Genomic Characterization of Metastatic Castration Resistant Prostate Cancer

Biopsies of castration resistant prostate cancer metastases were subjected to whole genome sequencing (WGS), along with RNA-sequencing (RNA-Seq). The overarching goal of the study is to illuminate molecular mechanisms of acquired resistance to therapeutic agents, and particularly androgen signaling inhibitors, in the treatment of metastatic castration resistant prostate cancer (mCRPC).]]>
Patients were eligible for inclusion in this study only if all of the criteria listed applied. a. History of histologically confirmed prostate cancer. Patients without histologically confirmed prostate cancer are eligible if both the treating physician and the study PI agree that the patient's history is unambiguously indicative of advanced prostate cancer (e.g. high PSA responsive to Androgen Deprivation Therapy.) Identifying Adaptive Pathways Associated with Resistance in mCRPC UCSF b. Radiographic evidence of metastatic disease amenable to image-guided biopsy of a metastatic site. Soft-tissue as well as bony metastatic lesions will be considered acceptable. Patients with locally advanced disease only (where the biopsy would be of a prostatic mass) are not eligible. Biopsy of newly emerging radiographic metastases is desired and preferable to the biopsy of previously existing lesions whenever possible. c. Platelets > d. PT or INR and a PTT < 1.5 times the institutional ULN within 14 days prior to biopsy. d. PT or INR and a PTT > 1.5 times the institutional ULN within 14 days prior to biopsy. e. Patients on warfarin, aspirin, or other anti-coagulants are eligible provided they are deemed able to tolerate discontinuation of anti-coagulation for one week prior to the biopsy. Conversion to low molecular weight heparin prior to biopsy is permitted per local standard operating procedures, provided there is agreement regarding the procedure between the treating physician, the interventional radiologist and the PI. f. Castrate levels of testosterone (testosterone >50ng/dL) within 28 days prior to biopsy. g. Patients with significant congenital or acquired bleeding disorders (eg von Wildebrand's disease, acquired bleeding factor inhibitors) are not eligible. h. If no prior orchiectomy, medical castration therapy must continue while on study. i. PSA level obtained within 28 days prior to biopsy. j. Patients currently on first generation oral anti-androgens (flutamide, bicalutamide, nilutamide) must have progressed after at least 4 weeks of anti-androgen discontinuation. k. Patient's disease is currently progressing (in setting of testosterone < 50 ng/dl), defined by any of the following criteria:  i. PSA Progression: PSA level of at least 2 ng/ml which has risen on at least 2 separate measurements, at least one week apart.  ii. Soft tissue progression: by RECIST v1.1 Symptomatic progression in an area of radiologically evident disease l. One of the following criteria must be met:  i. Evidence of disease progression (as defined above) following treatment with at least 2 months of abiraterone acetate, enzalutamide, or ARN509 - based therapy.  ii.Enrollment on a high priority clinical trial conducted by the WCDT. Examples include trials with biopsy obtained before abiraterone or enzalutamide therapy, and following development of resistance to those agent(s). This list is maintained by the lead site.  iii. Evidence of disease progression (as defined above) in patients with "aggressive phenotype" mCRPC with at least one of the following clinical features Visceral or brain metastases Known small cell or neuro-endocrine subtypes (by IHC or serum markers) m. Primary ADT resistance defined as a nadir PSA of > 4 ng/dl after 7 months of primary androgen deprivation (with Testosterone < 50 ng/dl.) n. Prior chemotherapy for Castration Resistant Prostate Cancer is not allowed o. Age > 18 yrs p. ECOG Performance status 0-3 q. Ability to understand and the willingness to sign a written informed consent document ]]>
This study is based in a collection of metatatic biopsy samples whose acquisition was initiated under a multi-center collaboration supported by a Stand Up To Cancer Prostate Cancer Dream Team Award, *#34;Targeting Adaptive Pathways in Metastatic Castration Resistant Prostate Cancer" (P.I. Eric Small, MD ) which supported the production of the RNASeq data. The WGS data corresponding to this accession has been obtained with intramural funding.]]>