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European Urology Oncology Mar 2024A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with...
Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide.
BACKGROUND
A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy.
OBJECTIVE
We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial.
DESIGN, SETTING, AND PARTICIPANTS
PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated.
RESULTS AND LIMITATIONS
A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point.
CONCLUSIONS
The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients.
PATIENT SUMMARY
A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.
PubMed: 38523017
DOI: 10.1016/j.euo.2024.03.001 -
Journal of Cancer 2024Bicalutamide (BIC) resistance impedes the treatment of prostate cancer (PCa) and seems to involve ferroptosis; however, the underlying mechanism remains unclear. Our...
Bicalutamide (BIC) resistance impedes the treatment of prostate cancer (PCa) and seems to involve ferroptosis; however, the underlying mechanism remains unclear. Our study aimed to explore how miR-15b-3p modulates ferroptosis in response to BIC resistance and determine whether the miRNA is suitable for early screening of PCa. Here, we found that PCa tissues had significantly higher miR-15b-3p expression than adjacent normal tissues. Analysis of blood samples in patients who underwent prostate-specific antigen (PSA) screening revealed that miR-15b-3p was a more accurate diagnostic than PSA (miR-15b-3p area under the curve [AUC] = 0.941, PSA AUC = 0.815). In vitro experiments then demonstrated that miR-15b-3p expression was markedly higher in LNCaP, PC-3, and DU145 cells than in RWPE-1 cells. Treatment with BIC decreased miR-15b-3p expression and progressive ferroptosis. Mechanistically, we identified KLF2 as the downstream target of miR-15b-3p. Overexpressing KLF2 facilitated ferroptosis via augmenting MDA and iron concentrations, in turn inhibiting the SLC7A11/GPX4 axis and decreasing GSH concentration. Through modulating ferroptosis, miR-15b-3p mimic and inhibitor weakened and enhanced BIC sensitivity, respectively. Furthermore, BIC treatment limited xenograft tumor volume in vivo, whereas agomir-15b-3p promoted tumor growth, indicating that miR-15b-3p attenuated the tumor-suppressive effects of BIC. Taken together, our results suggested that miR-15b-3p is crucial to BIC resistance, specifically via targeting KLF2 and thereby suppressing ferroptosis. High miR-15b-3p expression in early PCa screening should reflect a higher probability of cancer. In conclusion, miR-15b-3p has strong potential as a screening and diagnostic biomarker with reliable prospects for clinical application. Furthermore, because patients with high miR-15b-3p and low KLF2 expression have a greater risk of BIC resistance and malignant progression, targeting the miRNA and its downstream protein may be a new treatment strategy.
PubMed: 38495481
DOI: 10.7150/jca.92379 -
International Journal of Molecular... Feb 2024Many studies have demonstrated the mechanisms of progression to castration-resistant prostate cancer (CRPC) and novel strategies for its treatment. Despite these...
Many studies have demonstrated the mechanisms of progression to castration-resistant prostate cancer (CRPC) and novel strategies for its treatment. Despite these advances, the molecular mechanisms underlying the progression to CRPC remain unclear, and currently, no effective treatments for CRPC are available. Here, we characterized the key genes involved in CRPC progression to gain insight into potential therapeutic targets. Bicalutamide-resistant prostate cancer cells derived from LNCaP were generated and named Bical R. RNA sequencing was used to identify differentially expressed genes (DEGs) between LNCaP and Bical R. In total, 631 DEGs (302 upregulated genes and 329 downregulated genes) were identified. The Cytohubba plug-in in Cytoscape was used to identify seven hub genes (, , , , , , and ) associated with CRPC progression. Among these hub genes, and were markedly upregulated in CRPC cell lines and CRPC patient samples. The patients with high expression of and showed worse disease-free survival in patients with The Cancer Genome Atlas (TCGA)-prostate adenocarcinoma (PRAD) datasets. Our study revealed a potential association between and and the progression to CRPC. These results may contribute to the development of potential therapeutic targets and mechanisms underlying CRPC progression, aiming to improve clinical efficacy in CRPC treatment.
Topics: Humans; Male; Cell Line, Tumor; Computational Biology; Prostatic Neoplasms, Castration-Resistant; Transcription Factor CHOP; Treatment Outcome
PubMed: 38474084
DOI: 10.3390/ijms25052836 -
Annals of Pediatric Endocrinology &... Feb 2024Familial male-limited precocious puberty (FMPP) is a rare form of gonadotropin-independent precocious puberty that is caused by an activating mutation of the LHCGR gene....
Familial male-limited precocious puberty (FMPP) is a rare form of gonadotropin-independent precocious puberty that is caused by an activating mutation of the LHCGR gene. Herein, we report a case of FMPP with a mutation of the LHCGR gene in a Korean boy with familial history of precocious puberty through 3 generations. A 16-month-old boy presented with signs of precocious puberty, including pubic hair, acne, and increased growth velocity. The patient's grandfather and father had a history of precocious puberty and profound short stature. On physical examination, the patient had prepubertal testes with pubic hair development appropriate for Tanner stage II. The stretched penile length was 7 cm (>2 standard deviation score), and observed bone age was that of a 4-year-old boy. Laboratory findings showed high serum testosterone (5.74 ng/mL [appropriate for Tanner IV-V]; normal range, <0.05 ng/mL) with suppressed luteinizing hormone (<0.07 mIU/mL) and normal serum level of follicular stimulating hormone (0.56 mIU/mL; normal range, 0.38-1.11 mIU/mL). Genetic testing revealed a pathogenic variant of LHCGR (c.1730 C>T (p.Thr577Ileu)), confirming FMPP. Bicalutamide and anastrozole were administered, and pubertal progression was sufficiently suppressed without any specific side effects. To our knowledge, this is the first case of genetically confirmed FMPP in Korea.
PubMed: 38461807
DOI: 10.6065/apem.2346042.021 -
IScience Mar 2024Prostate cancer (PCa) is a serious health concern for men due to its high incidence and mortality rate. The first therapy typically adopted is androgen deprivation...
Prostate cancer (PCa) is a serious health concern for men due to its high incidence and mortality rate. The first therapy typically adopted is androgen deprivation therapy (ADT). However, patient response to ADT varies, and 20-30% of PCa cases develop into castration-resistant prostate cancer (CRPC). This article investigates the anti-PCa effect of a drug candidate named GL-V9 and highlights the significant mechanism involving the AKT-hexokinase II (HKII) pathway. In both androgen receptor (AR)-expressing 22RV1 cells and AR-negative PC3 cells, GL-V9 suppressed phosphorylated AKT and mitochondrial location of HKII. This led to glycolytic inhibition and mitochondrial pathway-mediated apoptosis. Additionally, GL-V9 inhibited AR activity in 22RV1 cells and disrupted the feedback activation of AKT signaling in condition of AR inhibition. This disruption greatly increased the anti-PCa efficacy of the AR antagonist bicalutamide. In conclusion, we present a novel anti-PCa candidate and combination drug strategies to combat CRPC by intervening in the AR-AKT-HKII signaling network.
PubMed: 38439974
DOI: 10.1016/j.isci.2024.109246 -
Journal of Medical Economics 2024This study assessed the treatment patterns, healthcare resource utilization (HRU), costs, and annual prevalence and incidence of metastatic hormone-sensitive prostate... (Observational Study)
Observational Study
Treatment patterns and healthcare resource utilization in patients with metastatic hormone-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer in China: a real-world observational study.
AIM
This study assessed the treatment patterns, healthcare resource utilization (HRU), costs, and annual prevalence and incidence of metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC) in China.
METHODS
A retrospective study was conducted using electronic medical records (EMR) of patients with prostate cancer from three tertiary-care hospitals in China between January 2014 and March 2021. Descriptive statistics were used to analyze study outcomes.
RESULTS
In total, 1086 patients with mHSPC and 679 patients with nmCRPC were included. From 2015 to 2020, the annual percentage of prevalent and incident cases of mHSPC decreased from 22.4% to 20.0% and 11.1% to 6.9%, respectively; for nmCRPC, these increased from 3.8% to 13.6% and 3.3% to 8.4%. Androgen-deprivation therapy and first-generation antiandrogens (bicalutamide or flutamide) were the most frequently prescribed prostate cancer-related medications at baseline and follow-up in patients with mHSPC. Bicalutamide was the most frequently prescribed prostate cancer-related medication during follow-up in patients with nmCRPC. For mHSPC, inpatient admission costs were the highest, with the median (interquartile range) costs per person-month being USD 403.00 (USD 85.50-1226.20), whereas outpatient visit costs were the highest for nmCRPC (USD 372.60 [USD 139.50-818.50]).
LIMITATIONS
EMR-based study design did not capture treatment patterns, HRU and associated costs, and healthcare encounters that occurred outside of participating hospitals, which could have led to underestimation of the true disease burden.
CONCLUSIONS
A contrasting trend of a decline in the prevalence and incidence of mHSPC and an increase in these for nmCRPC was observed between 2015 and 2020 in China. Androgen-deprivation therapy and first-generation antiandrogens were the most frequently prescribed prostate cancer-related medications. Healthcare resource utilization was driven by inpatient costs in mHSPC and outpatient costs in nmCRPC.
Topics: Male; Humans; Androgen Antagonists; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Androgens; Delivery of Health Care; Anilides; Nitriles; Tosyl Compounds
PubMed: 38375556
DOI: 10.1080/13696998.2024.2320001 -
Case Reports in Oncology 2024Small cell neuroendocrine carcinoma of the prostate (SCNECP) is a rare and highly malignant tumor that commonly transforms into conventional prostate adenocarcinoma...
INTRODUCTION
Small cell neuroendocrine carcinoma of the prostate (SCNECP) is a rare and highly malignant tumor that commonly transforms into conventional prostate adenocarcinoma (CPAC). Most of SCNECP cases cannot be detected and diagnosed early, and SCNECP is often diagnosed when there is liver and lung metastasis. Therefore, the early detection of the process from CPAC to SCNECP is crucial.
CASE REPORT
We present a case of a 73-year-old man who was initially admitted to our hospital with metastatic CPAC. He was administered goserelin acetate 3.6 mg combined with bicalutamide tablets (50 mg) once daily for endocrine therapy and docetaxel (100 mg) combined with prednisone (5 mg) twice a day. After treatment, the prostate-specific antigen (PSA) level decreased significantly, but the CEA, CA199, and CA125 levels began to increase progressively after a short decline. However, no solid tumor recurrence was observed in multiple reexaminations. It was not until 9 months after the elevation of tumor markers that multiple metastatic lesions appeared in the liver, which finally confirmed the diagnosis of metastatic SCNECP. After chemotherapy with etoposide 360 mg combined with carboplatin 200 mg, the tumor size was significantly reduced, and tumor markers decreased. However, the remission time was only 3 months. The patient's liver metastases continued to grow, and CEA, CA199, and CA125 levels continued to increase.
CONCLUSION
During CPAC treatment, PSA levels continued to decrease, whereas CEA, CA199, and CA125 levels continued to increase. This suggests the possibility of the transformation of CPAC into SCNECP.
PubMed: 38357684
DOI: 10.1159/000536351 -
Japanese Journal of Clinical Oncology May 2024Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of... (Observational Study)
Observational Study
Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.
BACKGROUND
Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide.
METHODS
The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients.
RESULTS
The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70.
CONCLUSIONS
In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.
Topics: Humans; Male; Phenylthiohydantoin; Nitriles; Prostatic Neoplasms, Castration-Resistant; Benzamides; Aged; Prospective Studies; Androgen Antagonists; Aged, 80 and over; Middle Aged; Tosyl Compounds; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Treatment Outcome; Anilides; Prostate-Specific Antigen
PubMed: 38305451
DOI: 10.1093/jjco/hyae004 -
Frontiers in Oncology 2023Aggressive angiomyxoma (AA) is a rare mesenchymal neoplasm, which is commonly diagnosed in females and located in the perineal and pelvic region. Tissue specimens of AA...
Aggressive angiomyxoma (AA) is a rare mesenchymal neoplasm, which is commonly diagnosed in females and located in the perineal and pelvic region. Tissue specimens of AA patients often show positivity for estrogen (ER) and progesterone receptors (PgR), while some cases of androgen receptor (AR) positivity have been reported in males. When feasible, surgical excision represent the most effective treatment of AA; however, when experiencing advanced or recurrent disease, local disease control could be achieved with systemic hormonal treatment. To date, evidence regarding AA management in male patients is scarce, and only a few cases have been reported in literature. Hereby, we describe the case of a 59-year-old-man suffering from perineal AA with positivity for androgen receptors (AR) showing a long-lasting disease stability during the treatment with an AR-blocking drug (bicalutamide). A literature review regarding the state of art of AA management with a particular look to male patients is also provided.
PubMed: 38298446
DOI: 10.3389/fonc.2023.1260668 -
Frontiers in Pharmacology 2023Rezvilutamide, a novel androgen-receptor inhibitor with limited blood-brain barrier penetration, exhibits significant antitumour activity against highvolume,...
Rezvilutamide, a novel androgen-receptor inhibitor with limited blood-brain barrier penetration, exhibits significant antitumour activity against highvolume, metastatic, hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to compare the cost-effectiveness of rezvilutamide and bicalutamide as first-line treatments for untreated prostate cancer among Chinese patients, in order to evaluate the efficacy of rezvilutamide. In this study, we utilized partition survival model to assess the cost-effectiveness of rezvilutamide and bicalutamide treatments for highvolume mHSPC. The model was developed using TreeAge Pro 2022 software and relied on clinical data obtained from the CHART trial. Transition probabilities were estimated from the reported survival probabilities in trials using parametric survival modeling. From the perspective of the Chinese healthcare system, we calculated quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), and lifetime cost. A lifetime horizon and an annual discount rate of 5% were employed. To address modeling uncertainties, we conducted one-way sensitivity analysis and probabilistic sensitivity analysis. The cost of rezvilutamide bicalutamide were $62700 and $13200. Rezvilutamide had an ICER of $41900 per additional QALYs gained compared with bicalutamide. Research indicated that rezvilutamide achieved at least an 28.20% probability of cost-effectiveness at the threshold of $38223.34/QALY. One-way sensitivity analysis revealed that the results were sensitive to utility of PD. Scenario analysis showed that rezvilutamide was cost-effectiveness if its price was reduced by more than 10%. Based on the analysis at the current price, rezvilutamide was found to be less cost-effective for patients with highvolume mHSPC compared to bicalutamide in China.
PubMed: 38264528
DOI: 10.3389/fphar.2023.1269129