Showing papers by "Peter S. Nelson published in 2022"
TL;DR: Griffin this article employs a GC correction procedure tailored to variable cfDNA fragment sizes, which generates a better representation of chromatin accessibility and improves the accuracy of cancer detection and tumor subtype classification.
Abstract: Cell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we develop Griffin, a framework for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing data. Griffin employs a GC correction procedure tailored to variable cfDNA fragment sizes, which generates a better representation of chromatin accessibility and improves the accuracy of cancer detection and tumor subtype classification. We demonstrate estrogen receptor subtyping from cfDNA in metastatic breast cancer. We predict estrogen receptor subtype in 139 patients with at least 5% detectable circulating tumor DNA with an area under the receive operator characteristic curve (AUC) of 0.89 and validate performance in independent cohorts (AUC = 0.96). In summary, Griffin is a framework for accurate tumor subtyping and can be generalizable to other cancer types for precision oncology applications.
13 citations
TL;DR: It is shown that DTCs traffic to and persist within skeletal muscle in mice and in humans, which raises the question of how this tissue suppresses colonization, and reveals a profound metabolic bottleneck imposed on D TCs and sustained by skeletal muscle.
12 citations
TL;DR: The results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC‐assisted pathology review and genomic analysis are highly concordant in nominating the ‘index’ primary PCA area.
Abstract: Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for the heterogeneity of primary PCa. In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration‐resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole‐exome sequencing (WES) and amplicon‐based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intratumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (eight patients). Activating AR alterations were seen in nine (75%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only). WES‐based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice. Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC‐assisted pathology review and genomic analysis are highly concordant in nominating the ‘index’ primary PCa area. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
9 citations
TL;DR: It is shown that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT, providing an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.
Abstract: The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.
8 citations
TL;DR: The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate, but the spatiotemporal expression patterns remain inadequately characterized.
Abstract: The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate. However, the spatiotemporal expression patterns of Wnt proteins in prostate cell lineages at different developmental stages and in prostate cancer remain inadequately characterized.
8 citations
TL;DR: In this article , a review of the development of the NIS gene therapy concept using selective non-viral gene delivery vehicles including synthetic polyplexes and genetically engineered mesenchymal stem cells is presented.
Abstract: Abstract Cloning of the sodium iodide symporter (NIS) in 1996 has provided an opportunity to use NIS as a powerful theranostic transgene. Novel gene therapy strategies rely on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of therapeutic radionuclides. This review highlights the remarkable progress during the last two decades in the development of the NIS gene therapy concept using selective non-viral gene delivery vehicles including synthetic polyplexes and genetically engineered mesenchymal stem cells. In addition, NIS is a sensitive reporter gene and can be monitored by high resolution PET imaging using the radiotracers sodium [ 124 I]iodide ([ 124 I]NaI) or [ 18 F]tetrafluoroborate ([ 18 F]TFB). We performed a small preclinical PET imaging study comparing sodium [ 124 I]iodide and in-house synthesized [ 18 F]TFB in an orthotopic NIS-expressing glioblastoma model. The results demonstrated an improved image quality using [ 18 F]TFB. Building upon these results, we will be able to expand the NIS gene therapy approach using non-viral gene delivery vehicles to target orthotopic tumor models with low volume disease, such as glioblastoma. Trial registration not applicable.
7 citations
TL;DR: This study demonstrates that further analytical validation and clinical qualification is required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.
Abstract: Background: Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR- targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance as predictive biomarker in CSPC remains understudied. Methods: We explored multiple approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines and patient-derived xenograft (PDX) models, in both publicly available and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein, and its association with clinical outcome. Results: In publicly available benign prostate, CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts and identified AR-V7 protein reactivity very rarely in CSPC cohorts, when compared to the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC cohorts, AR-V7 protein quantification by either assay did not associate with time to development of castration-resistance or overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant detectable AR-V7 mRNA or staining following treatment, and neither pre- nor post-treatment AR-V7 levels associated with the volume of residual disease after therapy. Conclusion: This study demonstrates that further analytical validation and clinical qualification is required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.
7 citations
TL;DR: In this paper , an outcome-based quantitative cut-off for the size of a prostate gland was identified as the optimal cutoff to identify more aggressive prostate cancer, and the cutoff was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort.
6 citations
TL;DR: Patients exposed to a decision aid were more likely to receive their preferred AAA repair type, suggesting that decision aids can help better align patient preferences and treatments in major cardiovascular procedures.
Abstract: Importance
Patients with abdominal aortic aneurysm (AAA) can choose open repair or endovascular repair (EVAR). While EVAR is less invasive, it requires lifelong surveillance and more frequent aneurysm-related reinterventions than open repair. A decision aid may help patients receive their preferred type of AAA repair.
Objective
To determine the effect of a decision aid on agreement between patient preference for AAA repair type and the repair type they receive.
Design, Setting, and Participants
In this cluster randomized trial, 235 patients were randomized at 22 VA vascular surgery clinics. All patients had AAAs greater than 5.0 cm in diameter and were candidates for both open repair and EVAR. Data were collected from August 2017 to December 2020, and data were analyzed from December 2020 to June 2021.
Interventions
Presurgical consultation using a decision aid vs usual care.
Main Outcomes and Measures
The primary outcome was the proportion of patients who had agreement between their preference and their repair type, measured using χ2 analyses, κ statistics, and adjusted odds ratios.
Results
Of 235 included patients, 234 (99.6%) were male, and the mean (SD) age was 73 (5.9) years. A total of 126 patients were enrolled in the decision aid group, and 109 were enrolled in the control group. Within 2 years after enrollment, 192 (81.7%) underwent repair. Patients were similar between the decision aid and control groups by age, sex, aneurysm size, iliac artery involvement, and Charlson Comorbidity Index score. Patients preferred EVAR over open repair in both groups (96 of 122 [79%] in the decision aid group; 81 of 106 [76%] in the control group; P = .60). Patients in the decision aid group were more likely to receive their preferred repair type than patients in the control group (95% agreement [93 of 98] vs 86% agreement [81 of 94]; P = .03), and κ statistics were higher in the decision aid group (κ = 0.78; 95% CI, 0.60-0.95) compared with the control group (κ = 0.53; 95% CI, 0.32-0.74). Adjusted models confirmed this association (odds ratio of agreement in the decision aid group relative to control group, 2.93; 95% CI, 1.10-7.70).
Conclusions and Relevance
Patients exposed to a decision aid were more likely to receive their preferred AAA repair type, suggesting that decision aids can help better align patient preferences and treatments in major cardiovascular procedures.
Trial Registration
ClinicalTrials.gov Identifier: NCT03115346.
5 citations
TL;DR: This study harnessed circulating tumor DNA to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation and designed a prediction model which distinguished NEPC from ARPC in patient plasma samples across three clinical cohorts with 97-100% sensitivity and 85- 100% specificity.
Abstract: Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and NR3C1. Using these features, we designed a prediction model which distinguished NEPC from ARPC in patient plasma samples across three clinical cohorts with 97-100% sensitivity and 85-100% specificity. While phenotype classification is typically assessed by immunohistochemistry or transcriptome profiling, we demonstrate that ctDNA provides comparable results with numerous diagnostic advantages for precision oncology. STATEMENT OF SIGNIFICANCE This study provides key insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. The new methods established for phenotype classification extend the utility of ctDNA beyond assessments of DNA alterations with important implications for molecular diagnostics and precision oncology.
4 citations
TL;DR: The frequency of pathogenic Germline mutations in penetrant cancer predisposition genes is extremely low in men with PC undergoing active surveillance and pathogenic germline mutations had no apparent association with grade reclassification or adverse characteristics.
Abstract: Pathogenic germline mutations in several rare penetrant cancer predisposition genes are associated with an increased risk of aggressive prostate cancer (PC). Our objectives were to determine the prevalence of pathogenic germline mutations in men with low‐risk PC on active surveillance, and assess whether pathogenic germline mutations associate with grade reclassification or adverse pathology, recurrence, or metastases, in men treated after initial surveillance.
TL;DR: A framework to understand the types and biological causes of resistance is described, providing translational opportunities to tackle drug resistance by rational therapeutic strategies.
Abstract: Abstract Decades of research into the molecular mechanisms of cancer and the development of novel therapeutics have yielded a number of remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in a personalized manner remains elusive for many patients, and drug resistance persists as a major problem. This is in part due to the well-documented heterogeneity of cancer, including the diversity of tumor cell lineages and cell states, the spectrum of somatic mutations, the complexity of microenvironments, and immune-suppressive features and immune repertoires, which collectively require numerous different therapeutic approaches. Here, we describe a framework to understand the types and biological causes of resistance, providing translational opportunities to tackle drug resistance by rational therapeutic strategies.
TL;DR: In this paper , RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients, however, three patients’ progression biopsies show evidence of lineage plasticity.
Abstract: Abstract The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression ( n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients’ progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.
TL;DR: Prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in vivo are investigated, revealing a complex tumor environment largely dominated by castration-resistant luminal cells and immunosuppressive infiltrates.
Abstract: Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigated prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in vivo. We observe a dramatic expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is in part androgen responsive. Androgen independent prostate cancer leads to significant diversification of intermediate luminal cell populations characterized by a range of androgen signaling activity inversely correlated with proliferation and mRNA translation. Accordingly, distinct epithelial populations are exquisitely sensitive to translation inhibition which leads to epithelial cell death, loss of pro-tumorigenic signaling, and decreased tumor heterogeneity. Our findings reveal a complex tumor environment largely dominated by castration-resistant luminal cells and immunosuppressive infiltrates.
TL;DR: Mor Morris et al. as discussed by the authors designed dual-targeted NIS plasmid DNA complexes containing targeting ligands for the transferrin receptor (TfR) and the epidermal growth factor receptor (EGFR), thus providing the potential for active transport across the BBB followed by targeting of tumor cells.
TL;DR: Subtyping of mCRPC based on cell differentiation states has potential clinical utility for identifying patients with divergent expression of treatment targets and responses to systemic therapy.
Abstract: Abstract Purpose: To determine whether metastatic castration–resistant prostate cancers (mCRPC) partition into molecular phenotypes corresponding to intrinsic differentiation states and ascertain whether these subtypes exhibit specific druggable features and associate with treatment outcomes. Experimental Design: We used RNAseq, digital spatial profiling, and histological assessments from metastatic biopsies and patient-derived xenografts to segregate mCRPCs into subtypes defined by the PAM50 breast cancer classification algorithm. Subtype associations with treatment responses in preclinical models and patients were determined. Results: Using the PAM50 algorithm, we partitioned 270 mCRPC tumors into LumA (42%), LumB (24%), and Basal (34%) subtypes with classification largely driven by proliferation rates and androgen receptor (AR) activity. Most neuroendocrine tumors classified as Basal. Pathways enriched in the LumA subtype include TGFß and NOTCH signaling. LumB subtype tumors were notable for elevated MYC activity. Basal subtype tumors exhibited elevated IL6-STAT3 signaling and features of adult stem cell states. In patients where multiple tumors were evaluated, the majority had concordant PAM50 subtype determination, though a subset exhibited marked inter- and intratumor heterogeneity, including divergent classifications between primary and metastatic sites. In preclinical models, LumA subtype tumors were highly responsive to androgen deprivation and docetaxel chemotherapy whereas Basal tumors were largely resistant. In clinical cohorts patients with Basal subtype tumors demonstrated a shorter time on treatment with AR signaling inhibitors and docetaxel relative to patients with luminal subtypes. Conclusions: Subtyping of mCRPC based on cell differentiation states has potential clinical utility for identifying patients with divergent expression of treatment targets and responses to systemic therapy.
TL;DR: In this paper , the authors show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context.
Abstract: Cancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity. Increasing prostatic stromal Foxf2 sensitizes prostate cancer to the immune checkpoint blockade therapies. Augmenting lung stromal Foxf2 also mediates an immunosuppressive milieu and inhibits lung colonization of prostate cancer. FOXF2 is expressed higher in the stroma of human transition zone (TZ) than peripheral zone (PZ) prostate. The stromal FOXF2 expression level in primary prostate cancers inversely correlates with the Gleason grade. Our study establishes Foxf2 as a stromal transcription factor modulating the tumor immune microenvironment and potentially explains why cancers are relatively rare and indolent in the TZ prostate.
TL;DR: This work uniformly characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing and defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes.
Abstract: The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.
TL;DR: Current efforts to better understand the heterogenous landscape of neuroendocrine prostate cancer are discussed and research efforts to define the interplay between tumor cells and the microenvironment are summarized, with an emphasis on the immune component.
Abstract: Neuroendocrine prostate cancer, generally arising late in the disease trajectory, is a heterogenous subtype that infers a worse prognosis and limited treatment options for patients. Characterization of the complex landscape of this disease subtype and scrutiny of the relationship between tumor cells and cells of the surrounding tumor microenvironment have aided in elucidating some of the mechanisms of neuroendocrine disease biology and have uncovered a multitude of signaling pathways involved in disease transdifferentiation under therapeutic selection. In this review, we discuss current efforts to better understand the heterogenous landscape of neuroendocrine prostate cancer and summarize research efforts to define the interplay between tumor cells and the microenvironment, with an emphasis on the immune component. Research efforts have uncovered several potential therapeutic approaches that may improve disease outcomes for patients diagnosed with neuroendocrine prostate cancer, including the potential for combination immunotherapies. However, additional research is required to fully address and exploit the contribution of tumor cell and microenvironment heterogeneity in developing effective treatment strategies.
TL;DR: The quantitative reactive stroma (qRS) is a measure of percentage tumor area with a distinct, reactive stromal architecture as mentioned in this paper , which is a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer.
TL;DR: A review of factors derived from neuroendocrine prostate cancers and their potential to influence the pathophysiology of localized and metastatic prostate cancer is presented in this paper , where a spectrum of uncommon tumor types occur, including those with small cell and neuro-endocrine cell features.
Abstract: Prostate cancer is a common malignancy affecting men worldwide. While the vast majority of newly diagnosed prostate cancers are categorized as adenocarcinomas, a spectrum of uncommon tumor types occur including those with small cell and neuroendocrine cell features. Benign neuroendocrine cells exist in the normal prostate microenvironment, and these cells may give rise to primary neuroendocrine carcinomas. However, the more common development of neuroendocrine prostate cancer is observed after therapeutics designed to repress the signaling program regulated by the androgen receptor which is active in the majority of localized and metastatic adenocarcinomas. Neuroendocrine tumors are identified through immunohistochemical staining for common markers including chromogranin A/B, synaptophysin and neuron specific enolase (NSE). These markers are also common to neuroendocrine tumors that arise in other tissues and organs such as the gastrointestinal tract, pancreas, lung and skin. Notably, neuroendocrine prostate cancer shares biochemical features with nerve cells, particularly functions involving the secretion of a variety of peptides and proteins. These secreted factors have the potential to exert local paracrine effects, and distant endocrine effects that may modulate tumor progression, invasion, and resistance to therapy. This review discusses the spectrum of factors derived from neuroendocrine prostate cancers and their potential to influence the pathophysiology of localized and metastatic prostate cancer.
TL;DR: In this paper , the authors explored target populations for recruitment and aims to identify potential modifiable and non-modifiable risk factors associated with reduced job satisfaction among practicing vascular surgeons to improve retention and prevent early retirement.
TL;DR: A population-based approach was used to understand the proportion of men with mPC undergoing germline genetic testing through clinical care, and the subsequent uptake of genetic testing when access and cost barriers are removed.
Abstract: 10501 Background: Approximately 10% of men with metastatic prostate cancer (mPC) have germline DNA damage response gene mutations (gDDRm), indicating candidacy for precision treatment. Consequently, national guidelines recommend germline genetic testing be offered to all men with mPC. It is currently unclear what the rates of testing are in the community, and barriers to testing are not well understood. We conducted a population-based study to better understand current rates of germline genetic testing in men with newly diagnosed mPC, and to determine whether removing major barriers of cost and access could expand uptake of germline genetic testing. Methods: This is a prospective observational study that identifies men ages 35-79y with mPC residing in a 13-county area of Washington State through the Surveillance, Epidemiology, and End Results (SEER) program (NCT04254133). Men with new diagnoses of mPC are contacted by mailed invitation and follow-up phone inquiry. Interested men are then invited to provide informed consent and complete a questionnaire about personal and family health history. A saliva collection kit for a 30-gene targeted panel of cancer predisposition genes (Color Genomics) is mailed to participants’ homes free of charge. Results are issued by phone and/or email with genetic counseling support, including discussion about cascade genetic testing if relevant. Results: As of Feb 9, 2022, 484 men with incident mPC diagnosed 1/2018-6/2021 were identified through SEER. 430 men were reached via a letter to their home address sent > 3 months after diagnosis. 175 of 430 (40.6%) men expressed interest and completed the questionnaire, the majority preferring to complete testing through mail after a phone-initiated introduction to the study. 164 of 175 men completed the consent process and were eligible. Of these 164 men, 45 (27.4%) reported prior genetic testing, and reports were requested and reviewed to ensure adequate testing. Ultimately, 121 of 164 (73.8%) participants initiated and 101/121 (83.5%) have completed genetic testing through the study. Nine percent (9/101) of participants completing testing as part of the study were found to have gDDRm. Conclusions: We used a population-based approach to understand the proportion of men with mPC undergoing germline genetic testing through clinical care, and the subsequent uptake of genetic testing when access and cost barriers are removed. The uptake of guideline-based germline genetic testing among men with mPC in the community prior to study enrollment is only 27.4%. With study interventions in the form of free testing through mail, and phone-based support, 83.5% of men in this community successfully completed testing. Further work in this study will aim to elucidate and attempt to eliminate other barriers in germline genetic testing to further improve testing rates in this community.
TL;DR: In this article , the authors show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI.
Abstract: Abstract Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4- O -sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4- O -sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer.
TL;DR: PSMA PET may impact decision making in patients with BCR after treatment of localized prostate cancer, particularly for those with equivocal findings on conventional imaging, regardless of clinical risk at diagnosis.
Abstract: e17009 Background: [68Ga]-PSMA-11 positron emission tomography (PSMA PET) detects sites of biochemically recurrent prostate cancer (BCR) at higher rates than conventional imaging. We hypothesized that PSMA PET would lead to high change in management (CIM) rates in this setting. Methods: We prospectively recruited patients (pts) with BCR, defined as confirmed PSA > 0.2 ng/mL > 6 weeks post-surgery or PSA ≥2 ng/mL above nadir post-radiation therapy, to undergo Ga-68 PSMA-11 PET. Some also had equivocal lesions on CT, MRI, bone scan, or fluciclovine PET obtained prior to PSMA PET. Pre-PET intended treatment, PSA (ng/mL), and PSA doubling time (PSAdt, months) from most recent 3 values were recorded prior to imaging. Post-PET treatment (intended or actual) was collected from medical record. CIM was categorized as major (change in or addition of treatment modality) vs minor (change within treatment modality, such as altered radiation field). Any lesion with uptake above blood pool was interpreted as positive for prostate cancer by an experienced PET reader (DLC). All values were represented as the median [interquartile range, IQR]. Kruskal Wallis analysis tested for significant differences among groups. Results: 44 pts with BCR age 71 [10] with Gleason scores (GS) at diagnosis of 6 (N = 2), 7 (N = 23), 8 (N = 5), and 9 (N = 13) enrolled, 14/44 with equivocal lesions on conventional imaging. 42 had post-PSMA PET treatment decisions available in medical records for CIM analysis. Time from PSA nadir to PSA at time of PSMA PET was 5 [7.25] months. PSMA PET was positive in 33 (8/33 with equivocal lesions on prior imaging; 7 local disease only; 11 regional nodal metastases, 2/11 also with local disease; and 15 with distant metastases, 4/15 also with local disease, 9/15 with regional nodal metastases), negative in 6, and equivocal in 5 pts. Of those with distant metastases, 8 had oligometastases, defined as 3 or fewer distinct sites (1 site = single nodal region or single bone lesion), 4 in bones and 4 in distant nodes. CIM rate was 71% (30/42) overall, 65.5% (16/29 major, 3/29 minor) in pts with BCR and negative conventional imaging; 84.6% (11/13, all major) in pts with equivocal lesions on conventional imaging. Of the patients with major CIM, a treatment modality was added in 21/27, modality switched in 3/27, and a modality removed in 3/27. PSA was significantly lower (p = 0.04) for those with negative or equivocal PSMA PET (0.5 [2.7]) than those with localized disease (4.1 [2.8]), regional nodal (1.1 [3.4]) or distant metastases (3.8 [5.3]), but not PSAdt (p = 0.2, negative/equivocal PET 5 [6.5], localized 15 [36], regional nodal metastases 11 [13], distant metastases 6 [6]). Conclusions: PSMA PET may impact decision making in pts with BCR after treatment of localized prostate cancer, particularly for those with equivocal findings on conventional imaging, regardless of clinical risk at diagnosis. Clinical trial information: NCT04777071.
TL;DR: Tumor immunity and metabolism in cancer metastasis was the goal of this Research Topic and the collection includes 29 original research papers and reviews directed toward the advancement of understanding of these important topics in cancer research.
Abstract: Primary tumor growth and the tumor metastasis are strongly linked to the adaption of the tumor tissues to environmental issues. These can include growth in low oxygen conditions and the selective use of substances for energy needs as well as means to escape detection by the immune system. Metastasis represents the major cause for poor prognosis for patients with cancers (1). Cancer patients are diagnosed with metastatic disease either at diagnosis of the disease, or later as they emerge during the course of treatment (2). Metabolic alterations and immune evasion represent some of the hallmark capabilities of tumor cells that develop during multistep metastatic progression (3). Cancer cells become adapted to survive with an energy supply and additional growth stimuli imparted through the tissue environment during the metastatic process. At the same time, cancer cells evade destruction by the immune system through various adaptions that enables them to progress. Various immune cells and immune processes have been linked to both the inhibition, and promotion, of metastatic processes. Recent advances in immunotherapy and the development of metabolic oncology inhibitors are providing exciting new approaches for the treatment of cancer (4). As we are learning more about the molecular basis of cancer metabolism and the general biology of the tumor immune microenvironment, novel strategies are emerging that may help prevent or control cancer metastasis. Tumor immunity and metabolism in cancer metastasis was the goal of this Research Topic. The collection includes 29 original research papers and reviews directed toward the advancement of our understanding of these important topics in cancer research.
TL;DR: In this paper , the authors sought to determine the key factors influencing the decision-making of veterans for endovascular repair of abdominal aortic aneurysm (EVAR) or open surgical repair (OSR).