scholarly journals Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275)

2021 ◽  
Vol 38 (5) ◽  
pp. 451-458
Author(s):  
G. Francolini ◽  
M. Loi ◽  
V. Salvestrini ◽  
M. Mangoni ◽  
B. Detti ◽  
...  
Keyword(s):  
Preliminary Analysis ◽  
Circulating Tumor Cell ◽  
Response To Therapy ◽  
Micro Rna ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Observational Trial ◽  
Mutational Status ◽  
Prospective Assessment ◽  
Patient Prognosis

AbstractIn our institution, a prospective observational trial testing micro-RNA (miRNA) and ARV7 mutational status in metastatic, castration resistant prostate cancer (mCRPC), is currently recruiting (PRIMERA trial, NCT04188275). A pre-planned interim analysis was performed when 50% of the planned accrual was reached. In this report, we explored the predictive value of Circulating Tumor Cell (CTC) detection in mCRPC patients undergoing 1st line therapy. Moreover, ARV7, ARFL, PSMA and PSA expression on CTC was reported to explore potential correlation with patient prognosis and response to therapy. PRIMERA is a prospective observational trial enrolling mCRPC patients undergoing standard treatment (ARTA + ADT) after I line ADT failure. Clinical and pathological features were collected. Outcomes selected for this preliminary analysis were time to castration resistance (TTCR), PSA at 8 weeks after ARTA therapy start, PSA drop at 8 weeks, Overall PSA drop, PSA nadir. Correlation between these outcomes and CTC detection was tested. Expression of ARV7, ARFL, PSA and PSMA was explored in CTC+ patients to assess their prevalence in this cohort and their impact on selected outcomes. Median TTCR was significantly shorter in CTC+ vs CTC− patients (32.3 vs 75 months, respectively, p = 0.03) and in ARFL+ vs ARFL− patients (30.2 vs 51.1 months, respectively, p = 0.02). ARV7, PSMA and PSA expression on CTC had no impact on median TTCR, nor on biochemical response to therapy. Patients in whom CTC and ARFL expression were detected had significant reduced TTCR. However, PSA response was not influenced by CTCs detection and specific biomarkers expression.

Circulating tumor cell (CTC) detection, N-terminal androgen (AR) characterization, and PTEN loss in metastatic or advanced castration resistant prostate cancer (CRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 195-195
Author(s):  
Shidong Jia ◽  
Sarah Baird ◽  
Amanda K. L. Anderson ◽  
Shannon L. Werner ◽  
Jane Petersen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Circulating Tumor Cell ◽  
Response To Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Patient Response ◽  
Invasive Approach ◽  
Disease Evolution ◽  
Pten Loss ◽  
Non Invasive

195 Background: Detection and characterization of CTCs offers a minimally invasive mechanism for understanding patient response to therapy and disease evolution. Here we describe a proprietary technology platform to examine CTC incidence, N-terminal AR expression, and PTEN loss in metastatic or advanced CRPC patient samples from a phase II clinical trial (GO27983) testing the combination of the AKT inhibitor ipatasertib and abiraterone. Methods: Blood samples from CRPC patients (n = 283) were collected at screening and shipped to Epic Sciences. Upon receipt, the nucleated cells were plated onto microscope slides and stored at -80C. Two slides were thawed per patient and analyzed with an N-terminal AR CTC assay. CTCs were detected using a combination of CD45 exclusion, CK and N-terminal AR expression, and morphologic criteria. Traditional (CD45-, CK+, DAPI+) and Non-Traditional (CD45-/CK- with distinct morphology or CD45-/CK+ with fragmented nuclei) CTCs were enumerated and N-terminal AR expression was quantified for each CTC. Samples with > 2 Traditional CTCs enumerated per slide were further evaluated for PTEN loss by FISH (n = 170). Results: Traditional CTCs were detected ( ≥ 1 cell/ml) in 86% (242 of 283) of samples. Non-traditional CTCs were detected in 93% (263 of 283) of patients. N-terminal AR positivity was detected ( ≥ 1 AR+ cell/ml) in 53% (128 of 242) of Traditional CTC-positive samples, with the % positivity ranging from 0.4-100%. PTEN status was determined for 66% (160 of 243) of patients with Traditional CTCs detected. Patients with homozygous (HO) PTEN loss had a significantly higher mean CTC/mL (p = 0.0013) and AR+ CTC/mL value (p = 0.0014) than patients with PTEN non-deleted status. Conclusions: The ability of the Epic Sciences platform to detect AR+ CTCs and PTEN loss at screening provides a non-invasive approach to characterizing and monitoring CTCs identified in advanced CRPC patients. The study is ongoing to monitor longitudinal changes in CTC incidence and AR expression in relation to PTEN status. Clinical trial information: NCT01485861.

scholarly journals Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Yuan Liu ◽  
Cuifu Yu ◽  
Zhenlong Shao ◽  
Xiaohong Xia ◽  
Tumei Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Selective Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Selective Degradation ◽  
Castration Resistant ◽  
Novel Drugs ◽  
The Stability ◽  
Androgen Receptor Splice Variant

AbstractAndrogen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.

scholarly journals Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 516 ◽  
Author(s):  
François-Clément Bidard ◽  
Nicolas Kiavue ◽  
Marc Ychou ◽  
Luc Cabel ◽  
Marc-Henri Stern ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Circulating Tumor Cell ◽  
Circulating Tumor Dna ◽  
Detection Sensitivity ◽  
Clinical Validity ◽  
Mutational Status ◽  
Prospective Phase ◽  
Polymerase Chain ◽  
Digital Polymerase Chain Reaction ◽  
Tumor Dna

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch®) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p < 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

scholarly journals Circulating Tumor Cell Analysis in Patients with Progressive Castration-Resistant Prostate Cancer

2007 ◽  
Vol 13 (7) ◽  
pp. 2023-2029 ◽  
Author(s):  
David R. Shaffer ◽  
Margaret A. Leversha ◽  
Daniel C. Danila ◽  
Oscar Lin ◽  
Rita Gonzalez-Espinoza ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cell ◽  
Circulating Tumor Cell ◽  
Cell Analysis ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Abstract A56: Identification of a micro RNA profile to predict response to therapy and improve patient survival in ovarian cancer

2013 ◽  
Author(s):  
Marina Rigau ◽  
Blanca Majem ◽  
Tatiana Altadill ◽  
Lucia Lanau ◽  
José-Luis Sánchez-Iglesias ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Patient Survival ◽  
Response To Therapy ◽  
Micro Rna ◽  
Improve Patient Survival ◽  
Improve Patient

scholarly journals Incidence of Skeletal-Related Events in Patients with Castration-Resistant Prostate Cancer: An Observational Retrospective Cohort Study in the US

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Alison Tse Kawai ◽  
David Martinez ◽  
Catherine W. Saltus ◽  
Zdravko P. Vassilev ◽  
Montse Soriano-Gabarró ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Incidence Rate ◽  
Incidence Rates ◽  
Negative Consequences ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Castration Resistant ◽  
The Us ◽  
History Of ◽  
Skeletal Related Events

Background and Objective. Skeletal-related events (SREs) are common in men with bone metastases and have negative consequences for patients with castration-resistant prostate cancer (CRPC), including pain, reduced quality of life, and increased mortality. We estimated incidence rates of first SREs in a cohort of men with CRPC in the Surveillance, Epidemiology, and End Results-Medicare database. Methods. We included men aged ≥ 65 years with a prostate cancer diagnosis in 2000-2011 if they had no prior malignancy (other than nonmelanoma skin cancer) and had surgical or medical castration with subsequent second-line systemic therapy, which was used to infer castration resistance. The first occurrence of an SRE (fracture, bone surgery, radiation therapy, or spinal cord compression) in Medicare claims was identified. Incidence rates of SREs were estimated in all eligible person-time and, in secondary analyses, stratified by any use of bone-targeted agents (BTAs) and history of SRE. Results. Of 2,234 men with CRPC (84% white, mean age = 76.6 years), 896 (40%) had an SRE during follow-up, with 74% occurring within a year after cohort entry. Overall, the incidence rate of SREs was 3.78 (95% CI, 3.53-4.03) per 100 person-months. The incidence rate of SREs before any BTA use was 4.16 (95% CI, 3.71-4.65) per 100 person-months, and after any BTA use was 3.60 (95% CI, 3.32-3.91) per 100 person-months. The incidence rate in patients with no history of SRE was 3.33 (95% CI 3.01-3.68) per 100 person-months, and in patients who had such a history, it was 4.20 (95% CI 3.84-4.58) per 100 person-months. Conclusions. In this large cohort of elderly men with CRPC in the US, SREs were common. A decrease in incidence of SREs after starting BTA is suggested, but the magnitude of the effect may be confounded by indication and other factors such as age and prior SRE.

scholarly journals P03.13 Evaluation of PIK3CA mutational status in glioma molecular subgroups

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii27-iii28
Author(s):  
C Brito ◽  
A Azevedo ◽  
S Esteves ◽  
C Martins ◽  
M Mafra ◽  
...  
Keyword(s):  
Who Classification ◽  
Response To Therapy ◽  
World Health ◽  
Diffuse Glioma ◽  
Molecular Subgroups ◽  
Egfr Amplification ◽  
Pik3ca Mutations ◽  
Mutational Status ◽  
Idh Mutations ◽  
Pten Deletion

Abstract BACKGROUND Gliomas are the most common and lethal malignant tumors of central nervous system. In 2016, World Health Organization (WHO) classification included IDH mutations and 1p/19q codeletion as diagnostic criteria to define glioma entities. However, new biomarkers for diagnosis, prognosis and response to therapy are needed. In this context, PIK3CA mutations have been described as constitutive mutations, which highlights their relevance in gliomas. Here we clarified the clinical relevance of PIK3CA mutations according to the 2016 WHO classification, the potential impact on diagnosis, prognosis, response to therapy, as well as their correlation with EGFR amplification and PTEN deletion. MATERIAL AND METHODS A cohort of 444 adult diffuse glioma samples from Instituto Português de Oncologia Lisboa Francisco Gentil (IPOLFG) was classified according to the 2016 WHO Classification. The mutational status of exon 9 and 20 of PIK3CA was evaluated in molecular subgroups of gliomas by Sanger sequencing. PTEN deletion and EGFR amplification were identified by Fluorescent in situ hybridization (FISH). RESULTS PIK3CA mutations showed a higher frequency in the subgroup of gliomas with IDH mutations and 1p/19q codeletion - oligodendrogliomas (10%). In Glioblastoma (GBM) IDH-mutant and IDH-wildtype these oncogenic mutations were observed in 9% and 3% of cases, respectively. Similar results were obtained using The Cancer Genome Atlas (TCGA) data, which was 8% and 2%, respectively. H1047R and E542K were the most frequent mutations identified in the glioma molecular subgroups. Importantly, we found 3 unreported pathogenic variants in exon 20 of PIK3CA (c.3112T>C, c.2988T>C, c.3040C>T) and one polymorphic variant (c.3210A>G). In addition, PIK3CA mutations, PTEN deletion and EGFR amplification were not mutually exclusive alterations in glioma molecular subgroups. For the first time in gliomas, it was identified the rs45455192 polymorphism at a frequency of 16% in astrocytomas IDH-mutant, 24% in oligodendrogliomas and 18% in both molecular subgroups of GBM, although this polymorphism did not have prognostic value. The analysis of PIK3CA mutations in glioma recurrences showed that these mutations are maintained during glioma progression. CONCLUSION In two independent cohorts (IPOLFG and TCGA), it was obtained similar frequencies of PIK3CA mutations in GBM molecular subgroups. In addition, these mutations are more relevant in less aggressive gliomas (IDH-mutated and 1p/19q codeleted). These alterations seem to be important in tumor maintenance and progression, which makes this gene a potential therapeutic target. In the future, we will investigate the effect of the in vitro pharmacological inhibition of PIK3CA in GBM mutant cell lines.

scholarly journals Reinduction of Hormone Sensitivity to Goserelin following Chemotherapy with Vinorelbine in Castration-Resistant Prostate Cancer

2010 ◽  
Vol 10 ◽  
pp. 1814-1817
Author(s):  
Tal Grenader ◽  
Anthony Goldberg
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Serum Levels ◽  
Symptomatic Improvement ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Luteinizing Hormone Releasing Hormone ◽  
Androgen Ablation ◽  
Castration Resistant ◽  
Cessation Of Treatment

Primary androgen ablation leads to symptomatic improvement and a reduction in prostate-specific antigen (PSA) serum levels in patients with advanced prostate cancer, but all patients eventually become refractory to hormone therapy with progression of the disease and a life expectancy of about a year. We describe a patient who developed castration resistance, was treated with vinorelbine, and continues to be progression free on therapy with luteinizing hormone releasing hormone agonists alone, more than 2.5 years following cessation of treatment with vinorelbine.

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