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Radiation Oncology (London, England) Aug 2023Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to...
BACKGROUND
Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach.
METHODS
A retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET.
RESULTS
103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures.
CONCLUSION
PSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years.
Topics: Male; Humans; Prostatic Neoplasms; Treatment Outcome; Prostate-Specific Antigen; Androgen Antagonists; Retrospective Studies; Radiosurgery; Neoplasm Recurrence, Local; Positron-Emission Tomography; Positron Emission Tomography Computed Tomography
PubMed: 37528487
DOI: 10.1186/s13014-023-02302-8 -
International Journal of Molecular... Feb 2024Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular... (Review)
Review
Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular treatment and result in resistant and aggressive disease. These breast cancers usually have fewer treatment options. Targeted therapies for cancer patients may offer fewer adverse side effects because of specificity compared to conventional chemotherapy. Signaling pathways of nuclear receptors, such as the estrogen receptor (ER), have been intensively studied and used as therapeutic targets. Recently, the role of the androgen receptor (AR) in breast cancer is gaining greater attention as a therapeutic target and as a prognostic biomarker. The expression of constitutively active truncated AR splice variants in breast cancer is a possible mechanism contributing to treatment resistance. Therefore, targeting both the full-length AR and AR variants, either through the activation or suppression of AR function, depending on the status of the ER, progesterone receptor, or human epidermal growth factor receptor 2, may provide additional treatment options. Studies targeting AR in combination with other treatment strategies are ongoing in clinical trials. The determination of the status of nuclear receptors to classify and identify patient subgroups will facilitate optimized and targeted combination therapies.
Topics: Humans; Male; Receptors, Androgen; Breast Neoplasms; Androgen Receptor Antagonists; Prostatic Neoplasms, Castration-Resistant
PubMed: 38339092
DOI: 10.3390/ijms25031817 -
Pharmacological Research May 2024In American men, the incidence of prostate cancer (PC) is the highest among all types of cancer, making it the second leading cause of mortality associated with cancer.... (Review)
Review
In American men, the incidence of prostate cancer (PC) is the highest among all types of cancer, making it the second leading cause of mortality associated with cancer. For advanced or metastatic PC, antiandrogen therapies are standard treatment options. The administration of these treatments unfortunately carries the potential risk of inducing neuroendocrine prostate cancer (NEPC). Neuroendocrine differentiation (NED) serves as a crucial indicator of prostate cancer development, encompassing various factors such as phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), Yes-associated protein 1 (YAP1), AMP-activated protein kinase (AMPK), miRNA. The processes of autophagy and ferroptosis (an iron-dependent form of programmed cell death) play pivotal roles in the regulation of various types of cancers. Clinical trials and preclinical investigations have been conducted on many signaling pathways during the development of NEPC, with the deepening of research, autophagy and ferroptosis appear to be the potential target for regulating NEPC. Due to the dual nature of autophagy and ferroptosis in cancer, gaining a deeper understanding of the developmental programs associated with achieving autophagy and ferroptosis may enhance risk stratification and treatment efficacy for patients with NEPC.
Topics: Humans; Ferroptosis; Autophagy; Male; Prostatic Neoplasms; Animals; Signal Transduction; Antineoplastic Agents; Neuroendocrine Tumors
PubMed: 38554788
DOI: 10.1016/j.phrs.2024.107162 -
European Journal of Cancer (Oxford,... Oct 2023For about a decade, poly [ADP ribose] polymerases (PARP) inhibitors have been used almost exclusively to treat tumours that are deficient in one of the BRCA genes. In... (Review)
Review
For about a decade, poly [ADP ribose] polymerases (PARP) inhibitors have been used almost exclusively to treat tumours that are deficient in one of the BRCA genes. In advanced prostate cancer, which is largely driven by the activity of the androgen receptor (AR), accumulating preclinical evidence has suggested an interplay between the AR and PARP, which could be therapeutically exploited independently of defects in the tumour's DNA homologous recombination repair (HRR) machinery. This includes the regulation of HRR genes by the AR, a mutual influence between the activities of PARP and the AR, and the co-localisation of BRCA2 to the retinoblastoma gene in the human genome. Based on these findings, randomised clinical trials have been initiated to study the addition of a PARP inhibitor to AR pathway inhibitor therapy. Three of four randomised studies demonstrated a significantly increased anti-tumour activity in men with metastatic prostate cancer, irrespective of HRR gene alterations. In this review, we summarise the available preclinical evidence that provides the rationale for the combination of inhibitors for PARP and the AR and discuss how it might contribute to the efficacy observed in the clinic.
Topics: Male; Humans; Poly(ADP-ribose) Polymerases; Receptors, Androgen; Androgens; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Androgen Receptor Antagonists; Adenosine Diphosphate Ribose; Biology; Randomized Controlled Trials as Topic
PubMed: 37672815
DOI: 10.1016/j.ejca.2023.113249 -
JAMA Network Open Sep 2023Hormonal contraception has been linked to mood symptoms and the ability to recognize emotions after short periods of treatment, whereas the mental health of users of...
IMPORTANCE
Hormonal contraception has been linked to mood symptoms and the ability to recognize emotions after short periods of treatment, whereas the mental health of users of long-term hormonal contraceptives has had limited investigation.
OBJECTIVE
To evaluate whether short-term hormonal withdrawal, which users of combined oral contraceptives (COCs) undergo once a month (pill pause), was associated with altered mood and emotional recognition in long-term users of COCs.
DESIGN, SETTING, AND PARTICIPANTS
This case-control study included a community sample of individuals assigned female sex at birth who identified as women and used COC for 6 months or longer. The control group included women with natural menstrual cycles who otherwise fulfilled the same inclusion criteria. The study was conducted between April 2021 and June 2022 in Salzburg, Austria.
EXPOSURE
COC users and women with natural menstrual cycles were tested twice within a month, once during their active pill phase or luteal phase and once during their pill pause or menses.
MAIN OUTCOMES AND MEASURES
Negative affect, anxiety, and mental health problems were assessed during each session. The percentage increase in mental health symptoms was calculated during the pill pause compared with that during the active intake phase in COC users. How this change compared with mood fluctuations along the menstrual cycle in women with natural menstrual cycles was assessed.
RESULTS
A total of 181 women aged 18 to 35 years (mean [SD] age, 22.7 [3.5] years) were included in the analysis (61 women with androgenic COC use, 59 with antiandrogenic COC use, 60 women with a menstrual cycle not taking COCs). COC users showed a 12.67% increase in negative affect (95% CI, 6.94%-18.39%), 7.42% increase in anxiety (95% CI, 3.43%-11.40%), and 23.61% increase in mental health symptoms (95% CI, 16.49%-30.73%; P < .001) during the pill pause compared with the active intake phase. The effect size of this change did not differ depending on progestin type (negative affect: F1,117 = 0.30, P = .59; state anxiety: F1,117 = 2.15, P = .15; mental health: F1,117 = .16, P = .69) or ethinylestradiol dose (negative affect: F1,57 = .99, P = .32; state anxiety: F1,57 = 2.30, P = .13; mental health: F1,57 = .14, P = .71) was comparable with mood changes along the menstrual cycle in women with natural cycles (negative affect: F2,175 = 0.13, P = .87; state anxiety: F2,175 = 0.14, P = .32; mental health: F2,175 = 0.65, P = .52). Mood worsening during the pill pause was more pronounced in women with higher baseline depression scores (negative affect increase of 17.95% [95% CI, 7.80%-28.10%] in COC users with higher trait depression [BDI >8]). Emotion recognition performance did not differ between active pill phase and pill pause.
CONCLUSIONS AND RELEVANCE
In this case-control study of long-term COC users, withdrawal from contraceptive steroids during the pill pause was associated with adverse mental health symptoms similar to those experienced by women during menses with withdrawal from endogenous steroids. These results question the use of the pill pause from a mental health perspective. Long-term COC users may benefit more from the mood-stabilizing effects of COCs in cases of continuous intake.
Topics: Infant, Newborn; Female; Humans; Young Adult; Adult; Mental Health; Case-Control Studies; Contraceptives, Oral, Combined; Contraception; Hormones
PubMed: 37755829
DOI: 10.1001/jamanetworkopen.2023.35957 -
Endocrine Sep 2023The selective androgen receptor modulator ostarine has been shown to have advantageous effects on skeletal tissue properties, reducing muscle wasting and improving...
PURPOSE
The selective androgen receptor modulator ostarine has been shown to have advantageous effects on skeletal tissue properties, reducing muscle wasting and improving physical function in males. However, data on effects in male osteoporosis remain limited. In this study, the effects of ostarine on osteoporotic bone were evaluated in a rat model of male osteoporosis and compared with those of testosterone treatments.
METHODS
Eight-month-old male Sprague-Dawley rats were either non-orchiectomized to serve as a healthy control (Non-Orx, Group 1) or orchiectomized (Orx, Groups 2-6) and then grouped (n = 15/group): (1) Non-Orx, (2) Orx, (3) Ostarine Therapy, (4) Testosterone Therapy, (5) Ostarine Prophylaxis and (6) Testosterone Prophylaxis. Prophylaxis treatments started directly after orchiectomy and continued for 18 weeks, whereas Therapy treatments were initiated 12 weeks after Orx. Ostarine and Testosterone were applied orally at daily doses of 0.4 and 50 mg/kg body weight, respectively. The lumbar vertebral bodies and femora were analyzed using biomechanical, micro-CT, ashing, and gene expression analyses.
RESULTS
Ostarine Prophylaxis showed positive effects in preventing osteoporotic changes in cortical and trabecular bone (femoral trabecular density: 26.01 ± 9.1% vs. 20.75 ± 1.2% in Orx and in L4: 16.3 ± 7.3% vs 11.8 ± 2.9% in Orx); biomechanical parameters were not affected; prostate weight was increased (0.62 ± 0.13 g vs 0.18 ± 0.07 g in Orx). Ostarine Therapy increased solely the cortical density of the femur (1.25 ± 0.03 g/cm vs. 1.18 ± 0.04 g/cm in Orx); other bone parameters remained unaffected. Testosteron Prophylaxis positively influenced cortical density in femur (1.24 ± 0.05 g/cm vs. 1.18 ± 0.04 g/cm in Orx); Test. Therapy did not change any bony parameters.
CONCLUSION
Ostarine Prophylaxis could be further investigated as a preventative treatment for male osteoporosis, but an androgenic effect on the prostate should be taken into consideration, and combination therapies with other anti-osteoporosis agents could be considered.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Receptors, Androgen; Bone Density; Osteoporosis; Androgens; Testosterone; Androgen Antagonists; Orchiectomy
PubMed: 37378829
DOI: 10.1007/s12020-023-03422-7 -
European Urology Jul 2024The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC.
METHODS
Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation.
KEY FINDINGS AND LIMITATIONS
Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51-1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92-1.42).
CONCLUSIONS AND CLINICAL IMPLICATIONS
There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings.
Topics: Humans; Male; Prostatic Neoplasms; Network Meta-Analysis; Androgen Antagonists; Randomized Controlled Trials as Topic; Neoplasm Metastasis
PubMed: 38570246
DOI: 10.1016/j.eururo.2024.03.018 -
JMIR Research Protocols Dec 2023Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments...
BACKGROUND
Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT.
OBJECTIVE
This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT.
METHODS
This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated.
RESULTS
This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication.
CONCLUSIONS
The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/53092.
PubMed: 38133914
DOI: 10.2196/53092 -
Clinical Nutrition ESPEN Dec 2023Exercise is known to reduce adverse side effects of androgen-deprivation therapy (ADT) on quality of life, bone health and fatigue for prostate cancer (PCa) patients. We... (Meta-Analysis)
Meta-Analysis
Efficacy of multidisciplinary interventions in preventing metabolic syndrome and improving body composition in prostate cancer patients treated with androgen deprivation therapy: A systematic review and meta-analysis.
BACKGROUND
Exercise is known to reduce adverse side effects of androgen-deprivation therapy (ADT) on quality of life, bone health and fatigue for prostate cancer (PCa) patients. We conducted a systematic review with meta-analysis to evaluate the effect of multidisciplinary interventions on body composition and metabolic syndrome (MetS) in ADT-treated PCa patients.
METHODS
A systematic review and meta-analysis were conducted based on searches of EMBASE, MEDLINE, CENTRAL and Scopus databases from inception to March 2023. Participants included ADT-treated PCa patients who received multidisciplinary interventions including exercise, diet, nutrition, pharmacotherapy, bariatric surgery, or psychological/behavioural therapy. Primary outcomes were changes in body composition and MetS, with prostate-specific antigen (PSA) as a secondary outcome. After meta-analysis, results were reported in mean difference, 95% confidence interval and p-value, with forest plots. Additionally, we conducted subgroup analyses to compare the effect of different interventions.
RESULTS
Thirty-three articles met the eligibility criteria out of 1443 articles and 28 studies were included in meta-analysis. Of 33 studies, 17 included exercise-only interventions and 10 included exercise + diet/nutrition interventions, but no studies included diet/nutrition-only interventions. All studies employed multidisciplinary approaches in developing or delivering the interventions. Most studies (85%) had low-moderate risk of bias, thus providing good evidence to this review. Overall, interventions had a positive effect on body composition measures; lean mass (LM):0.82 kg (95% CI:0.47,1.17;p < 0.00001), body fat mass (BFM):-0.68 kg (95% CI:-1.12,-0.24;p = 0.002), fat-free mass:0.75 kg (95% CI:0.14,1.37;p = 0.02) and body fat percentage (BFP):-0.99% (95% CI:-1.29,-0.68;p < 0.00001), as well as on MetS; waist circumference:-1.95 cm (95% CI:-3.10,-0.79;p = 0.0009), systolic blood pressure:-3.43 mmHg (95% CI:-6.36,-0.50;p = 0.02) and diastolic blood pressure:-2.48 mmHg (95% CI:-4.19,-0.76;p = 0.005). Subgroup-analyses showed that a combined approach including exercise + diet/nutrition was most effective in improving BFP, WC, SBP and DBP whereas exercise was more effective in improving LM and BFM.
CONCLUSIONS
In ADT-treated PCa patients, multidisciplinary interventions, especially those combining exercise and diet/nutrition, can improve body composition and metabolic health.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Metabolic Syndrome; Quality of Life; Body Composition
PubMed: 38057016
DOI: 10.1016/j.clnesp.2023.09.001 -
Cell Reports Jan 2024Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment is androgen deprivation therapy....
Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment is androgen deprivation therapy. Unfortunately, despite initial treatment response, resistance nearly always develops, and disease progresses to castration-resistant prostate cancer (CRPC), which remains driven by non-gonadal androgens synthesized in prostate cancer tissues. 3β-Hydroxysteroid dehydrogenase/Δ isomerase 1 (3βHSD1) catalyzes the rate-limiting step in androgen synthesis. However, how 3βHSD1, especially the "adrenal-permissive" 3βHSD1(367T) that permits tumor synthesis of androgen from dehydroepiandrosterone (DHEA), is regulated at the protein level is not well understood. Here, we investigate how hypoxia regulates 3βHSD1(367T) protein levels. Our results show that, in vitro, hypoxia stabilizes 3βHSD1 protein by suppressing autophagy. Autophagy inhibition promotes 3βHSD1-dependent tumor progression. Hypoxia represses transcription of autophagy-related (ATG) genes by decreasing histone acetylation. Inhibiting deacetylase (HDAC) restores ATG gene transcription under hypoxia. Therefore, HDAC inhibition may be a therapeutic target for hypoxic tumor cells.
Topics: Male; Humans; Androgens; Prostatic Neoplasms; Androgen Antagonists; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Cell Line, Tumor
PubMed: 38181788
DOI: 10.1016/j.celrep.2023.113575