Intraprostatic cell cycle proteins in relation to the risk of prostate cancer recurrence

Authors

• MB Cook
• SE Daugherty
• P Lenz
• LT Amundadottir
• LR Sternberg
• A Kibel
• H Parikh
• JN Sampson
• SB Coburn
• WY Huang
• ND Freedman
• A Black
• SI Berndt
• SM Hewitt
• RN Hoover

Abstract

Introduction Predictive models of prostate cancer recurrence are suboptimal with areas under the receiving operating characteristic curve of 67–74%. We assessed whether IHC quantitation of selected cell cycle proteins in prostate cancer tissue was associated with recurrence with a view to potentially improving predictive models. Methods We used tissue microarrays (TMAs) comprised of tumor and adjacent normal FFPE prostatectomy tissues from 696 prostate cancer cases in the PLCO Cancer Screening Trial. Four cell cycle-related proteins were selected from an RNA-sequencing study on a distinct set of samples: RAD9, cyclin B1, survivin, and RAF1. Stained TMAs were scanned, processed and scored using automated technologies with manual-verification. Cox proportional hazards regression estimated hazard ratios (HRs) of associations between intraprostatic cell cycle proteins and prostate cancer recurrence. Results Of the 696 prostate cancer cases, 79 had a recurrence. Multivariable regression—adjusted for arm, center, PSA, age, stage, gleason score, weight, and comorbidity score— provided evidence for a “U-shaped” relation between tumor survivin cytoplasmic H-score and prostate cancer recurrence with HRs of 0.39 (p=0.02) and 0.46 (p=0.03) for quartiles 2 and 3, respectively. The related variable—tumor survivin cytoplasmic average positive intensity—demonstrated similar associations. Importantly, adjacent normal survivin staining was not associated with prostate cancer recurrence. RAD9, cyclin B1, and RAF1—of tumor and of adjacent normal tissues—were also not associated with recurrence. Discussion This study provides evidence that cell cycle-related and apoptosis-inhibitor survivin is related to prostate cancer biochemical recurrence. The potential independent predictive value of survivin requires external validation.

Scientific Focus Area: Epidemiology

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