scholarly journals Genetic Aberrations of DNA Repair Pathways in Prostate Cancer: Translation to the Clinic

2021 ◽  
Vol 22 (18) ◽  
pp. 9783
Author(s):  
Aruni Ghose ◽  
Michele Moschetta ◽  
George Pappas-Gogos ◽  
Matin Sheriff ◽  
Stergios Boussios
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Large Scale ◽  
Expression Patterns ◽  
Specific Antigen ◽  
Distant Metastases ◽  
Parp Inhibitors ◽  
High Recurrence Rate ◽  
Clinical Implications ◽  
Genomic Landscape

Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 (BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.

scholarly journals Prognostic value of subclassification (pT2 stage) of pathologically organ-confined prostate cancer: Confirmation of the changes introduced in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system

2018 ◽  
Vol 90 (3) ◽  
pp. 191-194 ◽  
Author(s):  
Hugo Pontes Antunes ◽  
Belmiro Parada ◽  
João Carvalho ◽  
Miguel Eliseu ◽  
Roberto Jarimba ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Staging System ◽  
Distant Metastases ◽  
Grade Group ◽  
Pathological Evaluation ◽  
Ajcc Staging System ◽  
Oncological Results ◽  
Ajcc Staging ◽  
8Th Edition

Objective: The last edition of the AJCC staging system eliminated the pT2 subclassification of prostate cancer (PCa). Our objective was to evaluate the association of pT2 subclassification with the oncological results of patients with PCa who underwent radical prostatectomy (RP). Material and methods: We evaluated 367 patients who underwent RP between 2009 and 2016, with pT2 disease in the final pathological evaluation. We assessed differences in rates of biochemical recurrence (BCR), metastasis and mortality between T2 substages (pT2a/b vs pT2c). Results: Fifty-three (14.4%) patients presented pT2a/b disease and 314 (85.6%) pT2c disease. The mean follow-up time was 4.9 ± 2.6 years. Grade group scores (p = 0.1) and prostate specific antigen (PSA) (p = 0.2) did not differed between pT2 substages. The rate of BCR in pT2a/b and pT2c patients was 11.3% and 18.2%, respectively (p = 0.2). Five (9.4%) patients with pT2a/b and 45 (14.3%) with pT2c substage underwent salvage radiotherapy (p = 0.3). The rate of positive surgical margins did not differ between groups (p = 0.2). Seven (2.2%) patients with pT2c had lymph nodes or distant metastases. The overall survival was 92.5% and 93.6% in pT2a/b and pT2c, respectively (p = 0.2). Conclusion: Our results are in accordance with the changes introduced in the 8th edition of the AJCC staging system in which the pT2 subclassification was eliminated.

Clinical implications of a prostate-specific antigen bounce after radiation therapy for prostate cancer

2014 ◽  
Vol 20 (3) ◽  
pp. 598-604 ◽  
Author(s):  
Arash O. Naghavi ◽  
Tobin J. Strom ◽  
Kevin Nethers ◽  
Alex A. Cruz ◽  
Nicholas B. Figura ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiation Therapy ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Clinical Implications

scholarly journals Chronic Myelomonocytic Leukemia—Hematopathology Perspective

2021 ◽  
Author(s):  
Siba El Hussein ◽  
Sa A. Wang ◽  
Naveen Pemmaraju ◽  
Joseph D. Khoury ◽  
Sanam Loghavi
Keyword(s):  
Risk Stratification ◽  
Large Scale ◽  
Chronic Myelomonocytic Leukemia ◽  
Clinical Implications ◽  
The Past ◽  
Genomic Landscape ◽  
Sequencing Studies ◽  
Myelomonocytic Leukemia ◽  
Insight Into

ABSTRACT Our understanding of chronic myelomonocytic leukemia (CMML) has evolved tremendously over the past decade. Large-scale sequencing studies have led to increased insight into the genomic landscape of CMML and clinical implications of these changes. This in turn has resulted in refined and improved risk stratification models, which to date remain versatile and subject to remodeling, as new and evolving studies continue to refine our understanding of this disease. In this article, we present an up-to-date review of CMML from a hematopathology perspective, while providing a clinically practical summary that sheds light on the constant evolution of our understanding of this disease.

scholarly journals PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 565 ◽  
Author(s):  
Virtanen ◽  
Paunu ◽  
Ahlskog ◽  
Varnai ◽  
Sipeky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Dna Repair ◽  
Therapeutic Potential ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Treatment Modalities ◽  
Cancer Type ◽  
Castration Resistance ◽  
Single Strand Break

Prostate cancer is globally the second most commonly diagnosed cancer type in men.Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an extensive overview of publishedand ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss theunderlying biology. Several clinical trials are currently studying PARP inhibitor mono‐andcombination therapies in the treatment of prostate cancer. Integration of drugs targeting DNArepair pathways in prostate cancer treatment modalities allows developing of more personalizedcare taking also into account the genetic makeup of individual tumors.

scholarly journals DNA Repair in Prostate Cancer: Biology and Clinical Implications

2017 ◽  
Vol 71 (3) ◽  
pp. 417-425 ◽  
Author(s):  
Joaquin Mateo ◽  
Gunther Boysen ◽  
Christopher E. Barbieri ◽  
Helen E. Bryant ◽  
Elena Castro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cancer Biology ◽  
Clinical Implications

scholarly journals Assay of prostate-specific antigen from whole blood spotted on filter paper and application to prostate cancer screening

1996 ◽  
Vol 42 (4) ◽  
pp. 536-544 ◽  
Author(s):  
B R Hoffman ◽  
H Yu ◽  
E P Diamandis
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Filter Paper ◽  
Whole Blood ◽  
Large Scale ◽  
Prostate Cancer Screening ◽  
Specific Antigen ◽  
Blood Concentrations ◽  
Hot Climate ◽  
Plasma Fraction

Abstract We report the measure of prostate-specific antigen (PSA) from extracts of blood dried on filter paper. Five 3-mm (diameter) paper discs containing approximately 25 microL of dried whole blood were punched from the filter paper and extracted with 500 microL of buffer. Recovery of PSA was > 92%. Imprecision of the filter paper procedure was <10% when corresponding whole-blood concentrations were >0.35 micrograms/L. PSA recovery was unaffected whether blood was applied to the filter as one 85-microL aliquots, two 43-microL aliquots, or three 28-microL aliquots. PSA is contained in the plasma fraction. Variation in hematocrit from 0.61 to 0.31 caused <+/-10% change in filter paper PSA. Regression analysis showed: filter paper PSA = 0.86 whole-blood PSA - 0.02; Sy/x = 0.44. Men (153) without prostate cancer gave a 95th percentile of 4.8 micrograms /L. PSA in filter paper dried blood was stable for >1 month at -20 to 37 degrees C and showed no loss of recovery after being mailed to a hot climate. We conclude that the filter paper procedure can reliably distinguish normal from increased concentrations of PSA and that it could facilitate screening to detect occult prostate cancer in large-scale mail-in programs to centralized laboratories.

miRNAs as novel biomarkers in the management of prostate cancer

2017 ◽  
Vol 55 (5) ◽  
Author(s):  
Xavier Filella ◽  
Laura Foj
Keyword(s):  
Prostate Cancer ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Specific Antigen ◽  
Digital Rectal Examination ◽  
New Approach ◽  
Novel Biomarkers ◽  
Non Coding Rnas ◽  
Underlying Mechanisms ◽  
New Biomarkers

AbstractmicroRNAs (miRNAs) are small non-coding RNAs that control gene expression posttranscriptionally and are part of the giant non codifying genoma. Cumulating data suggest that miRNAs are promising potential biomarkers for many diseases, including cancer. Prostate cancer (PCa) detection is currently based in the serum prostate-specific antigen biomarker and digital rectal examination. However, these methods are limited by a low predictive value and the adverse consequences associated with overdiagnosis and overtreatment. New biomarkers that could be used for PCa detection and prognosis are still needed. Recent studies have demonstrated that aberrant expressions of microRNAs are associated with the underlying mechanisms of PCa. This review attempts to extensively summarize the current knowledge of miRNA expression patterns, as well as their targets and involvement in PCa pathogenesis. We focused our review in the value of circulating and urine miRNAs as biomarkers in PCa patients, highlighting the existing discrepancies between different studies, probably associated with the important methodological issues related to their quantitation and normalization. The majority of studies have been performed in serum or plasma, but urine obtained after prostate massage appears as a new way to explore the usefulness of miRNAs. Large screening studies to select a miRNA profile have been completed, but bioinformatics tools appear as a new approach to select miRNAs that are relevant in PCa development. Promising preliminary results were published concerning miR-141, miR-375 and miR-21, but larger and prospective studies using standardized methodology are necessary to define the value of miRNAs in the detection and prognosis of PCa.

scholarly journals ADENOSQUAMOUS CELL CANCER OF THE PROSTATE: A CLINICAL CASE

2020 ◽  
Vol 1 (1) ◽  
pp. 60-68
Author(s):  
A. A. Krasheninnikov ◽  
K. M. Nyushko ◽  
N. V. Vorobev ◽  
H. R. Maltzagova ◽  
B. Ya. Alekseev ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Squamous Cell ◽  
Clinical Case ◽  
Cell Cancer ◽  
Combined Treatment ◽  
Specific Antigen ◽  
Morphological Structure ◽  
Distant Metastases ◽  
Treatment Standards ◽  
Surgical Interventions

Prostate cancer (Pca) is the most common urogenital tumour in men. The most common histological form of prostate cancer is acinar adenocarcinoma. Rare morphological types of prostate cancer present an urgent clinical problem due to their aggressive course and the lack of rigorous standards for the management of such patients. Squamous and combined adenosquamous (ASC) prostate cancers are extremely rare histological forms of Pca, occurring in 0.5–1% of cases. The age of patients with these conditions varies from 52 to 79 years. Squamous cell and ASC cancers are among the most aggressive morphological types of prostate cancer. By the time of the diagnosis, most patients develop distant metastases, which are frequently localized in the lymph nodes and bones. In tumours of such a morphological structure, bone metastases are of osteolytic nature. The prognosis is unfavourable due to the rapid metastasis and development of the malignant process. The survival rate of patients averages 16 months after combined treatment. Only 20% of the patients with distant metastases at the time of diagnosis live longer than 6 months. In most cases, squamous cell Pca manifests itself through local symptoms, such as dysuria, bone pain and hematuria. The vast majority of patients have a normal level of prostate-specific antigen (PSA) in serum. Since ASC Pca is a fairly rare form of prostate cancer, no treatment standards have thus far been developed. Hormone therapy, chemotherapy and radiation therapy are believed to either be ineffective or show low efficacy in the treatment of ASC Pca. In cases where ASC Pca is localized, surgical treatment in the amount of radical prostatectomy, cystoprostatectomy or simultaneous surgical interventions with rectal resection can significantly extend the life of such patients. The article presents the clinical case of managing a patient with ASC Pca.

scholarly journals A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone

2020 ◽  
Vol 8 (2) ◽  
pp. e000642 ◽  
Author(s):  
Julie N Graff ◽  
Tomasz M Beer ◽  
Joshi J Alumkal ◽  
Rachel E Slottke ◽  
William L Redmond ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Specific Antigen ◽  
Subsequent Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Entire Cohort ◽  
Castration Resistant

BackgroundCheckpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response.MethodsWe evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens.ResultsFive (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression.ConclusionsPembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects.Trial registration numberclinicaltrials.gov (NCT02312557).

scholarly journals Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors

2019 ◽  
Vol 20 (12) ◽  
pp. 3100 ◽  
Author(s):  
Daniela Criscuolo ◽  
Francesco Morra ◽  
Riccardo Giannella ◽  
Aniello Cerrato ◽  
Angela Celetti
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Novel Biomarkers

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

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