Hormone Therapy For Prostate Cancer Research Articles

Stability analysis on a hybrid PDE–ODE system describing intermittent hormonal therapy of prostate cancer

We consider the stability of control prescribed by hybrid PDE–ODE systems modeling intermittent hormonal therapy of prostate cancer. Hybrid systems can be regarded as a generalization of optimal control. However, since the purpose of hybrid systems is not only minimization or maximization of a corresponding functional, it is not clear what is optimal in hybrid systems. In this paper, we shall give a concept of stability of the control prescribed by the hybrid PDE–ODE systems. Moreover, we show a sufficient condition on initial data for the existence of the stable control. Finally, we apply the main result to several mathematical models describing intermittent hormonal therapy of prostate cancer.

Managing Male Mammary Maladies.

This review examines the symptoms, need for referral and management of the benign breast conditions which afflict males, together with the steps that are necessary to exclude or confirm male breast cancer. The most common complaint is gynaecomastia, either true or pseudo, and the majority of these cases need reassurance without over-investigation. Drugs that induce breast enlargement are described in order that, when possible, a medication switch can be made. Men receiving endocrine therapy for prostate cancer may develop painful gynaecomastia and this can be relieved with tamoxifen. All men with breast cancer need mammography as part of their work-up but this should not be used as a screening technique for symptomatic males. Because of lack of lobular development, both cysts and fibroadenomas are very rare in men; but those with nipple discharge need referral and investigation as some will have underlying malignancy.

Maintaining Bone Health During Hormonal Therapy for Prostate Cancer.

Alibhai and colleagues report a systematic review of therapies to maintain bone health in patients receiving hormonal therapy for prostate cancer. The editorialists discuss the findings and the nee...

Prognostic significance of the digit ratio after hormone therapy for prostate cancer: a prospective multicenter study

The digit ratio has been used as a retrospective noninvasive biomarker to investigate the putative effects of prenatal exposure to androgens. In recent years, many scholars have paid attention to the association between 2D:4D (the second and fourth digits) and prostatic cancer. This study explored the prognostic significance of digit ratio in prostate cancer patients. We reviewed the progressive status and survival of 382 prostate cancer patients who had received hormone therapy at our institutions. Survival of clinicopathological variables analyzed as categorical variables were determined by the log-rank test. According to Cox’s proportional hazards analysis, R2D:4D, L2D:4D, PSA at 6 month,bone metastasis were significant independent factors for prostate cancer. The risk of any progression of prostate cancer similarly depressed with increasing 2D:4D, for any progression (R2D:4D HR = 0.71, p = 0.003; L2D:4D HR = 0.67, p = 0.001), for cancer-specific death (R2D:4D HR = 0.67, p = 0.025; L2D:4D HR = 0.74, p = 0.036). Digit ratio may not only have predictive value in risk but also prognosis of prostatic cancer. This finding suggests that low 2D:4D can be used as prognostic factors to identify patients with a poor prognosis. These patients may benefit from more aggressive management.

Study on the choice of medication time and with drawal time of intermittent endocrine therapy for prostate cancer

Objective: To determine the best timing of discontinuance of intermittent endocrine therapy for prostate cancer (PCa). Methods: From February 2012 to September 2014, 120 PCa patients confirmed by biopsy at the Department of Urology Surgery, Beijing Shijitan Hospital Affiliated to Capital Medical University, were included. They were divided into high-, moderate- and low-risk groups according to EAU Guidelines in 2015. All patients received intermittent endocrine therapy. When the serum level of prostate-specific antigen (PSA) dropped to 0.2 μg/L, the medication was not discontinued until 3 months later for the observation group; however, the medication was immediately discontinued after reaching the above-mentioned threshold for the control group. When the PSA level during the period of medication discontinuance increased to 4 μg/L, another course of intermittent endocrine therapy was administered until the occurrence of the failure event. The Cox proportional regression model was used to compare the difference between the two groups in the androgen-independent signs, progression of PCa and severe adverse events. Result: After correction for multiple confounding factors, including severity grading before treatment, average duration of medication, average duration of medication discontinuance and the number of courses of therapy, it was found that the medication scheme adopted in the observation group was a protective factor against androgen-independent signs in the high-risk PCa patients (HR: 0.535, 95% CI: 0.458-0.612; P<0.001); it was also a protective factor against disease progression for the high- and moderate-risk patients (high-risk group, HR: 0.387, 95% CI: 0.297-0.477; P<0.001; moderate-risk group, HR: 0.697, 95% CI: 0.581-0.813; P<0.001). However, there was no significant difference in the incidence of severe adverse events among PCa patients treated by different medication schemes (HR: 1.003, 95% CI: 0.906-1.100; P=0.798). The medication scheme adopted in the observation group was an independent risk factor for severe adverse events in the low-risk PCa patients (HR: 1.489, 95% CI: 1.305-1.673; P<0.001). Conclusion: As compared with the scheme of immediately discontinuing the medication after reaching the indicator threshold, maintenance medication for another 3 months was beneficial for the high- and moderate-risk PCa cases. The maintenance medication could reduce the androgen-independent signs and disease progression, without increasing the risk of severe adverse events. However, for the low-risk patients, there was no major difference between the two medication schemes, immediate discontinuance and maintenance medication for another 3 months. Instead, further medication may bring about a higher risk of severe adverse events.

Hormone therapy for prostate cancer increases the risk of Alzheimer’s disease: a nationwide 4-year longitudinal cohort study

Introduction: Androgen-deprivation therapy (ADT) is recognized to be the preferred first-line treatment for advanced prostate cancer. However, the risk–benefit ratio of ADT remains poorly defined and the relationship between androgen depletion and dementia is not clear.Aim: To investigate the risk of developing Alzheimer’s disease (AD) in patients undergoing ADT for prostate cancer.Methods: Data from 24 360 prostate cancer patients were collected from the Longitudinal Health Insurance Database of Taiwan. In total, 15 959 patients who underwent ADT were included in the study cohort, and another 8401 patients who did not receive ADT were included as a non-ADT cohort.Results: During the average 4-year follow-up period, the incidence of AD was 2.78 per 1000 person-years in the non-ADT cohort and 5.66 per 1000 person-years in the ADT cohort. After adjusting for age and all comorbidities, the combined ADT cohort was found to be 1.84 times more likely to develop AD than the non-ADT control group (95%CI 1.33–2.55, p < 0.001).Conclusions: The present results suggest that ADT use is associated with an increased risk of developing AD.

Resistance to Hormonal Therapy in Prostate Cancer.

Several therapeutic strategies are actually available in the management of prostate cancer: Targeting the androgen receptor (AR) is the goal both for initial androgen deprivation therapy (ADT) and second-generation androgen ablative agents (abiraterone and enzalutamide). Chemotherapy with taxanes, administered upon progression or as first line approach in association with ADT, is another therapeutic option. Unfortunately, none of these therapies is curative and patients are destined to develop a resistant phenotype.Progression to ADT leads to the attainment of a castration resistant disease whose mechanisms remain incompletely understood. Reactivation of AR has been shown to occur and second-generation of AR targeting drugs are usually prescribed. Upon progression to these agents AR signaling still remains the primary driver although it often becomes ligand independent, since it can be either restored through mutations on the ligand binding domain and/or formation of AR splicing variants or by passed through a cross talk with other oncogenic signaling pathways.AR-independent signaling pathways may represent additional mechanisms underlying castration resistant progression. It is clear that castration resistant prostate cancer is a group of diverse diseases and new treatment paradigms need to be developed.

18F-Fluorocholine PET/CT of Incidental Male Breast Cancer

Breast cancer is approximately 100 times less common among men. Estrogen-related receptor α was detected in human prostate cancer tissue, and androgen receptors are expressed in both normal and malignant breast tissue. Thus, prostate cancer hormonal therapy may increase breast cancer risk. A 67-year-old man with prostate cancer history presented with rising prostate-specific antigen level. F-Fluorocholine PET/CT showed intense uptake in his right breast and moderate uptake in right axillary lymph node. Complementary F-FDG PET/CT demonstrated more intense tracer uptakes in both the right breast and axillary lymph node. Breast histological findings were invasive ductal cancer, with axillary lymph node invasion.

P14.07 Posterior reversible encephalopathy syndrome and new hormone therapy for prostate cancer

P14.07 Posterior reversible encephalopathy syndrome and new hormone therapy for prostate cancer

Next generation sequencing panels to predict response to hormonal therapy in prostate cancer

Next generation sequencing panels to predict response to hormonal therapy in prostate cancer

881 - Urine biomarker profiling contains structure and predicts prostate cancer hormone therapy relapse

881 - Urine biomarker profiling contains structure and predicts prostate cancer hormone therapy relapse

Rapid progression of mixed neuroendocrine carcinoma-acinar adenocarcinoma of the prostate: A case report.

The current study presents the case of a 78-year-old male with mixed neuroendocrine (NE) carcinoma-acinar adenocarcinoma of the prostate. The patient received endocrine therapy (maximal androgen blockade) after the initial diagnosis resulting in a significant decrease in serum prostate-specific antigen (PSA) level. The patient underwent transurethral resection of the prostate after 6 months of androgen-deprivation therapy for extraordinarily salient difficulty in urination, and histopathology demonstrated mixed NE carcinoma-acinar adenocarcinoma once again. The NE prostate cancer progressed rapidly even though the serum PSA was controlled at a low level on account of the endocrine therapy. Previous treatment protocols were replaced by combined chemotherapy and endocrine therapy, and the patient responded well. The patient's serum PSA remained at a low level, however, urethral dilatation for acute urinary retention was required again 5 months later and the lower urinary tract symptoms became increasingly evident. The patient eventually died of cachexia.. These findings indicate that mixed NE carcinoma-acinar adenocarcinoma has a higher degree of malignancy and that endocrine therapy for prostate cancer has a propensity to facilitate progression of this tumor.

Endometriosis of the Bladder

Endometriosis is characterized by the presence of functional endometrial tissue outside the uterus. Endometriosis is common entity, but the involvement of the urinary tract is rare (1). Although endometriosis frequently occurs in women of reproductive age, bladder endometriosis is an uncommon condition (approximately 1% of all endometriosis cases). On the other hand, the bladder is the most affected organ in the urinary tract (2). Two forms of bladder endometriosis have been defined: One occurs in women without a history of uterine surgery (primary), and the other one develops after pelvic operation (iatrogenic or secondary) (3). The average age of cases is approximately 35 years. Frequency, hematuria, dysuria and urgency are the most common symptoms, however, approximately 50% of patients are asymptomatic. Severity of symptoms is related to the size of endometriotic lesions and the location. Endometriosis of the muscularis propria may show similar symptoms to those of interstitial cystitis. There is a palpable suprapubic mass in almost 50% of cases, and it may undergo catamenial expansion. Therefore, it must be kept in mind in the differential diagnosis of hematuria especially in female patients in the reproductive age (4,5). Rarely, endometriosis has been described in postmenopausal female patients treated with estrogen, likewise in men treated with hormone therapy for prostate cancer (5). Cystoscopic examination of endometriosis reveals edematous, erythematous mucosal elevations overlying blue-black or red-blue cysts, a grossly hemorrhagic, ill-defined, polypoid lesion. The overlying urothelium sometimes may be eroded. If the lesions are located in the muscularis propria or serosa, the mucosa may be intact. The bladder wall around the lesion may be thickened because of hyperplasia and fibrosis (1). Microscopically, the lesion is consisted of endometrial glands and stroma which is identical endometriosis as seen elsewhere (Figure 1). The diagnosis depends on identification Tepecik Training and Research Hospital, Clinic of Pathology, Izmir Turkey Mesanenin Endometriozisi

Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting.

While there are myriad mechanisms of primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer, the potential role of androgen receptor splice variants (AR-Vs) has recently gained momentum. AR-Vs are abnormally truncated isoforms of the androgen receptor (AR) protein that lack the COOH-terminal domain but retain the NH2-terminal domain and DNA-binding domain and are thus constitutively active even in the absence of ligands. Although multiple preclinical studies have previously implicated AR-Vs in the development of castration resistance as well as resistance to abiraterone and enzalutamide, recent technological advances have made it possible to reliably detect and quantify AR-Vs from human clinical tumor specimens including blood samples. Initial clinical studies have now shown that certain AR-Vs, in particular AR-V7, may be associated with resistance to abiraterone and enzalutamide but not taxane chemotherapies when detected in circulating tumor cells. Efforts are now underway to clinically validate AR-V7 as a relevant treatment-selection biomarker in the context of other key genomic aberrations in men with metastatic castration-resistant prostate cancer. Additional efforts are underway to therapeutically target both AR and AR-Vs either directly or indirectly. Whether AR-Vs represent drivers of castration-resistant prostate cancer, or whether they are simply passenger events associated with aggressive disease or clonal heterogeneity, will ultimately be answered only through these types of clinical trials.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

SummaryBackgroundLong-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.MethodsStandard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).Findings2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.InterpretationZoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.FundingCancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Clinical significance of D4A in prostate cancer therapy with abiraterone

Androgen deprivation therapy (ADT), either by surgical or medical castration depletes testicular production of testosterone (T) and has long been considered as the mainstay of upfront treatment for advanced prostate cancer. Despite the initial response to this treatment, disease progression to castration-resistant prostate cancer (CRPC) usually occurs. The adrenal production of androgen precursor steroids, such as dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), permits intratumoral production of T and 5α-dihydrotestosterone (DHT), activation of androgen receptor (AR) and AR-dependent gene expression. Abiraterone (Abi; given as Abi acetate) and enzalutamide (Enz) are 2 of the agents that target different parts of the androgen pathway by blocking androgen production and signaling, ultimately improving overall survival for patients with metastatic CRPC.1,2 Abi is a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), which is a key enzyme required for DHEA and DHEA-S production. Synthesis of DHT, the most potent androgen, from DHEA necessitates a series of enzymes, including 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A), and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. This process enables the conversion of ADT-responsive prostate cancer into CRPC. Multiple retrospective reviews have shown the limited efficacy of Enz after Abi treatment failure and vice versa.3,4 To date there are very little data on the appropriate sequence of Enz and Abi utilization, which might thereby maximize the potential efficacy and duration of response to treatment with these agents. Our recently published research demonstrates that Δ4, 3-keto-abi (D4A) is a metabolite of Abi that is formed in patients with prostate cancer and has CYP17A1 inhibition activity that is comparable to Abi.5 Furthermore, D4A inhibits 3βHSD (a key enzyme involved in CRPC progression) more potently than Abi and at higher concentrations it demonstrates significant SRD5A inhibitory effects as well. Moreover, although Abi has been shown to have AR antagonistic activity,6 we observed more potent AR inhibition activity with D4A that is comparable to Enz in our experiments.5 As a result, by targeting multiple steps of the AR signaling pathway, D4A showed a significant increase in progression free survival compared to Abi and Enz in our xenograft models, suggesting that it might play an important role in the clinical activity of Abi in CRPC patients. Abi is converted to D4A by 3βHSD. Increased 3βHSD enzymatic function, with the HSD3B1(1245C) genetic variant encoding a missense in 3βHSD1 as one known mechanism, also increases intratumoral flux to DHT that may result in the development of treatment resistance.7 Therefore, D4A conversion ratio could serve as an indicator of 3βHSD activity and ultimately may predict resistance to hormonal therapy for prostate cancer. On the other hand, higher 3βHSD activity would translate into a higher D4A concentration, which is a more potent metabolite than Abi as described above. Although the Abi to D4A conversion ratio is low (at about 5%) in most patients, it appears to be quite variable. A higher conversion ratio might mimic conditions of treatment with Enz, particularly given the AR antagonist activity of D4A. In other words, 3βHSD activity level in a patient might be helpful in predicting the potential response to Abi and ultimately a patient with higher concentration of D4A with Abi treatment might be less likely to benefit from subsequent Enz treatment. Conversely, increasing D4A levels by increasing Abi concentrations or the conversion to D4A might increase the clinical benefit of treatment with Abi. In addition, because 3βHSD is required for mineralocorticoid synthesis, 3βHSD inhibition by D4A might reduce mineralocorticoid production that could translate into a better side effect profile (less hypertension and hypokalemia) and potentially lower dose of prednisone requirement in patients with higher D4A levels. These questions have yet to be answered in clinical studies. Finally, it is possible that steroidogenic metabolites of Abi are not limited to D4A, and that other metabolites with clinically relevant biochemical activity contribute to response and resistance to treatment with Abi.

Cardiovascular effects of hormone therapy for prostate cancer.

Androgen deprivation therapy (ADT) has been the mainstay of treatment for advanced prostate cancer for decades, and has been shown to control disease and improve symptoms. In addition, for men with high-risk localized or locally advanced prostate cancer, short-course ADT in combination with radiotherapy improves survival. There is evidence that ADT increases cardiovascular risk, particularly in men with preexisting cardiovascular disease. This increased risk may apply even with short-course ADT. In an individual patient, the benefits of ADT should be balanced against the risk, and patients who require ADT should have risk factors for cardiovascular disease optimized. There is some evidence to suggest that more contemporary methods of delivering ADT may reduce cardiovascular risk.

P0061 Identification of CD44, α2β1-integrin, and CD133 expressing prostate cancer stem cells in patients from South Korea with prostate cancer

Background Existing therapies for prostate cancer eradicate most cells within a tumour. However, most patients develop androgen-independent disease that cannot be cured. Prostate cancer cells originate from rare stem cells responsible for maintenance of the tumour. Identification of a prostate cancer stem cell provides a useful target from which to develop therapies targeted at these stem cells. Methods Four patients with prostate cancer were included. Their mean age was 72.3 (SD ± 6.6) years. PSA (ng/ml), Gleason score, node involvement, or metastasis in patients were recorded (88.1/7 [4+3], none or bone; 77.7/9 [5+4], iliac node, or bone; 31.4/9 [4+5], none or bone; 299/9 [5+4], iliac node or bone, respectively). Hormonal therapy of prostate cancer was given as a luteinising hormone-releasing hormone agonist and anti-androgen agent. A transurethral resection of the prostate was done and prostate tissue was obtained. Paraffin embedded serial sections (4 μm) were processed for prostate cancer tissue using immunofluorescent staining. Anti-CD133 antibody (1:10, clone 293C3), anti- α 2 β 1-integrin antibody (clone AK-7; TCS), and anti-CD44 (clone G44-26) were used to identify the prostate cancer cells. Stained sections of tissue were then examined under a Olympus laser confocal fluorescence microscope. Findings CD44, α 2 β 1-integrin, and CD133 expressing cancer stem cells were randomly located throughout acini of prostate cancer. High levels of PSA, Gleason score, or lymph node involvement of prostate cancer was not predicted by the presence of cancer stem cells. Interpretation We identified CD133, CD44, and α 2 β 1-integrin expressing cancer stem cells in patients in South Korea with prostate cancer.

PO-0724: Hypofractionated RT, radiosurgical boost, hormone therapy for prostate cancer: a dose escalation study (ISIDEP3)

PO-0724: Hypofractionated RT, radiosurgical boost, hormone therapy for prostate cancer: a dose escalation study (ISIDEP3)

PO-0722: Impact on radio-induced toxicity of adjuvant hormone therapy in prostate cancer: a "pooled analysis"

PO-0722: Impact on radio-induced toxicity of adjuvant hormone therapy in prostate cancer: a "pooled analysis"