and adapted to Clinical Laboratory Improvement Amendments laboratory standards.[5,7,8] PTEN loss is very heterogeneous varying from partial (1%–99% cancer cells) to complete loss (100% cancer cells).[5,7] The prognostic significance of this variability has not been identified or validated, nor have specific clinical applications been identified for PTEN as a biomarker.

Because PTEN loss is strongly associated with prostate cancer recurrence after surgery, its assessment might help guide decisions around adjuvant radiation therapy (RT), which can improve survival for patients at higher risk for relapse.[9,10] The intensity of postoperative monitoring and the optimal timing of RT are controversial.[11,12] For many patients, risk may be unclear, and the choice between early (adjuvant) and late (salvage) RT can be difficult.[9–12] In select populations, biomarkers of recurrence may improve decision-making in this context.

In the current study, we determine and independently validate a quantitative scoring method, qPTEN, analyze the prognostic significance of qPTEN thresholds, and investigate a potential clinical application of qPTEN in postoperative treatment decisions.

processing....