Haitao Wang

Medical Oncology,Tianjin Medical University Cancer Hospital

Objective: Castration-resistantprostate cancer (CRPC) remains a major clinical challenge. To date, themechanisms responsible for histological evolution and subsequent acquired drugresistant clinical behavior in prostate cancer remain poorly elucidated. Method:Biopsies of paired castration-sensitive and castration-resistant tumorswere obtained from 30 prostate cancer patients. DNA was extracted from alltumor and corresponding normal tissue samples and underwent whole exomesequencing using the Illumina HiSeq2500. Histology was confirmed by H&Estaining, and immunohistochemical staining for AR, Ki-67, CD56, Syn, P53,AURKA, N-myc, RB, E-cadherin, vimentin were performed on both the castrationsensitive and castration resistant samples to be suggestive of subtypingprogressive diseases. Result: The histological and molecular phenotypechanges of CRPC shows high between-tumor heterogeneity. CRPC specimens harboredrecurrent gene alterations including AR amplification, P53 mutation, PTEN loss,MYCN amplification, RB loss, PIK3CA mutation, PLK1 mutation, etc. According tohistological and molecular phenotype change, we propose the following CRPCsubtyping: 1) AR-dependent adenocarcinoma (60%, 18/30); 2) AR-negativeadenocarcinoma (13.3%, 4/30); 3) transformed neuroendocrine carcinoma (6.7%,2/30); 4) Others, including adenocarcinoma with EMT transformation (10%, 3/30)and with neuroendocrine differentiation (10%, 3/30). The “one size fits all”model should no longer be used in CRPC and therapy should be tailored toindividual patients according to patient and tumor characteristics, as well asmolecular subtypes and targets. Conclusion: The histological andmolecular phenotype changes of CRPC shows high between-tumor heterogeneity.There is evidence of an increase in Ki67, p53 mutation, PTEN loss, MYCNamplification, PLK1 mutation in some individuals that may explain resistance inindividuals and merit treatment targeted to those pathways. Biopsy atprogressive disease will be necessary to identify the relevant target forindividuals.

KeyWords: Castration resistant, Prostate cancer,Acquired resistance