An estimated 50% of newly-diagnosed prostate cancer (PC) patients without pathologic evidence of pelvic lymph node (PLN) metastasis (NO) fail definitive local treatment. Although the risk of recurrence can be estimated from risk factors at presentation: size of the primary (cT stage), Gleason score and serum prostate specific antigen (sPSA) levels, direct evidence for PC metastasis in PLN has been lacking. Using a highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay to identify PC cells by PSA and prostate specific membrane antigen (PSM) gene messenger RNA (mRNA) expression, we found that 27 (82%) of 33 patients with localized PC and high risk features (T _ 2b or Gleason _7 or PSA _10 ng/ml), were RT-PCR positive while pathology identified PLN metastasis in only 4 (12%) (two sided P <0.0001). Moreover, 23 (79%) of 29 NO patients were RT-PCR positive. More recently we determined that while NO LNs from 29 normal male controls were RT-PCR negative for both markers, 72% of 80 NO PC patients were positive (two sided P <0.001). The hypothesis driving this proposal is that NO PLN tissues contain occult micrometastasis predictive of later systemic failure. The primary objective is to determine the value of PSA and/or PSM RT-PCR positive signals detected in NO PLN tissues of PC patients to identify occult micrometastasis and to predict outcome at 5 years independent of other prognostic indicators at presentation. We propose to prospectively collect fresh frozen bilateral PLN samples and peripheral blood mononuclear cells (PBMNC) from 315 NO PC patients undergoing definitive local therapy, to perform PSA/PSM RT-PCR analysis and follow their outcome over 5 years. We will correlate RT-PCR results between PLN and PBMNC, with cTstage, Gleason score, sPSA, age and race/ethnic background. To assess whether neoadjuvant/adjuvant hormonal therapy (HT) in conjunction to local therapy affects RT-PCR results and prognostic associations we will perform two parallel studies, one for patients receiving HT and the other for patients not receiving HT. The sample size of this study will allow for detection of a disease free survival hazard ratio of 2.0 or greater of the RT-PCR positive and negative groups with power of 0.80 for two sided test at the 0.05 level for each of the two hormonal therapy groups. If corroborated, the study will provide definitive information that will impact upon the current management of localized PC by identifying a group of patients bearing a residual tumor cell population which could be targeted for eradication with systemic therapy and perhaps avoid the morbidity of local treatment.