Plasma tumor gene conversions after one cycle abiraterone acetate for metastatic castration-resistant prostate cancer: a biomarker analysis of a multicenter international trial.

BACKGROUND: Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment. PATIENTS AND METHODS: Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS). RESULTS: Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients. CONCLUSIONS: Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.

Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.

BACKGROUND: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. METHODS: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). RESULTS: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P < 0.001 and HR 3.81; 95% CI 2.28-6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P = 0.03, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. CONCLUSION: Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. CLINICAL TRIAL NUMBER: NCT02288936 (PREMIERE trial).

Post-translational control of Nur77.

Nur77 is a nuclear orphan receptor that has been implicated in both cell survival and apoptosis. With the exception of T-cells, translocation of Nur77 to the cytoplasm promotes cell death, while its retention in the nucleus promotes survival and proliferation. Nur77 appears to be a true orphan receptor, indicating that its activity must be controlled by ligand-independent mechanisms. Here, we discuss the role of phosphorylation in the regulation of Nur77.

Defining and measuring fatigue.

In response to a long history of problems with defining and measuring fatigue, the University of Kansas School of Nursing established a Center for Biobehavioral Studies of Fatigue Management to facilitate the study of fatigue in diverse populations. The purpose of this article is to review past efforts to define and measure fatigue and the conceptual problems relevant to currently used measures of fatigue. Several distinct characteristics and corresponding measures of fatigue are identified and a definition and framework for the study of fatigue are discussed. Future research on fatigue must attend to the conceptual distinctions among various measures and the measures of fatigue most appropriate to the goals of a study.

Community prostate cancer screening.

Health promotion and cancer prevention, including screening, are two important aspects of cancer care. However barriers exist to patients receiving recommended cancer screening procedures. One way to overcome these barriers is through the use of community cancer screening programs. This article presents a prototype of a community prostate cancer screening program. The program planning, staffing, promotion, cost and finance, and follow-up activities are explained. Furthermore, examples of communication tools and follow-up protocol, and results of 4 years of community screening programs are described. Recommendations for future community screening give insight for program improvement.

A description of the needs of noninstitutionalized cancer patients and their primary care givers.

The purpose of this descriptive study was twofold: to identify the needs of the noninstitutionalized patient with cancer as defined by patients, primary care givers, and nurses, and to identify the needs of the primary care giver as defined by the same three groups of subjects. Each subject completed two forms of the Objects Content Test, an open-ended questionnaire on which subjects were asked to list the needs of patients and care givers. Content analysis was applied to the two sets of data to formulate categories of need responses; each set of data with category labels and definitions was submitted for q-sort by two successive groups of nurse experts to establish the validity of need item responses in categories. Findings revealed that patient needs were represented by six categories and caregivers' needs by seven categories. For both sets of data, the largest number of needs were in the psychological needs category. For patients, physical needs and information needs were the next largest categories; for care givers, the categories of household management needs (which encompassed patient care) and information needs were the second and third largest. Some disparity between perceived needs as generated by the three groups of subjects was noted. Further research utilizing quantitative methods is needed to determine whether suggested trends (such as nurse subjects' emphasis on informational needs for care givers and patients' infrequent listing of informational needs for themselves) have validity.