There are other reports of similar mutation rates in the PI3K/AKT pathway, but mostly in metastatic disease [4], and in these studies there was no gene or pathway that was consistently mutated outside of the androgen signaling pathway. the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse free survival, 19 vs. 106 months (p = .01). == Conclusions == This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. While point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high risk prostate cancer treated with chemotherapy followed by surgery. == Background == A major focus of current clinical oncology is shifting from treating cancers based on organ of origin to treating cancers based on molecular characteristics of the tumor. Characterization of targetable genomic and molecular aberrations is a Alvelestat prerequisite to development of successful targeted and individualized cancer therapies. In several tumor types, genetic and molecular alterations that are targets for therapy, or guide selection of therapies have been reproducibly described, but to date this has not been consistently described in prostate cancer, the most common malignancy in men. The vast majority of prostate cancers respond to targeting of the androgen signaling pathway, but most eventually regain the ability to proliferate despite therapeutic manipulation of androgen receptor signaling [1]. Thus, new targets are needed to improve therapy for these castration-resistant prostate cancers. Multiple groups of researchers have described genomic alterations in prostate cancer [24]. However, these have not yet been utilized as predictive biomarkers or as targets for personalized therapy. Many of the prior mutational studies in prostate cancer have investigated early stage, low risk prostate cancers, or metastatic disease deposits. Our study utilizes cases CCR3 of high risk localized prostate cancers (selected as high risk based on clinical stage T2c or surgically resectable T3a, serum PSA greater than or equal to 15 ng/mL, or a Gleason grade of at least 4+3 (i.e. 4+3, 4+4, or any 5 elements)) that were prospectively treated and collected as part of a Alvelestat study of neo-adjuvant chemotherapy. Notably, there is a higher mutation rate in the PI3K/AKT pathway in our series than has previously been published. The PI3K/AKT pathway is one of the most commonly altered signaling pathways in prostate cancer. PTEN loss and up-regulation of the AKT pathway Alvelestat have begun to emerge as potentially important players in prostate cancer biology [5,6]. Abnormalities of this pathway has been shown to induce proliferation in multiple cancers, including prostate cancer [7]. The loss of PTEN, a tumor suppressor gene that regulates the AKT pathway through negative feedback mechanisms [8,9], has been shown to be associated with a more aggressive prostate cancer in both mouse models, and in human prostate cancer tumor interrogations [1014]. Fusion of the TMPRSS2 and ERG genes is the most common genetic translocation in prostate cancer and is seen in approximately 50% of human prostate cancer specimens [15]. However, there has not been a consistent link between TMPRSS2-ERG fusion and prostate cancer progression or aggressiveness [1618]. Our study combines the investigation of potentially targetable point mutations in multiple cancer growth pathways, Alvelestat in addition to PTEN loss and TMPRSS-ERG fusion in localized prostate cancer and correlates this genetic and molecular information with prostate cancer biochemical relapse. == Methods == == Patients == Forty eight samples were utilized from a previously reported neo-adjuvant chemotherapy trial with institutional review board approval [19]. This study includes all evaluable prostate cancer specimens from this neo-adjuvant trial. The original neo-adjuvant chemotherapy trial involved patients with high-risk prostate cancer defined as clinical stage T2c or surgically resectable T3a, serum PSA greater than or equal to 15 ng/mL, or at least Gleason grade 4+3 (i.e. 4+3, 4+4, or any 5 elements). Patients were recruited from four sites in the Pacific Northwest. Patients were treated with docetaxel and escalating doses of mitoxantrone for 16 weeks prior to prostatectomy. Biochemical relapse was defined as a PSA greater than or equal to 0.4 ng/mL after.