Purpose: While the detection of AR-V7 in circulating tumor cells (CTC) is associated with resistance to abiraterone or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance. Experimental Design: PROPHECY was a multicenter prospective study of men with high-risk mCRPC starting abiraterone or enzalutamide. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abiraterone or enzalutamide and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression-free survival and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY). Results: We enrolled 118 men with mCRPC starting on abiraterone or enzalutamide; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS [HR, 2.2; 95% confidence interval (CI), 1.2–4.0 and HR 3.8; 95% CI, 1.2–12.3, respectively] when treated with abiraterone/enzalutamide. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n = 173; HR, 5.7; 95% CI, 2.6–12.7). Conclusions: A high CIN and NE CTC phenotype is independently associated with worse survival in men with mCRPC treated with abiraterone/enzalutamide, warranting further prospective controlled predictive studies to inform treatment decisions.

PURPOSE: We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model.METHODS: Data from 8,083 docetaxel-naïve mCRPC men randomly assigned on seven phase III trials were used to validate the prognostic model of OS. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low and high) and three-risk prognostic groups (low, intermediate, and high).RESULTS: The tAUC was 0.74 (95% CI, 0.73 to 0.75), and when adjusting for the first-line androgen receptor (AR) inhibitor trial status, the tAUC was 0.75 (95% CI, 0.74 to 0.76). Similar results were observed by the different racial, age, and treatment subgroups. In patients enrolled on first-line AR inhibitor trials, the median OS (months) in the low-, intermediate-, and high-prognostic risk groups were 43.3 (95% CI, 40.7 to 45.8), 27.7 (95% CI, 25.8 to 31.3), and 15.4 (95% CI, 14.0 to 17.9), respectively. Compared with the low-risk prognostic group, the hazard ratios for the high- and intermediate-risk groups were 4.3 (95% CI, 3.6 to 5.1; P < .0001) and 1.9 (95% CI, 1.7 to 2.1; P < .0001).CONCLUSION: This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.[Media: see text]

Purpose: In men with metastatic castration-resistant prostate cancer (mCRPC), prostate-specific membrane antigen (PSMA)-targeted radioligand therapy has drastically improved clinical outcomes. A liquid biopsy characterizing PSMA expression could be useful in guiding optimal therapy. Experimental Design: We conducted a retrospective analysis of the prospective multicenter PROPHECY (Prospective CiRculating PrOstate Cancer Predictors in HighEr Risk mCRPC StudY) trial of men with mCRPC (n = 118) treated with abiraterone (abi) or enzalutamide (enza). Circulating tumor cells (CTC) were enriched (CTC/mL) and characterized for PSMA protein expression/heterogeneity at baseline and progression. We utilized proportional hazards modeling of the association between PSMA-positive (PSMA+) CTC enumeration with overall survival (OS) and progression-free survival (PFS). Results: Overall, 97 men with mCRPC had evaluable blood samples for baseline CTC PSMA detection; 78 men (80%) had detectable CTCs. Of these, 55% (43/78) of men had any PSMA CTC detection, 21% (16/78) had ≥2 PSMA+ CTCs/mL, and 19% (8/43) were 100% PSMA+. At progression on abi/enza, 88% (50/57) of men had detectable CTCs, 68% (34/50) had any PSMA CTCs, and 12% (4/34) had 100% PSMA+ CTCs. Among paired cases (n = 57), PSMA+ CTC detection increased slightly after abi/enza progression. Using an optimal cutoff of ≥2 PSMA+ CTCs/mL, median OS was 26, 21, and 11 months for men without CTCs, PSMA− CTCs, and PSMA+ CTCs. Adjusting for prior abi/enza therapy, Halabi clinical risk score, and CTC enumeration, the HRs for OS and PFS for PSMA+ CTC+ were 3.0 [95% confidence interval (CI) = 1.1–7.8] and 2.3 (95% CI = 0.9–5.8). Conclusions: We observed PSMA CTC heterogeneity between and within patients with mCRPC over time during abi/enza progression. CTC PSMA enumeration was adversely prognostic independent of clinical factors and disease burden. Further validation is warranted in the context of PSMA-targeted therapies.

Background: Integrase strand transfer inhibitors (INSTIs) and the menopausal transition have been associated with body composition changes in women with human immunodeficiency virus (WWH), but their interaction is unknown. Methods: From 2006 to 2019, 1131 virally-suppressed WWH (419 who switched to INSTI [INSTI+]; 712 who did not switch [INSTI–]) and 887 women without HIV (WWOH) from the Women's Interagency HIV Study were included. Mixed-effects models were used to evaluate change in waist circumference (WC) and body mass index (BMI) by menopausal phase defined using anti-Müllerian hormone, a biomarker of ovarian reserve. Results: During premenopause, WWH had increases in WC (INSTI+: 0.01 cm per 6 months [95% confidence interval {CI}: −.29 to .32] and INSTI−: 0.22 cm per 6 months [95% CI: −.01 to .44]) that were not statistically significantly different from WWOH; there was also little difference by INSTI status. In late perimenopause, INSTI+ had faster increases in WC (0.37 cm per 6 months [95% CI: .15–.60]) while INSTI− had smaller increases (0.14 cm per 6 months [95% CI: −.06 to .34]) compared to WWOH. In menopause, INSTI+ had faster increases, peaking at 43 months then declining, while INSTI− had smaller increases (0.14 cm per 6 months [95% CI: −.02 to .30]). Compared to INSTI−, in late perimenopause, INSTI+ had 0.26 cm per 6 months (95% CI: .02–.50) faster linear increases in WC and in menopause, INSTI+ was associated with faster increases, peaking at 41 months. Conclusions: Switching to an INSTI-based regimen during late perimenopause and menopause is associated with faster increases in WC when compared to women who did not switch. Menopausal status should be considered when switching to an INSTI.

Background: The impact of integrase strand-transfer inhibitors (INSTIs) on steatotic liver disease in women with HIV (WWH) is unknown. Methods: Using data collected in the Women's Interagency HIV Study from 2007–2020, change in Fibrosis-4 index (FIB4), aspartate aminotransferase to platelet ratio index (APRI), and nonalcoholic fatty liver disease fibrosis score (NFS) over 5 years was compared between virologically suppressed WWH who switched to or added an INSTI to their antiretroviral therapy (ART) and WWH remaining on non-INSTI ART. In participants with transient elastography (TE) measures, estimates of hepatic steatosis (controlled attenuation parameter [CAP]), fibrosis (liver stiffness [LS]), and steatohepatitis (FibroScan-aspartate aminotransferase [FAST] scores) were compared by group. Results: A total of 872 WWH (323 INSTI, 549 non-INSTI) were included, and 280 (146 INSTI, 134 non-INSTI) had TE. Of these, 61% were non-Hispanic Black; mean age was 47 years and body mass index was 31.4 kg/m2. Among non-obese women, those in the INSTI versus non-INSTI group had a greater increase in NFS (but not FIB4 or APRI) over time (study group × time, P = .015). Those in the INSTI versus non-INSTI group also had greater CAP (+25; 95% CI: .28–49; P = .048), LS (+1.23; 1.01–1.49; P = .038), and FAST scores (+1.97; 1.17–3.31; P = .011) and a 3.7 (1.2–11.4; P = .021) greater odds of having hepatic steatosis (CAP ≥248 dB/m) within 1 year of starting an INSTI. Conclusions: Hepatic steatosis risk was increased only within the first year following INSTI initiation among WWH. Longitudinal hepatic assessments are warranted to evaluate whether these changes are associated with clinically significant liver disease.

Over 43 million U.S. residents rely on private unregulated wells for their drinking water, raising public health concerns, particularly in regions like northern New England where widespread groundwater arsenic contamination is now recognized. Children are particularly vulnerable to adverse health effects from arsenic exposure. Despite AAP Guidelines, approaches to engage pediatric clinicians in promoting private well testing have not been previously described. We sought to determine the most effective practice approaches to achieve successful well water testing in routine pediatric care. 12 primary care clinics were block randomized to one of four study arms. Two intervention variables were assessed: (1) test results access (parent only vs. parent and clinic) and (2) follow up approaches (yes/no). Parents of children under 12 months using a private well were eligible. Prepaid water tests were provided. Primary outcome was parental water test completion. Eleven clinics successfully implemented processes identifying well users. 240 testing kits were dispensed. Completion rates averaged 29% (range 10 to 61%). The study arm with both clinic results access and staff follow up system was 2.3 times more likely to achieve test completion than other arms (95% CI 1.12-4.86, p = .03). Kit distribution by clinicians versus nursing staff, irrespective of study arm, had 2.4 times greater completion (95% CI 1.13-5.11, p = .02). Systematic drinking water source screening can be improved in pediatric care. Higher testing completion was found in practices randomized to reminders and structured follow up versus single visit discussion, but clinician involvement was the most predictive factor.