Elisa Ledet

The association between germline BRCA2 variants and sensitivity to platinum‐based chemotherapy among men with metastatic prostate cancer

Breast cancer 2 (BRCA2)‐associated breast and ovarian cancers are sensitive to platinum‐based chemotherapy. It is unknown whether BRCA2‐associated prostate cancer responds favorably to such treatment.

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.

Alternative Digit Ratios and Their Relationship to Prostate Cancer

BACKGROUND The ratio of the second to the fourth digits (2D:4D) has been linked to prenatal androgen exposure and prostate cancer (PCa). The use of alternative finger ratios has been shown to be a greater indicator of sexual dimorphism when compared with the traditional 2D:4D ratio. This study aimed to assess the relationship between alternative digit ratios, racial demographics, and clinical/pathologic parameters associated with PCa. MATERIALS AND METHODS Digital finger length measurements were made from scanned images of hands from patients with PCa. Race, age, family history, history of metastasis, and Gleason score at diagnosis were assessed in a cross-sectional clinic-based study. Demographic and clinical parameters were analyzed with respect to various alternative finger length ratios. RESULTS Hand measurements were obtained in 354 white and 98 African-American patients with PCa. African-American men were more likely to have a smaller 2D:3D (P < .0001) and 2D:4D digit ratio (P < .0001) in both hands. Larger right (R)3D:5D (P = .0005), R4D:5D (P = .0014), and R2T:2D (P = .0501) digit ratios were present in African-Americans compared with whites. In exploratory analyses, African-American men with a smaller left (L)2T:2D ratio were younger at the time of PCa diagnosis (P = .0125). No relationship was found between the various digit ratios and Gleason score, the presence of metastatic disease, or family history. CONCLUSION Various alternative finger length ratios show strong differences between African-American and white men in this study. The potential relationship between the 2T:2D ratio and age at diagnosis in African-Americans needs additional verification.

Prostate-specific Antigen Response and Eradication of Androgen Receptor Amplification with High-dose Testosterone in Prostate Cancer

Metastatic castrate-resistant prostate cancer (CRPC) has been studied from a tissue-based molecular perspective [1] and much has been learned. Alterations in the androgen receptor (AR) are common, as are a multiplicity of other genetic changes. More recent studies indicate that plasma cell-free DNA (cfDNA) may be used to assess the molecular genetics of tumors, and potentially direct therapy [2]. Resistance to newer hormonal agents such as abiraterone and enzalutamide can be predicted by cfDNA changes, including both AR amplification and select AR mutations [3,4]. Here we describe a case involving a heavily pretreated patient for whom

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.

Laboratory‐Based Biomarkers and Liver Metastases in Metastatic Castration‐Resistant Prostate Cancer

BACKGROUND Metastatic castrate-resistant prostate cancer (mCRPC) patients with liver metastases have a poor prognosis. No large studies have investigated the clinical and biochemical parameters associated with liver metastases in this population. MATERIALS AND METHODS Patient data made available via Project Data Sphere were collected from 1,281 men with mCRPC who were enrolled on to three phase III clinical trials for the treatment of their disease. Multiple logistic regression was performed on eight clinical and biochemical baseline variables to test their association with the presence of liver metastases on baseline radiographic imaging. Variables of interest included prior docetaxel exposure, Eastern Cooperative Oncology Group performance status, albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase (AST), hemoglobin (HGB), lactate dehydrogenase (LDH), prostate-specific antigen, and total bilirubin. Final models were compared when treating the variables as either continuous or categorized. RESULTS Multiple variable analysis demonstrated that an increasing serum AST or LDH or a decreasing HGB was associated with an increased probability of having documented radiographic liver metastases (p < .0001). The area under the curve for the continuous model was 0.6842 and 0.6890 for the categorical one, with the latter model containing a dichotomized AST and LDH based on the upper limit of normal and tertile ranges of HGB based on the distribution of the outcome. CONCLUSION Our analysis demonstrated a significant association between the presence of liver metastases and laboratory levels of AST, LDH, and HGB. These have implications for patient management. More research is needed to validate these biomarkers and prospectively determine their application in the clinical setting. IMPLICATIONS FOR PRACTICE The purpose of this study was to evaluate biochemical and clinical biomarkers associated with the presence of liver metastases in men diagnosed with metastatic castrate-resistant prostate cancer. The results indicate that quantitative assessments of aspartate transaminase, lactate dehydrogenase, and hemoglobin are significantly associated with an increased probability of having documented radiographic liver metastases. Analysis of these simple variables can alert clinicians to those at high risk for prostate cancer that has spread to the liver, a finding of clear importance for clinical management.

Extreme Prostate‐Specific Antigen Response to Infusional 5‐Flourouracil in Castrate‐Resistant Prostate Cancer

Prostate cancer that has progressed after androgen deprivation, abiraterone, and taxane therapy is challenging to treat successfully. Herein we report a dramatic response to continuous-infusion 5-fluorouracil (5-FU) at a dose of 200 mg/m2 in a patient with rapidly progressive, heavily pretreated, metastatic castrate-resistant prostate cancer. Baseline prostate-specific antigen values declined from 1,890 ng/mL to <1 ng/mL after 5-FU therapy. We hypothesized that prostate-specific membrane antigen overexpression may result in cancer cells uniquely susceptible to antifolate therapies.

Utility of PCA3 and TMPRSS2:ERG urinary biomarkers in African American men undergoing prostate biopsy.

126 Background: To determine the performance characteristics of urinary PCA3 andTMPRSS2:ERG (T2:ERG) in a racially diverse group of men. Methods: Following IRB approval, from 2013-2015, post digital rectal exam (DRE) urine was prospectively collected in patients without known prostate cancer (PCa), prior to biopsy. PCA3 and T2:ERG RNA copies were quantified and normalized to PSA mRNA copies using Progensa assay (Hologic, San Diego, CA). Prediction models for PCa and high-grade PCa were created using standard of care (SOC) variables (age, race, family history of PCa, prior prostate biopsy and abnormal DRE) plus PSA. Decision Curve Analysis was performed to compare the net benefit of using SOC, plus PSA, with the addition of PCA3 and T2:ERG. Results: Of 304 patients, 182 (60%) were AA; 139(46%) were diagnosed with PCa (69% AA). PCA3 and T2:ERG scores were greater in men with PCa, ≥ 3 cores, ≥ 33.3% cores, > 50% involvement of greatest biopsy core and Epstein significant PCa (p-values < 0.04). PCA3 added to ...