Clinical Variables Associated With Overall Survival in Metastatic Castration-Resistant Prostate Cancer Patients Treated With Sipuleucel-T Immunotherapy.

BACKGROUND: Sipuleucel-T is an autologous cell-based cancer immunotherapy for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its approval by the Food and Drug Administration was based on demonstration of an overall survival (OS) benefit in randomized placebo-controlled phase III trials. However, treatment was associated with a prostate-specific antigen (PSA) decline in only a small minority of patients. Understanding the clinical factors that are associated with OS could help guide treatment decisions, including patient selection and the timing of sipuleucel-T relative to other therapies. PATIENTS AND METHODS: We retrospectively identified 94 mCRPC patients treated with sipuleucel-T from April 2010 to April 2016. The Kaplan-Meier method was used to estimate the distribution of OS. Univariate and multivariate Cox proportional hazard modeling was used to identify the prognostic factors for OS. RESULTS: With a median follow-up of 24.9 months, the median OS was 34.9 months. On multivariate analysis, Eastern Cooperative Oncology Group performance status, pretreatment PSA doubling time, and previous abiraterone and/or enzalutamide were significant prognostic factors for OS. CONCLUSION: A poorer baseline performance status, faster disease pace measured by the PSA doubling time, and previous novel androgen signaling inhibitor exposure could be important prognostic considerations for the treatment of mCRPC patients with sipuleucel-T. Further studies are needed to validate these findings.

HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer.

IMPORTANCE: The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense in 3ß-hydroxysteroid dehydrogenase isoenzyme 1 (3ßHSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC). OBJECTIVE: To determine whether the HSD3B1 (1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC. DESIGN, SETTING, AND PARTICIPANTS: An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco. EXPOSURES: Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC. MAIN OUTCOMES AND MEASURES: The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype. RESULTS: A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively. The median duration of therapy increased with the number of inherited HSD3B1 (1245C) variant alleles: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall comparison for trend, P = .01). Median progression-free survival also increased with number of HSD3B1 (1245C) variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, P = .03). CONCLUSIONS AND RELEVANCE: Inheritance of the HSD3B1 (1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.

Role of muscle stem cells during skeletal regeneration.

Although the importance of muscle in skeletal regeneration is well recognized clinically, the mechanisms by which muscle supports bone repair have remained elusive. Muscle flaps are often used to cover the damaged bone after traumatic injury yet their contribution to bone healing is not known. Here, we show that direct bone-muscle interactions are required for periosteum activation and callus formation, and that muscle grafts provide a source of stem cells for skeletal regeneration. We investigated the role of satellite cells, the muscle stem cells. Satellite cells loss in Pax7(-/-) mice and satellite cell ablation in Pax7(Cre) (ERT) (2/) (+) ;DTA(f/f) mice impaired bone regeneration. Although satellite cells did not contribute as a large source of cells endogenously, they exhibited a potential to contribute to bone repair after transplantation. The fracture healing phenotype in Pax7(Cre) (ERT) (2/) (+) ;DTA(f/f) mice was associated with decreased bone morphogenetic proteins (BMPs), insulin-like growth factor 1, and fibroblast growth factor 2 expression that are normally upregulated in response to fracture in satellite cells. Exogenous rhBMP2 improved bone healing in Pax7(Cre) (ERT) (2/) (+) ;DTA(f/f) mice further supporting the role of satellite cells as a source of growth factors. These results provide the first functional evidence for a direct contribution of muscle to bone regeneration with important clinical implications as it may impact the use of muscle flaps, muscle stem cells, and growth factors in orthopedic applications.