PTEN Loss Is Associated with Adverse Outcomes in the Setting of Salvage Radiation Therapy.

BACKGROUND: Salvage radiation therapy (SRT) is a mainstay of treatment for biochemical relapse following radical prostatectomy; however, few studies have examined genomic biomarkers in this context. OBJECTIVE: We characterized the prognostic impact of previously identified deleterious molecular phenotypes-loss of PTEN, ERG expression, and TP53 mutation-for patients undergoing SRT. DESIGN, SETTING, AND PARTICIPANTS: We leveraged an institutional database of 320 SRT patients with available tissue and follow-up. Tissue microarrays were used for genetically validated immunohistochemistry assays. INTERVENTION: All men underwent SRT with or without androgen deprivation therapy OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox-proportional hazard models assessed the association of molecular phenotypes with biochemical recurrence-free (bRFS) and metastasis-free (MFS) survival after SRT. RESULTS AND LIMITATIONS: Loss of PTEN (n = 123, 43%) and ERG expression (n = 118, 39%) were common in this cohort, while p53 overexpression (signifying TP53 missense mutation) was infrequent (n = 21, 7%). In univariable analyses, any loss of PTEN portended worse bRFS (hazard ratio [HR] 1.86; 95% confidence interval 1.36-2.57) and MFS (HR 1.89; 1.21-2.94), with homogeneous PTEN loss being associated with the highest risk of MFS (HR 2.47; 1.54-3.95). Similarly, p53 overexpression predicted worse bRFS (HR 1.95; 1.14-3.32) and MFS (HR 2.79; 1.50-5.19). ERG expression was associated with worse MFS only (HR 1.6; 1.03-2.48). On the multivariable analysis adjusting for known prognostic features, homogeneous PTEN loss remained predictive of adverse bRFS (HR 1.82; 1.12-2.96) and MFS (HR 2.08; 1.06-4.86). The study is limited by its retrospective and single-institution design. CONCLUSIONS: PTEN loss by immunohistochemistry is an independent adverse prognostic factor for bRFS and MFS in prostate cancer patients treated with SRT. Future trials will determine the optimal approach to treating SRT patients with adverse molecular prognostic features. PATIENT SUMMARY: Loss of the PTEN tumor suppressor protein is associated with worse outcomes after salvage radiotherapy, independent of other clinical or pathologic patient characteristics.

A report on the safety of acitretin use in patients with renal failure on haemodialysis.

Acitretin, commonly used for severe psoriasis and keratinocyte carcinoma chemoprevention in high-risk patients, is contraindicated in patients with end-stage renal disease (ESRD) on haemodialysis (HD). However, these patients often lack medication choices and in certain clinical scenarios the benefits of acitretin may outweigh the potential risks. We identified 24 patients with ESRD on HD undergoing acitretin treatment from the Duke and Vanderbilt University Medical Centers. While adverse effects were common, they were not a frequent cause of treatment discontinuation among patients. We also found no association between acitretin treatment and hospital admissions or mortality. Lastly, we found statistically significant increases in alkaline phosphatase (ALP; P = 0.03) and total bilirubin (P < 0.001) when patients were receiving acitretin and HD compared with baseline. However, there was no dose dependency or temporal association with acitretin or HD initiation. Based on these preliminary findings, we find that acitretin may safely be used in patients receiving HD, with close monitoring of ALP and bilirubin.

Induction of double-strand breaks with the non-steroidal androgen receptor ligand flutamide in patients on androgen suppression: a study protocol for a randomized, double-blind prospective trial.

BACKGROUND: Prostate cancer remains the most prevalent malignancy and the second-leading cause of cancer-related death in men in the USA. Radiation therapy, typically with androgen suppression, remains a mainstay in the treatment of intermediate- and high-risk, potentially lethal prostate cancers. However, local recurrence and treatment failure remain common. Basic and translational research has determined the potential for using androgen receptor (AR) ligands (e.g., dihydrotestosterone and flutamide) in the context of androgen-deprived prostate cancer to induce AR- and TOP2B-mediated DNA double-strand breaks (DSBs) and thereby synergistically enhance the effect of radiation therapy (RT). The primary aim of this study is to carry out pharmacodynamic translation of these findings to humans. METHODS: Patients with newly diagnosed, biopsy-confirmed localized prostatic adenocarcinoma will be recruited. Flutamide, an oral non-steroidal androgen receptor ligand, will be administered orally 6-12 h prior to prostate biopsy (performed under anesthesia prior to brachytherapy seed implantation). Key study parameters will include the assessment of DNA double-strand breaks by γH2A.x foci and AR localization to the nucleus. The initial 6 patients will be treated in a single-arm run-in phase to assess futility by establishing whether at least 2 subjects from this group develop γH2A.x foci in prostate cancer cells. If this criterion is met, the study will advance to a two-arm, randomized controlled phase in which 24 participants will be randomized 2:1 to either flutamide intervention or placebo standard-of-care (with all patients receiving definitive brachytherapy). The key pharmacodynamic endpoint will be to assess whether the extent of γH2A.x foci (proportion of cancer cells positive and number of foci per cancer cell) is greater in patients receiving flutamide versus placebo. Secondary outcomes of this study include an optional, exploratory analysis that will (a) describe cancer-specific methylation patterns of cell-free DNA in plasma and urine and (b) assess the utility of serum and urine samples as a DNA-based biomarker for tracking therapeutic response. DISCUSSION: This study will confirm in humans the pharmacodynamic effect of AR ligands to induce transient double-strand breaks when administered in the context of androgen deprivation as a novel therapy for prostate cancer. The findings of this study will permit the development of a larger trial evaluating flutamide pulsed-dose sequencing in association with fractionated external beam RT (+/- brachytherapy). The study is ongoing, and preliminary data collection and recruitment are underway; analysis has yet to be performed. TRIAL REGISTRATION: ClinicalTrials.gov NCT03507608. Prospectively registered on 25 April 2018.

Impact of Patient Navigation on Reducing Breast Imaging Disparities and Applications in the COVID-19 Era.

The coronavirus (COVID-19) pandemic has impacted breast cancer screening with concerns that this may lead to increased overall breast cancer mortality and worsened racial and ethnic disparities in breast cancer survival. As pandemic recovery efforts are underway, we must be prepared to address barriers to timely access of breast imaging services, including those that existed prior to the pandemic, as well as any new barriers that may arise as a result of the pandemic. Patient navigation is an important tool that has been shown to address barriers to timely breast imaging access and help reduce disparities. Patient navigation programs can serve as a key part of the strategy to mitigate the impact of the COVID-19 pandemic on timely breast cancer diagnosis. These programs have been shown to be successful in promoting adherence to breast cancer screening guidelines as well as encouraging timely diagnostic follow-up, particularly in underserved communities. Further research is needed to explore the role of using a telehealth platform for patient navigation and evaluate the cost-effectiveness of patient navigator programs as well as more randomized controlled trials to further explore the impact of patient navigation programs.