Allie E. Steinberger

A Whole Blood Assay for AR-V7 and ARv567es in Patients with Prostate Cancer

PURPOSE Most prostate cancer mortality can be attributed to metastatic castration resistant prostate cancer, an advanced stage that remains incurable despite recent advances. The AR (androgen receptor) signaling axis remains active in castration resistant prostate cancer. Recent studies suggest that expression of the AR-V (AR splice variant) AR-V7 may underlie resistance to abiraterone and enzalutamide. However, controversy exists over the optimal assay. Our objective was to develop a fast and sensitive assay for AR-Vs in patients. MATERIALS AND METHODS Two approaches were assessed in this study. The first approach was based on depletion of leukocytes and the second one used RNA purified directly from whole blood preserved in PAXgene® tubes. Transcript expression was analyzed by quantitative reverse transcription-polymerase chain reaction. RESULTS Through a side-by-side comparison we found that the whole blood approach was suitable to detect AR-Vs. The specificity of the assay was corroborated in a cancer-free cohort. Using the PAXgene assay samples from a cohort of 46 patients with castration resistant prostate cancer were analyzed. Overall, AR-V7 and ARv567es were detected in 67.53% and 29.87% of samples, respectively. Statistical analysis revealed a strong association of AR-V positivity with a history of second line hormonal therapies. CONCLUSIONS To our knowledge this is the first study to demonstrate that PAXgene preserved whole blood can be used to obtain clinically relevant information regarding the expression of 2 AR-Vs. These data on a castration resistant prostate cancer cohort support a role for AR-Vs in resistance to therapies targeting the AR ligand-binding domain.

Exceptional Duration of Radium-223 in Prostate Cancer With a BRCA2 Mutation

Clinical Practice PointsIt is now recognized that patients with prostate cancer have a higher rate of DNA repair gene mutations than previously appreciated.The prevalence of germline alterations in DNA repair genes may be as high as 11.8% in patients with metastatic prostate cancer.Several targeted agents for DNA repair defects (poly ADP ribose polymerase inhibitors and platinums) have shown increased sensitivity in the setting of biallelic breast cancer susceptibility gene 2 (BRCA2) loss.The mechanism of action of Radium‐223, a bone‐targeted radiopharmaceutical, raises the possibility of clinical exploitation among patients with a BRCA2 mutation.We hypothesize that the extraordinary duration of disease control with Radium‐223 described herein is owing to the presence of a unique sensitivity in patients with a BRCA2 mutation.

Radium-223 Use in Clinical Practice and Variables Associated With Completion of Therapy

Micro‐Abstract Radium‐223 has shown improvements in overall survival in men with metastatic castration‐resistant prostate cancer (mCRPC). In this study, we investigated clinical variables associated with radium‐223 therapy completion in mCRPC. We show the previous and concurrent mCRPC therapies and laboratory data that are associated with the number of radium‐223 doses received. These data are hypothesis‐generating and warrant prospective testing. Background: Radium‐223 has shown clinical efficacy in metastatic castration‐resistant prostate cancer. Despite improvement in quality of life and survival, practice patterns and utility of this agent outside the context of clinical trials have not been fully characterized. The primary objective in this study was to evaluate variables associated with completion of 5 to 6 radium‐223 doses. Patients and Methods: We conducted retrospective analyses of patients who received radium‐223 (n = 135). Patients were classified into 3 cohorts: 1 to 2, 3 to 4, or 5 to 6 radium‐223 doses. We evaluated the association of clinical and laboratory variables with the number of cycles administered (5‐6 vs. 1‐4 doses). Results: Twenty‐five patients (18.5%) received 1 to 2 radium‐223 doses, 27 (20.0%) received 3 to 4, and 83 (61.5%) received 5 to 6. The most common reasons for treatment discontinuation included disease progression (61.5%, n = 40), patient preference (15.4%, n = 10), and toxicity (10.8%, n = 7). Factors associated with therapy completion in univariate analysis included previous sipuleucel‐T treatment (P = .068), no previous abiraterone or enzalutamide treatment (P = .007), hemoglobin ≥ lower limit of normal (LLN; P = .006), white blood cell count ≥ LLN (P = .045), absolute neutrophil count (ANC) ≥ LLN (P = .049), lower alkaline phosphatase (P = .029), and lower lactate dehydrogenase levels (P = .014). Factors associated with therapy completion in multivariable analysis included previous sipuleucel‐T treatment (P = .009), hemoglobin ≥ LLN (P = .037), and ANC ≥ LLN (P = .029). Conclusion: Several clinical parameters are associated with radium‐223 therapy completion. In general, these parameters reflect earlier disease stage. These data are hypothesis‐generating and prospective testing of the optimal number of radium‐223 doses is warranted.

Characterizations of Clinical and Therapeutic Histories for Men With Prostate Cancer-Specific Mortality

BACKGROUND Careful descriptions of men with prostate cancer (PCa)-specific mortality are scant in nontrial settings. The present retrospective review describes the clinical characteristics, timelines, and treatment histories from initial presentation to death in a cohort of men with metastatic, castrate-resistant PCa (mCRPC). Unique to the present study is the unequivocal attribution of PCa death by a single experienced clinician. PATIENTS AND METHODS A total of 119 patients who had been treated at Tulane Cancer Center and had died of mCRPC from 2008 to 2015 were studied through a retrospective review of the medical records. RESULTS The median age at diagnosis was 65 years (range, 40-85 years), and 34.4% of the patients presented with metastatic disease (stage M1). Of these patients, 56% had received definitive primary therapy, all had received androgen-deprivation therapy, and 52% had received docetaxel. The patients had received a median of 7 (1-14) systemic therapies before death. Most were secondary hormonal manipulations after the diagnosis of mCRPC (median, 4; range, 0-9). The median survival was 69 months (range, 5-270 months) after diagnosis, and the median age at death was 73 years (range, 47-95 years). The presence of metastases at diagnosis was a significant predictor of early death (hazard ratio, 4.33; P < .001), and definitive primary therapy was a significant predictor of longer survival (P < .001). The median survival for patients presenting with metastases was 39 months (range, 5-235 months) compared with 100 months (range, 6-270 months) for those with localized disease (P < .001). The median age at diagnosis between the docetaxel- and non-docetaxel-treated patients was significantly different at 62 and 71 years, respectively (P = .002). CONCLUSION The present retrospective analysis provides initial views clarifying the clinical characteristics of men dying of mCRPC and the therapies they received before death. Additional data are needed in multi-institutional settings to confirm these findings.

Sequencing of treatments in metastatic CRPC for patients who have completed all therapeutic interventions.

339 Background: The current treatment paradigm for metastatic, castrate-resistant prostate cancer (mCRPC) has rapidly changed and six therapies [abiraterone (Abi), enzalutamide (Enza), docetaxel (Doc), cabazitaxel (Cab), radium-223 (Ra-223), and sipuleucel-T (Sip-T)] have now been proven to prolong overall survival. Though sequential therapy is the norm, few studies have reported on the variety and prevalence of these agents over the course of patients lifetime. Herein, we sought to describe the temporal frequencies of mCRPC therapies in patients who completed all of their therapies. Methods: Retrospective chart reviews were conducted on 119 patients who died from mCRPC at Tulane Cancer Center from 2008-2015 (thus completing all possible therapies). Many patients were not treated with multiple life-prolonging therapies given the timing of their death. Post-mCRPC therapies were longitudinally sequenced and a frequency table was generated for first, second, third, etc. line of therapies. Results: Median du...