Molecular Analysis Of Oncogenes And Resistance Mechanisms Of Hormone Therapy In Castration Resistant Prostate Cancer

ObjectiveProstate cancer is one of the most common cancer among men. Most of the patients get advanced or metastastic disease at the time of diagnosis, and lost the opportunity to surgery, they require surgical castration or androgen deprivation therapy. Although most of the patient has superior effects in the early time, almost all patients eventually developed into Castration-resistant prostate cancer(CRPC), which produced the acquired drug resistance. There is a significant difference when given the same treatment regime to different patients with CRPC because of different molecular classification. To explore the resistance mechanisms of hormone therapy in CRPC and provide the individual decision-making for patients with CRPC.Methords1. Collect the clinical pathologic data and acquired the second biopsy tissue of40 patients with CRPC in multicenter clinical trial(ID:NCT02208583); 2.Immunohistochemical staining were applied to detect immunophenotype, the markers including AR, Epithelial-mesenchymal transition(EMT)-related indicators E-cadherin and Vimentin, Neuroendocrine differentiation(Neuroendocrine differentiation,NED)-related indicators CD56 and Syn, P53, AURKA, N- myc and Ki- 67.3. Exome sequencing identifies the mutations.4. Provide the individual decision-making for patients with CRPC according the immunophenotype and gene mutations.Results1. All patients get the transformation of immunophenotype: AR positive expression in 50% of patients, low differentiation in 34% of patients, NED transformation in 8% of patients, EMT transformation in 4% of patients, SCPC in 4%of patients.2. All patients get the gene mutations: TP53 in 31.6% of patients, KDR in19.3% of patients, MET and PIK3 C in 8.8% of patients, respectively, KIT, PTEN, RB,APC in 7% of patients, respectively, EGFR in 3.5% of patients. In addition, TP53 is one of the most common genetic alterations in CRPC, and most TP53 mutations accompanied by other mutations.3.Provide individual treatment regime for 5 patients with CRPC according to the immunophenotype and gene mutations. Two received abiraterone, 1 received EP chemotherapy, 1 received EP chemotherapy combined with abiraterone, 1 received EP chemotherapy combined with Bevacizumab. The progression-free survival(PFS) were 4 months, 8 months, 10 months, 6 months and12 months,respectively.Conclusions1. CRPC is one of the late malignant tumor with a group of highly heterogeneous.There are a variety of resistance mechanisms of hormone therapy including immunophenotype and gene mutations in the process of PCa to CRPC.2.All patients get the transformation of immunophenotype: AR positive expression in50% of patients, low differentiation in 34% of patients, NED transformation in 8% of patients, EMT transformation in 4% of patients, SCPC in 4% of patients. AURKA expression accompanied by TP53 mutations.3. All patients get the gene mutations:TP53 in 31.6% of patients, KDR in 19.3% of patients, MET and PIK3 C in 8.8% of patients, respectively, KIT, PTEN, RB, APC in 7% of patients, respectively, EGFR in3.5% of patients. In addition, TP53 is one of the most common genetic alterations in CRPC, and most TP53 mutations accompanied by other mutations.4. The patients received individual treatment regime has superior effects according the immunophenotype and gene mutations, and no serious side effects.5. In the different stages of prostate cancer, especially the CRPC, we should carefully evaluate different individual’s physical condition and the characteristics of immunophenotype and gene mutations, and the secondary biopsy is necessary for patients with CRPC.