PTEN Protein Loss by IHC Is an Adverse Prognostic Indicator in a High Risk Surgical Cohort of Prostate Cancer Patients
TL Lotan, S Sutcliffe, B Gurel, BH Park, E Humphries, AW Partin, M Han, PC Walsh, AM De Marzo. Johns Hopkins Hospitals, Baltimore, MD
Background: PTEN is a tumor suppressor commonly inactivated in prostate cancer. While studies have shown that PTEN deletions and protein loss are more common in advanced prostate cancers, no prior studies examined whether PTEN protein loss in tumors from men treated by radical prostatectomy (RRP) is associated with time to metastasis or prostate cancer-specific death. Further, some deletions at the PTEN locus are focal and difficult to detect with FISH. Thus, we examined PTEN loss by immunohistochemistry (IHC) in a series of prostate cancer patients with biochemical recurrence after RRP.
Design: Six TMAs were made from 217 patients who underwent RRP by a single surgeon (1986-1996) and developed biochemical recurrence (PSA≥0.2 ng/mL). At RRP, 22% (n=49) had a Gleason score (GS) of ≤6, 51% (n=110) had GS of 7 and 27% (n=58) had a GS of 8-10. 83% (n=181) had extracapsular extension, 34% (n=74) had seminal vesicle invasion and 27% (n=58) had lymph node metastases. 36% (n=78) had positive margins. IHC for PTEN (Cell Signaling #9188) was performed after optimization with genetic cell line controls and scored as “markedly decreased” (0-1+) or “normal” (2+) in tumor tissue relative to adjacent benign tissue.
Results: Average patient follow-up was 15.1 years. 25% (52/210) of patients recurred locally and 60% (124/208) recurred with distant metastases. 38% (79/207) of patients died of prostate cancer. In Kaplan-Meier analysis, markedly decreased PTEN immunostaining was associated with decreased time to metastasis (p=0.03, Figure 1) and decreased time to prostate-specific death (p=0.06). In multivariate Cox regression analysis, GS and pathological stage, but not PTEN protein levels, were significantly associated with time to metastasis and prostate cancer-specific death.
Conclusions: PTEN expression by IHC is simple to perform and score with appropriate controls. Further, loss of PTEN by IHC is associated with decreased time to metastasis in a surgical series. These studies validate PTEN protein loss as a biomarker of poor prognosis in prostate cancer and support further dissection and therapeutic targeting of this pathway in high risk prostate cancer.
Category: Genitourinary (including renal tumors)
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 94, Wednesday Morning