Serum Neuroendocrine Markers Predict Therapy Outcome of Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis

Liu, Yangzhou; Zhao, Shankun; Wang, Jiamin; Zhu, Zhiguo; Luo, Lianmin; Li, Ermao; Tang, Fucai; Zhao, Zhigang

doi:10.1159/000495512

Cited by 13 publications

(12 citation statements)

References 40 publications

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Section: Neuroendocrine Markersmentioning

confidence: 99%

“…Serum NE markers such as NSE and CgA have been reported to be prognostic in patients with mCRPC [61,[91][92][93][94][95][96][97][98]. Their role as predictors of response in unselected mCRPC patients is still under investigation, with some reports suggesting such a role [93]. For instance, CgA rise and velocity have been reported to be associated with androgen-independent progression under hormonal therapy [99], while CgA and NSE elevation during the first months of treatment with abiraterone was found to be associated with worse treatment outcome [98].…”

Section: Neuroendocrine Markersmentioning

confidence: 99%

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Neuroendocrine and Aggressive-Variant Prostate Cancer

Spetsieris

Boukovala

Patsakis

et al. 2020

Cancers

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In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies.

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Section: Neuroendocrine Markersmentioning

confidence: 99%

Section: Neuroendocrine Markersmentioning

confidence: 99%

Neuroendocrine and Aggressive-Variant Prostate Cancer

Spetsieris

Boukovala

Patsakis

et al. 2020

Cancers

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“… Small cell carcinoma Pure small cell carcinoma histology associated with worse OS than mixed small cell carcinoma and adenocarcinoma histology in metastatic tumor biopsies, with OS calculated both from the time of PC diagnosis and the time of diagnosis of metastatic disease [39] ; detection of treatment-emergent small cell neuroendocrine PC associated with worse OS in patients with prior AR-targeting therapy for mCRPC [40] Pure small cell carcinomas may need to be managed more aggressively than mixed NEPC cases [39] . NED prostate cancer tissue and serum markers High serum chromogranin A (CHGA) and neuron-specific enolase (NSE) associated with worse PFS and OS in mCRPC patients [39] , [41] ; immunohistochemical CHGA expression associated with worse PFS and OS in patients receiving ADT early after diagnosis of PC [42] ; SRRM4 gene expression associated with worse OS [43] Generally, NED is more common in high-grade and high-stage PC and, especially after ADT, during tumor progression and in CRPC [44] ; altered renal function and treatment with proton pump inhibitors may induce high serum CHGA levels, so interpretation must be done cautiously in patients with these situations [44] ; on SRRM4, studies needed on whether (1) SRRM4 expression is associated with other neuroendocrine carcinoma in patients, (2) anticancer therapies induce SRRM4 expression in these patients, and (3) SRRM4 drives tumor progression to neuroendocrine carcinoma through reprogramming RNA splicing gene networks [43] . Local (seminal vesicle or bladder invasion) or regional (pelvic lymph node) metastatic spread Local metastatic spread associated with worse PFS [36] ; regional metastatic spread associated with worse CSS [45] Noninvasive detection of seminal vesicle, bladder, and pelvic lymph node mPC status by imaging would be useful to patients, but there are still problems regarding accuracy [46] .…”

Section: Resultsmentioning

confidence: 99%

Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine

Jasu

Tolonen

Antonarakis

et al. 2021

European Urology Open Science

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Background Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology. Objective To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials. Design, setting, and participants We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature. Intervention Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC. Outcome measurements and statistical analysis Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression. Results and limitations Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of “skeletal-related events” complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index <0.89 in 24/31 patients) but limited to the last year of life. Biomarker review identified 30 categories of mPC biomarkers in need of winnowing in future trials. All findings require validation in larger cohorts, preferably alongside data from this study. Conclusions The study identified novel outcome subgroups for future validation and provides “vision for mPC precision oncology 2020–2050” draft recommendations for future data collection and biomarker studies. Patient summary To better understand variation in metastatic prostate cancer behavior, we assembled and analyzed longitudi...

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“… 19 In addition, a high level of serum NSE strongly predicts a worsened prognosis of CRPC patients. 20 Thus, the downregulation of NSE by EPOR knockdown suggests that the EPO signaling pathway promotes the neuroendocrine transmission of PCa by interacting with functional EPOR.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of erythropoietin and erythropoietin receptor in castration-resistant progression of prostate cancer

Wang

Chen

et al. 2020

Asian J Androl

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Hypoxia-induced erythropoietin signaling plays an important role in tumor growth and invasion. In the present study, we investigated the contribution of erythropoietin signaling pathway to castration-resistant prostate cancer and the development of a neuroendocrine phenotype. Immunohistochemical staining showed that the erythropoietin and erythropoietin receptor scores in castration-resistant prostate cancer and androgen-dependent prostate cancer were 7.55 versus 4.5 and 7.45 versus 5.9, respectively ( P < 0.001). Furthermore, a cell proliferation assay was conducted, and the differential expression of erythropoietin and erythropoietin receptor in LNCaP cells and hypoxia-induced LNCaP cells was evaluated using western blot and quantitative real-time PCR. The proliferation capacity of hypoxia-induced LNCaP cells was similar in cultures of both fetal bovine serum and charcoal-stripped fetal bovine serum, suggesting that LNCaP cells acquired hypoxia-induced androgen-independent growth. After 2 weeks of hypoxic culture, LNCaP cells showed a neuroendocrine cell change and increased expression of neuron-specific enolase, erythropoietin, and erythropoietin receptor; knockdown of erythropoietin receptor reversed the hypoxia-induced upregulation of neuron-specific enolase in the LNCaP cells. In conclusion, the concurrent upregulation of erythropoietin and erythropoietin receptor in castration-resistant prostate cancer suggests that the erythropoietin/erythropoietin receptor autocrine loop plays an important role in the progression of castration resistance and is responsible for the development of a neuroendocrine phenotype.

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Serum Neuroendocrine Markers Predict Therapy Outcome of Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis

Cited by 13 publications

References 40 publications

Neuroendocrine and Aggressive-Variant Prostate Cancer

Neuroendocrine and Aggressive-Variant Prostate Cancer

Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine

Upregulation of erythropoietin and erythropoietin receptor in castration-resistant progression of prostate cancer

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