Delivering Genetic Testing for Patients with Prostate Cancer: Moving Beyond Provider Knowledge as a Barrier to Care.

INTRODUCTION: The 2018 National Comprehensive Cancer Network guidelines for prostate cancer genetic testing expanded access to genetic services. Few studies have examined how this change has affected provider practice outside of large cancer centers. METHODS: We conducted a qualitative study of multi-disciplinary health care providers treating patients with prostate cancer at a safety-net hospital. Participants completed an interview that addressed knowledge, practices, and contextual factors related to providing genetic services to patients with prostate cancer. A thematic analysis using both inductive and deductive coding was undertaken. RESULTS: Seventeen providers completed interviews. Challenges in identifying eligible patients for genetic testing stemmed from a lack of a) systems that facilitate routine patient identification, and b) readily available family history data for eligibility determination. Providers identified non-medical patient characteristics that influenced their referral process, including health literacy, language, cultural beliefs, patient distress, and cost. Providers who see patients at different times along the cancer care continuum viewed benefits of testing differently. CONCLUSION: The use of digital technologies that systematically identify those eligible for genetic testing referrals may mitigate some but not all challenges identified in this study. Further research should determine how individual provider perceptions influence referral practices and patient access to genetics both within and across cancer specialties.

Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins.

In patients with prostate cancer, the duration of remission after treatment with androgen deprivation therapies (ADTs) varies dramatically. Clinical experience has demonstrated difficulties in predicting individual risk for progression due to chemoresistance. Drug combinations that inhibit androgen biosynthesis (e.g., abiraterone acetate) and androgen signaling (e.g., enzalutamide or apalutamide) have proven so effective that new forms of ADT resistance are emerging. In particular, prostate cancers with a neuroendocrine transcriptional signature, which demonstrate greater plasticity, and potentially, increased predisposition to metastasize, are becoming more prevalent. Notably, these subtypes had in fact been relatively rare before the widespread success of novel ADT regimens. Therefore, better understanding of these resistance mechanisms and potential alternative treatments are necessary to improve progression-free survival for patients treated with ADT. Targeting the bromodomain and extra-terminal (BET) protein family, specifically BRD4, with newer investigational agents may represent one such option. Several families of chromatin modifiers appear to be involved in ADT resistance and targeting these pathways could also offer novel approaches. However, the limited transcriptional and genomic information on ADT resistance mechanisms, and a serious lack of patient diversity in clinical trials, demand profiling of a much broader clinical and demographic range of patients, before robust conclusions can be drawn and a clear direction established.

"I'm in My Feelings Now": Examination of Advance Care Planning Video Declarations by People with Advanced Cancer from a Safety Net Hospital.

Background: Advance care planning (ACP) is underutilized among those with advanced cancer, leading to the potential of not receiving goal-concordant care. Objectives: To understand the experience of patients in creating a video declaration (ViDec) of their ACP preferences and their family member/caregivers' perceptions after viewing their ViDec. Design: Qualitative study among patients and family members/caregivers. Setting/Subjects: Patients were recruited from a large safety net hospital in the United States. Patients with any type of advanced cancer were enrolled to create a ViDec and participate in an individual interview. Patients also identified a family member/caregiver to participate. Measurements: Content and perceptions of usefulness of ViDecs among patients and family members/caregivers. Results: In total, 32 patients participated. Patients had a mean age of 61 (10) years, 15 (47%) were women, 14 (44%) were Black or African American, and 12 (37%) had a high school education or less; 25 family members/caregivers participated. Across all ViDecs, the most common theme pertained to ACP for preferred medical treatments (97%). We describe three case studies of patient and caregiver pairs to represent salient dimensions of our data: (1) high perceived usefulness of ViDec, (2) populations at risk for not receiving goal-concordant care, and (3) varied responses to ViDec among family members/caregivers. Recommendations to improve the ViDec process included providing structured prompts to patients. Conclusions: These case studies highlight the potential high-perceived usefulness of ViDecs across patients and caregivers. ViDecs have the potential to improve care among patients with advanced cancer.

Novel plasma exosome biomarkers for prostate cancer progression in co-morbid metabolic disease.

Comorbid Type 2 diabetes (T2D), a metabolic complication of obesity, associates with worse cancer outcomes for prostate, breast, head and neck, colorectal and several other solid tumors. However, the molecular mechanisms remain poorly understood. Emerging evidence shows that exosomes carry miRNAs in blood that encode the metabolic status of originating tissues and deliver their cargo to target tissues to modulate expression of critical genes. Exosomal communication potentially connects abnormal metabolism to cancer progression. Here, we hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. We demonstrate that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genes CD274 and CD155. We demonstrate that specific exosomal miRNAs that are differentially abundant in plasma of T2D adults compared to nondiabetic controls (miR374a-5p, miR-93-5p and let-7b-3p) are delivered to cancer cells, thereby regulating critical target genes. We build on our previous reports showing BRD4 controls migration and dissemination of castration-resistant prostate cancer, and transcription of key EMT genes, to show that T2D exosomes require BRD4 to drive EMT and immune ligand expression. We validate our findings with gene set enrichment analysis of human prostate tumor tissue in TGCA genomic data. These results suggest novel, non-invasive approaches to evaluate and potentially block progression of prostate and other cancers in patients with comorbid T2D.

Outcomes for Young Men With Localized Intermediate-Risk Prostate Cancer: An Analysis of the NCDB.

BACKGROUND: Primary management of localized, intermediate-risk prostate cancer consists of radical prostatectomy (RP), radiotherapy (RT) with short-course androgen deprivation therapy (ADT), or RT alone. The purpose of this study was to determine if these treatment strategies have equivalent overall survival (OS) in patients < 55 years old with intermediate-risk prostate cancer. PATIENTS AND METHODS: We identified 35,134 patients in the National Cancer Data Base with localized intermediate-risk prostate cancer treated with RP, RT + ADT, or RT from 2004 to 2013. Ten-year OS rates were estimated by the Kaplan-Meier method. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were computed by multivariate Cox regression. RESULTS: A total of 29,920 patients (85.2%) underwent RP, 1393 (4.0%) RT + ADT, and 3821 (10.9%) RT. Median patient age was 51 years old, and median follow-up was 59.9 months. Ten-year OS was estimated to be 94.2% for RP, 80.7% for RT + ADT, and 85.2% for RT (P < .0001). On multivariate analysis, treatment with RT + ADT or RT was associated with significantly worse OS compared to treatment with RP (RT + ADT HR = 2.06, 95% CI 1.67-2.54, P < .0001; RT HR = 2.0, 95% CI 1.71-2.33, P < .0001). Patients who met all 3 of the intermediate-risk criteria showed worse OS compared to patients who met only one criterion (HR = 1.80; 95% CI, 1.32-2.44; P = .0002). CONCLUSION: RP is significantly more likely than RT + ADT or RT to be used as a primary treatment for young men with localized intermediate prostate cancer. RP was also associated with improved OS compared to RT + ADT and RT.

Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer.

PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We estimated the probability of survival over time by the Kaplan-Meier method. The concordance probability estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.

Risk factors involved in treatment delays and differences in treatment type for patients with prostate cancer by risk category in an academic safety net hospital.

OBJECTIVES: Understanding the drivers of delays from diagnosis to treatment can elucidate how to reduce the time to treatment (TTT) in patients with prostate cancer. In addition, the available treatments depending on the stage of cancer can vary widely for many reasons. This study investigated the relationship of TTT and treatment choice with sociodemographic factors in patients with prostate cancer who underwent external beam radiation therapy (RT), radical prostatectomy (RP), androgen deprivation therapy (ADT), or active surveillance (AS) at a safety-net academic medical center. METHODS AND MATERIALS: A retrospective review was performed on 1088 patients who were diagnosed with nonmetastatic prostate cancer between January 2005 and December 2013. Demographic data as well as data on TTT, initial treatment choice, American Joint Committee on Cancer stage, and National Comprehensive Cancer Network risk categories were collected. Analyses of variance and multivariable logistic regression models were performed to analyze the relationship of these factors with treatment choice and TTT. RESULTS: Age, race, and marital status were significantly related to treatment choice. Patients who were nonwhite and older than 60 years were less likely to undergo RP. Black patients were 3.8 times more likely to undergo RT compared with white patients. The median TTT was 75 days. Longer time delays were significant in patients of older age, nonwhite race/ethnicity, non-English speakers, those with noncommercial insurance, and those with non-married status. The average TTT of high-risk patients was 25 days longer than that of low-risk patients. Patients who underwent RT had an average TTT that was 34 days longer than that of RP patients. CONCLUSIONS: The treatment choice and TTT of patients with prostate cancer are affected by demographic factors such as age, race, marital status, and insurance, as well as clinical factors including stage and risk category of disease.

Long-term medical care of testicular cancer survivors.

Testicular cancer is the most common solid tumor diagnosed in men 20 to 35 years of age. Because of highly effective treatments that may include surgery, chemotherapy, and radiation therapy, most patients become long-term survivors. Health-related issues that confront testicular cancer survivors include the late medical effects of chemotherapy, the late relapse of disease, the development of second cancers, the effect of the disease and treatment on fertility, and the psychosocial consequences. This case-based discussion focuses on the primary care physician's evaluation and management of a long-term survivor of testicular cancer who was previously treated with surgery and chemotherapy.

Cardiometabolic and skeletal risk factors in black men with prostate cancer starting androgen deprivation therapy.

BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. METHODS: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between -1 to -2.5 and osteoporosis when T scores ≤-2.5. RESULTS: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. CONCLUSIONS: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

Anatomic differences after robotic-assisted radical prostatectomy and open prostatectomy: implications for radiation field design.

PURPOSE: To investigate the anatomy of the pelvis following robotic-assisted radical prostatectomy (RARP) compared to the anatomy of the pelvis following open prostatectomy (OP), and to determine if postoperative radiation field design should take surgical approach into consideration. METHODS AND MATERIALS: This report is a retrospective review of the postoperative pelvic magnetic resonance imaging (MRI) scans for all OP patients (10) and all RARP patients (15) who presented consecutively to the radiation oncology clinic and subsequently underwent MRI scanning between January 2007 and December 2008. All patients who presented are included in the study. We measured 13 distinct anatomic distances, and we used t tests to examine mean differences in each of the parameters between RARP and OP and analysis of variance to examine mean differences controlling for length of follow-up MRI postsurgery (in days) and body mass index as covariates. RESULTS: Of the measurements, we found that the superior levator separation is statistically significantly greater in the post-RARP group than in the post-OP group (P < .01). Similarly, the post-RARP group had a greater mean resection defect measurement (P = .01) as measured by a larger width of the bladder infundibulum. This suggests that the size of trigonal musculature defect is more pronounced after RARP. The total urethral length was statistically significantly longer in the RARP group (P = .03). The vesicorectal distance was variable depending on the location along the rectal wall but trended toward larger separation in the post-RARP group (P = .05). CONCLUSIONS: The pelvic anatomy after RARP is considerably different from that after OP. The current standard field design for post-prostatectomy radiation is defined by the post-OP pelvis. Our data support that the clinical target volume borders be expanded posteriorly and laterally in men who have undergone RARP. As RARP continues to become a more widespread surgical option for the management of localized prostate cancer, radiation field design may need to be adjusted.

Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer.

PURPOSE: Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam. PATIENTS AND METHODS: Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m(2) and (153)Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and (153)Sm-EDTMP was administered on day -1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression. RESULTS: Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of (153)Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 (153)Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption. CONCLUSION: Docetaxel and (153)Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.

Assessing outcomes in prostate cancer clinical trials: a twenty-first century tower of Babel.

BACKGROUND: Because of the osseous distribution of prostate cancer metastases, progression is more readily identified than response in prostate cancer clinical trials. As a result, there is an increased focus on progression-free survival (PFS) as a phase 2 endpoint. PFS, however, is vulnerable to inter-study design variability. The authors sought to identify and quantify this variability and the resultant error in PFS across prostate cancer clinical trials. METHODS: The authors reviewed phase 2 clinical trials of cytotoxic agents in castration-resistant metastatic prostate cancer over 5 years to evaluate the policies determining extent of disease and the definitions of disease progression. A simulation model was created to define the degree of error in estimating PFS in 3 hypothetical cohorts (median PFS of 12, 24, and 36 weeks) when the frequency of outcome assessments varies. RESULTS: Imaging policies for trial entry were heterogeneous, as were the type, timing, and indications for outcome assessments. In the simulation, error in the reported PFS varied according to the interval between assessments. The difference between the detected and the true PFS could vary as much as 6.4 weeks per cycle, strictly resulting from the variability of assessment schedules tested. CONCLUSIONS: Outcome assessment policies are highly variable in phase 2 studies of castration-resistant prostate cancer patients, despite published guidelines designed to standardize authentication of disease progression. The estimated error in PFS can exceed 6 weeks per cycle, exclusively because of variations in the assessment schedules. Comparisons of PFS times from different studies must be made with circumspection.

Castration resistant, taxane naïve metastatic prostate cancer: current clinical approaches and future directions.

PURPOSE: With the wide use of prostate specific antigen to detect response and disease progression resistance to androgen deprivation is being detected at an increasingly earlier stage. We focused on the current management and novel investigational strategies for the chemonaïve patient population with castration resistant metastatic disease. MATERIALS AND METHODS: We reviewed standard and investigational hormonal, chemotherapeutic, biological and immune based strategies for patients with castration resistant metastatic prostate cancer who have not yet received taxane based chemotherapy. RESULTS: Our understanding of the natural history of this group of patients is evolving. A variety of standard and experimental treatment options are available for this group of patients. Manipulating the androgen receptor signaling axis, targeting antiapoptotic pathways, using antiangiogenic strategies, harnessing the immune system and optimizing docetaxel based regimens and novel cytotoxic agents are under investigation. CONCLUSIONS: Multiple agents currently under development offer a promise of palliation and prolongation of survival above and beyond that of docetaxel. In the absence of guidance from randomized trials with regard to chemotherapy timing, and considering the modest effects of docetaxel on survival, decisions regarding choice of therapy (standard chemotherapy or experimental therapies) must be based on careful consideration of the functional status of each individual, presence of symptoms, comorbidities and overall therapeutic objectives.