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The British Journal of General Practice... Jun 2024Prostate Cancer (PCa) is the commonest cancer in the UK. Androgen deprivation therapy (ADT) is a mainstay of treatment. It increases fragility fractures causing a huge... (Observational Study)
Observational Study
BACKGROUND
Prostate Cancer (PCa) is the commonest cancer in the UK. Androgen deprivation therapy (ADT) is a mainstay of treatment. It increases fragility fractures causing a huge burden to patients and the NHS. As men live longer with PCa, many require prolonged ADT. Reducing fracture risks and improving cancer survivorship is becoming increasingly important. Primary care plays an important role.
AIM
To evaluate how fracture risk of PCa patients taking ADT (PCa-ADT) was assessed and managed in primary care.
METHOD
A retrospective multi-practice database study. PCa patients were identified using SNOMED codes from five sociodemographically diverse practices (registered population 49 400). Data were extracted by hand-searching records, including hospital letters, and included: demographics; a 10-year fragility fracture score (FRAX); NOGG intervention threshold; DEXA requests; and use of bisphosphonates.
RESULTS
Of the 261 PCa patients identified, 6% were Black African/Caribbean and 89% White British. Half had been prescribed ADT, 28% being current users. No fracture risk assessment was documented for any patients. ADT current users had significantly increased FRAX scores for both major osteoporotic fractures (MOF) (9.61%±1.12%) and hip fracture (HF) (5.30%±1.02%) compared with PCa patients without ADT (7.08%±0.57% [MOF] and 3.06%±0.46% [HF], <0.001). For ADT current users, 39% showed intermediate fracture risk (NOGG amber), warranting a DEXA scan, with only 30% performed. Patients in more affluent areas received more DEXA scans and bisphosphonate treatment.
CONCLUSION
Osteoporosis is underdiagnosed and undertreated in men with PCa-ADT, especially in those with deprived backgrounds. There is an unmet need to manage the fracture prevention in this population.
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Retrospective Studies; Aged; Risk Assessment; Osteoporotic Fractures; Primary Health Care; Bone Density Conservation Agents; United Kingdom; Middle Aged; Diphosphonates; Databases, Factual; Absorptiometry, Photon; Osteoporosis; Aged, 80 and over; Risk Factors
PubMed: 38902070
DOI: 10.3399/bjgp24X737637 -
Cancer Letters Jun 2024With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a...
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
PubMed: 38901665
DOI: 10.1016/j.canlet.2024.217068 -
Journal of Clinical Medicine May 2024The most common type of alopecia in women is female androgenetic alopecia (FAGA), characterized by progressive hair loss in a patterned distribution. Many oral... (Review)
Review
The most common type of alopecia in women is female androgenetic alopecia (FAGA), characterized by progressive hair loss in a patterned distribution. Many oral therapies, including spironolactone (an aldosterone antagonist), androgen receptor blockers (e.g., flutamide/bicalutamide), 5-alpha-reductase inhibitors (e.g., finasteride/dutasteride), and oral contraceptives, target the mechanism of androgen conversion and binding to its respective receptor and therefore could be administered for the treatment of FAGA. Despite significant advances in the oral treatment of FAGA, its management in patients with a history of gynecological malignancies, the most common cancers in women worldwide, may still be a concern. In this review, we focus on the safety of antiandrogens for the treatment of FAGA patients. For this purpose, a targeted literature review was conducted on PubMed, utilizing the relevant search terms. To sum up, spironolactone seems to be safe for the systemic treatment of FAGA, even in high-risk populations. However, a general uncertainty remains regarding the safety of other medications in patients with a history of gynecologic malignancies, and further studies are needed to evaluate their long-term safety in patients with FAGA and risk factors to establish an optimal risk assessment and treatment selection protocol.
PubMed: 38892763
DOI: 10.3390/jcm13113052 -
Cancer Science Jun 2024Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality...
Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality for advanced disease states, but it often leads to the development of resistance. Enzalutamide (Enz), a second-generation antiandrogen drug, initially offers substantial therapeutic benefit, but its efficacy wanes as drug resistance ensues. In this study, we found that synaptotagmin 4 (SYT4) is an upregulated gene in enzalutamide-resistant (EnzR) cell lines. The downregulation of SYT4, in combination with enzalutamide therapy, substantially enhances the antiproliferative effect on resistant prostate cancer cells beyond the capacity of enzalutamide monotherapy. SYT4 promotes vesicle efflux by binding to the synaptosome-associated protein 25 (SNAP25), thereby contributing to cell resistance against enzalutamide. The elevated expression of SYT4 is mediated by bromodomain-containing protein 4 (BRD4), and BRD4 inhibition effectively suppressed the expression of SYT4. Treatment with a therapeutic dose of enzalutamide combined with ASO-1, an antisense oligonucleotide drug targeting SYT4, shows promising results in reversing the resistance of prostate cancer to enzalutamide.
PubMed: 38889208
DOI: 10.1111/cas.16239 -
Cureus May 2024Bicalutamide, a nonsteroidal androgen receptor inhibitor, is an established therapeutic agent for advanced prostate cancer but is associated with severe cardiovascular...
Bicalutamide, a nonsteroidal androgen receptor inhibitor, is an established therapeutic agent for advanced prostate cancer but is associated with severe cardiovascular side effects in rare cases. This case report discusses a rare occurrence of severe systolic congestive heart failure (CHF) in a 68-year-old male undergoing treatment for advanced prostate cancer with bicalutamide, without concurrent use of gonadotropin-releasing hormone antagonists. The patient presented with non-specific abdominal and bilateral foot pain. The initial assessment indicated anemia and severe dyspnea, revealing a significant decrease in left ventricular ejection fraction (LVEF) from 55% to 15% on transthoracic echocardiography (TTE), indicative of severe CHF. Bicalutamide was identified as the likely culprit given the temporal association and lack of other identifiable causes, leading to its discontinuation and initiation of guideline-directed medical therapy (GDMT). A remarkable recovery of cardiac function was subsequently observed, with LVEF improving to 60%. The patient was managed with GDMT, and a gonadotropin-releasing hormone antagonist, degarelix, was later introduced for prostate cancer treatment, along with ongoing cardiac monitoring. The recovery of LVEF and the absence of other etiologies reinforce the likelihood of bicalutamide-induced cardiotoxicity. This report underscores the importance of vigilant cardiovascular monitoring in patients receiving bicalutamide, prompt identification of cardiac dysfunction and possible mechanisms of bicalutamide cardiotoxicity, and the potential for cardiac recovery upon drug discontinuation and initiation of GDMT.
PubMed: 38872672
DOI: 10.7759/cureus.60298 -
BMC Cancer Jun 2024This paper attempted to clarify the role and mechanism of vacuolar protein sorting-associated protein 72 homolog (VPS72) in the progression of prostate cancer (PCa).
BACKGROUND
This paper attempted to clarify the role and mechanism of vacuolar protein sorting-associated protein 72 homolog (VPS72) in the progression of prostate cancer (PCa).
METHODS
Clinical information and gene expression profiles of patients with prostate cancer were obtained from The Cancer Genome Atlas (TCGA). VPS72 expression in PCa and the potential mechanism by which VPS72 affects PCa progression was investigated. Next, we performed COX regression analysis to identify the independent prognostic factors of PCa, and constructed a nomogram. The sensitivity of chemotherapeutic medications was anticipated using "pRRophetic". Subsequently, in vitro assays to validate the effect of VPS72 on PCa cell proliferation, migration and susceptibility to anti-androgen therapy.
RESULTS
The expression of VPS72 was considerably higher in PCa tissues compared to normal tissues. Significant correlations were found between high VPS72 expression and a poor prognosis and adverse clinicopathological factors. The nomogram model constructed based on VPS72 expression has good predictive performance. According to GSEA, VPS72-related genes were enriched in the NF-kB pathways, cytokine-cytokine receptor interaction and chemokine signaling pathway in PCa. Although PCa with low VPS72 expression was more adaptable to chemotherapeutic medications, our in vitro experiment showed that VPS72 knockdown significantly decreased the PCa cell migration, proliferation, and resistance to anti-androgen therapy.
CONCLUSIONS
In summary our findings suggests that VPS72 could play a crucial role in the malignant progression of PCa, and its expression level can be employed as a possible biomarker of PCa prognosis.
Topics: Aged; Humans; Male; Middle Aged; Androgen Antagonists; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Nomograms; Prognosis; Prostatic Neoplasms; Vesicular Transport Proteins
PubMed: 38858662
DOI: 10.1186/s12885-024-12488-z -
JAMA Network Open Jun 2024Prostate cancer in Black men compared with White men may be more sensitive to radiation therapy resulting in better outcomes in equal-access settings. The outcomes of...
IMPORTANCE
Prostate cancer in Black men compared with White men may be more sensitive to radiation therapy resulting in better outcomes in equal-access settings. The outcomes of androgen-deprivation therapy (ADT) vs radiation therapy itself remains uncharacterized.
OBJECTIVES
To quantify any outcome modification by receipt of ADT on the association between Black race and prostate cancer outcomes following radiation therapy.
DESIGN, SETTING, AND PARTICIPANTS
This was a retrospective, nationwide cohort study of Black and White patients treated in the US Veterans Healthcare system between 2000 and 2020 receiving definitive radiation for localized prostate cancer. Data were analyzed from January 2000 to December 2020.
EXPOSURE
Patient self-identified race and use of ADT defined as any gonadotrophin-releasing hormone agonist or antagonist prescription within 6 months of radiation.
MAIN OUTCOMES AND MEASURES
Biochemical recurrence (BCR) from time of completion of radiation therapy (prostate-specific antigen nadir plus 2 ng/mL) and development of metastatic disease or prostate cancer mortality (PCSM) from time of recurrence.
RESULTS
A total of 26 542 patients (8716 Black men with median [IQR] age of 64 [59-69] years and 17 826 White men with median [IQR] age of 67 [62-72] years) received definitive radiation therapy for nonmetastatic prostate cancer and had complete staging and follow-up data. A total of 5144 patients experienced BCR (3384 White and 1760 Black patients). The cumulative incidence of BCR at 10 years was not significantly different between Black and White men (1602 [22.14%] vs 3099 [20.13%], respectively) with multivariable hazard ratio (HR) of 1.03 (95% CI, 0.97-1.09; P = .33). In men receiving ADT, Black men had an HR for BCR of 0.90 (95% CI, 0.82-0.99; P = .03) compared with White men, and in men not receiving ADT, Black men had an HR of 1.13 (95% CI, 1.05-1.22; P = .002). Black race was associated with a decreased risk of developing metastatic disease (HR, 0.90; 95% CI, 0.82-0.98; P = .02) or PCSM (subdistribution HR, 0.72; 95% CI, 0.63-0.82; P < .001) from time of biochemical recurrence.
CONCLUSIONS AND RELEVANCE
Black patients treated with radiation appear to specifically benefit from the addition of ADT with regard to biochemical control. Additionally, BCR in Black men results in a lower rate of metastatic disease and death from prostate cancer. Future analyses of radiosensitivity in Black men should evaluate for the possibility of outcome modification by ADT.
Topics: Humans; Male; Prostatic Neoplasms; Aged; Middle Aged; Retrospective Studies; Androgen Antagonists; Black or African American; White People; United States; Treatment Outcome; Neoplasm Recurrence, Local
PubMed: 38857047
DOI: 10.1001/jamanetworkopen.2024.15911 -
Journal of the Endocrine Society May 2024Apalutamide (APT) is a nonsteroidal antiandrogen medication used to treat metastatic castrate-sensitive and nonmetastatic castrate-resistant prostate cancer. Early...
CONTEXT
Apalutamide (APT) is a nonsteroidal antiandrogen medication used to treat metastatic castrate-sensitive and nonmetastatic castrate-resistant prostate cancer. Early clinical trials of APT identified thyroid dysfunction as a common adverse effect of therapy, but the clinical presentation and management of APT-induced hypothyroidism has not been studied.
OBJECTIVE
The objective of our study is to elucidate the clinical presentation and treatment approach of APT-associated thyroid dysfunction in prostate cancer patients.
METHODS
We report a case series of 16 patients with APT-associated thyroid dysfunction during prostate cancer treatment at 2 academic medical centers. Patient clinical parameters, thyroid function laboratory data, and thyroid hormone requirements over the course of APT treatment were analyzed.
RESULTS
Among the 16 patients in our case series with APT-associated hypothyroidism, 3 had no prior thyroid disease and 13 had preexisting hypothyroidism. The patterns of thyroid dysfunction included overt and subclinical hypothyroidism. The median time from APT initiation to thyroid function test abnormality was 19 weeks, but occurred in some cases as early as 2 to 4 weeks. Hypothyroidism was effectively managed with thyroid hormone replacement using levothyroxine (LT4), though some patients with preexisting hypothyroidism required a 2- to 3-fold dose increase while on APT to achieve a euthyroid state. In the subset of patients who completed or stopped APT therapy, thyrotropin levels fell at a median of 11 weeks post APT therapy and thyroid hormone requirements decreased to near pre-APT levels.
CONCLUSION
APT-associated thyroid dysfunction presents as new or worsening hypothyroidism and should prompt initiation or increase in thyroid hormone replacement. Monitoring of thyroid function tests is recommended every 1 to 2 months for all patients on APT and 2 to 3 months after completion of APT.
PubMed: 38854906
DOI: 10.1210/jendso/bvae105 -
Journal of Drugs in Dermatology : JDD Jun 2024Clascoterone cream 1% is a topical androgen receptor inhibitor approved to treat acne vulgaris in patients =>12 years of age. This report provides details of patients...
BACKGROUND
Clascoterone cream 1% is a topical androgen receptor inhibitor approved to treat acne vulgaris in patients =>12 years of age. This report provides details of patients who developed laboratory signs of hypothalamic-pituitary-adrenal (HPA) axis suppression without clinical signs of adrenal suppression during the clascoterone development program.
METHODS
Two open-label, multicenter, Phase 2 trials evaluated HPA axis suppression in patients with moderate-to-severe acne vulgaris. Study 1 (NCT01831960) enrolled cohorts of adults =>18 years of age and adolescents =>12 to <18 years of age. Study 2 (NCT02720627) enrolled adolescents 9 to <12 years of age. Patients applied clascoterone twice daily at maximum-exposure dosages for 14 days. Adrenal suppression was evaluated via cosyntropin stimulation test (CST) at baseline and day 14. Patients with an abnormal CST result (serum cortisol level =<18 µg/dL) had a follow-up CST approximately 4 weeks later. Blood was collected for pharmacokinetic analysis. Other safety assessments included adverse events (AEs), physical examination/vital signs, and electrocardiography.
RESULTS
Overall, 5/69 clascoterone-treated patients had an abnormal CST result on day 14, including 1/20 adults, 2/22 patients aged =>12 to <18 years, and 2/27 patients aged 9 to <12 years. All patients had normal cortisol levels at follow-up testing approximately 4 weeks later. No relationship was observed between abnormal CST results and clascoterone plasma concentrations or the amount of study drug applied. No clinically relevant AEs or clinically significant changes in safety measures were observed in patients with adrenal suppression.
CONCLUSION
Clascoterone induced laboratory evidence of mild, reversible HPA axis suppression under maximum-use exposure. J Drugs Dermatol. 2024;23(6):433-437. doi:10.36849/JDD.7997.
Topics: Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Acne Vulgaris; Adolescent; Male; Female; Adult; Child; Young Adult; Hydrocortisone; Cortodoxone; Administration, Cutaneous; Skin Cream; Androgen Receptor Antagonists; Treatment Outcome; Cosyntropin; Propionates
PubMed: 38834220
DOI: 10.36849/JDD.7997 -
JAMA Network Open Jun 2024It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with...
IMPORTANCE
It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with adverse consequences.
OBJECTIVE
To report transitions to androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC), death from PCa, or death from other causes in men treated with a WW strategy.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide, population-based cohort study included men with nonmetastatic PCa diagnosed since 2007 and registered in the National Prostate Cancer Register of Sweden with WW as the primary treatment strategy and with life expectancy less than 10 years. Life expectancy was calculated based on age, the Charlson Comorbidity Index (CCI), and a drug comorbidity index. Observed state transition models complemented observed data to extend follow-up to more than 20 years. Analyses were performed between 2022 and 2023.
EXPOSURE
Nonmetastatic PCa.
MAIN OUTCOMES AND MEASURES
Transitions to ADT, CRPC, death from PCa, and death from other causes were measured using state transition modeling.
RESULTS
The sample included 5234 men (median [IQR] age at diagnosis, 81 [79-84] years). After 5 years, 954 men with low-risk PCa (66.2%) and 740 with high-risk PCa (36.1%) were still alive and not receiving ADT. At 10 years, the corresponding proportions were 25.5% (n = 367) and 10.4% (n = 213), respectively. After 10 years, 59 men with low-risk PCa (4.1%) and 221 with high-risk PCa (10.8%) had transitioned to CRPC. Ten years after diagnosis, 1330 deaths in the low-risk group (92.3%) and 1724 in the high-risk group (84.1%) were from causes other than PCa.
CONCLUSIONS AND RELEVANCE
These findings suggest that the WW management strategy is appropriate for minimizing adverse consequences of PCa in men with a baseline life expectancy of less than 10 years.
Topics: Humans; Male; Watchful Waiting; Aged; Prostatic Neoplasms; Sweden; Aged, 80 and over; Androgen Antagonists; Cohort Studies; Life Expectancy; Registries; Prostatic Neoplasms, Castration-Resistant; Disease Progression
PubMed: 38833251
DOI: 10.1001/jamanetworkopen.2024.14599