Dataset Information

Persistence of senescent prostate cancer cells following prolonged neoadjuvant androgen deprivation therapy.

ABSTRACT:

Purpose

Androgen deprivation therapy (ADT) commonly leads to incomplete cell death and the fate of persistent cells involves, in part, a senescent phenotype. Senescence is terminal growth arrest in response to cell stress that is characterized by increased lysosomal-?-galactosidase (GLB1) the origin of senescence associated-?-gal activity (SA-?-gal). In the current study senescence is examined in vivo after ADT use in a neoadjuvant trial.

Methods and materials

Tissue microarrays were generated from prostate cancer specimens (n = 126) from a multicenter neoadjuvant ADT trial. Arrays were subjected to multiplexed immunofluorescent staining for GLB1, Ki67, cleaved caspase 3 (CC3) and E-cadherin. Automated quantitative imaging was performed using Vectra™ and expression correlated with clinicopathologic features.

Results

Tissue was analyzed from 59 patients treated with neoadjuvant ADT and 67 receiving no therapy preoperatively. Median follow-up was 85.3 mo and median ADT treatment was 5 mo. In PC treated with neoadjuvant ADT, GLB1 expression increased in intermediate Gleason score (GS 6-7; p = 0.001), but not high grade (GS 8-10) cancer. Significantly higher levels of GLB1 were seen in tissues undergoing neoadjuvant ADT longer than 5 months compared to untreated tissues (p = 0.002). In contrast, apoptosis significantly increased earlier (1-4 mo) after ADT treatment (p<0.5).

Conclusions

Increased GLB1 after neoadjuvant ADT occurs primarily among more clinically favorable intermediate grade cancers and enrichment of the phenotype occurs in a temporally prolonged fashion. Senescence may explain the persistence of PCa cells after ADT. Given concerns for the detrimental longer term presence of senescent cells, targeting these cells for removal may improve outcomes.

SUBMITTER: Blute ML

PROVIDER: S-EPMC5325224 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Persistence of senescent prostate cancer cells following prolonged neoadjuvant androgen deprivation therapy.

Blute Michael L ML Damaschke Nathan N Wagner Jennifer J Yang Bing B Gleave Martin M Fazli Ladan L Shi Fangfang F Abel E Jason EJ Downs Tracy M TM Huang Wei W Jarrard David F DF

PloS one 20170224 2

<h4>Purpose</h4>Androgen deprivation therapy (ADT) commonly leads to incomplete cell death and the fate of persistent cells involves, in part, a senescent phenotype. Senescence is terminal growth arrest in response to cell stress that is characterized by increased lysosomal-β-galactosidase (GLB1) the origin of senescence associated-β-gal activity (SA-β-gal). In the current study senescence is examined in vivo after ADT use in a neoadjuvant trial.<h4>Methods and materials</h4>Tissue microarrays w ...[more]

PMID: 28234906

Similar Datasets

Project description:ContextDespite a lack of data, increasing numbers of patients are receiving primary androgen deprivation therapy (PADT) as an alternative to surgery, radiation, or conservative management for the treatment of localized prostate cancer.ObjectiveTo evaluate the association between PADT and survival in elderly men with localized prostate cancer.Design, setting, and patientsA population-based cohort study of 19,271 men aged 66 years or older receiving Medicare who did not receive definitive local therapy for clinical stage T1-T2 prostate cancer. These patients were diagnosed in 1992-2002 within predefined US geographical areas, with follow-up through December 31, 2006, for all-cause mortality and through December 31, 2004, for prostate cancer-specific mortality. Instrumental variable analysis was used to address potential biases associated with unmeasured confounding variables.Main outcome measuresProstate cancer-specific survival and overall survival.ResultsAmong patients with localized prostate cancer (median age, 77 years), 7867 (41%) received PADT, and 11,404 were treated with conservative management, not including PADT. During the follow-up period, there were 1560 prostate cancer deaths and 11,045 deaths from all causes. Primary androgen deprivation therapy was associated with lower 10-year prostate cancer-specific survival (80.1% vs 82.6%; hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.03-1.33) and no increase in 10-year overall survival (30.2% vs 30.3%; HR, 1.00; 95% CI, 0.96-1.05) compared with conservative management. However, in a prespecified subset analysis, PADT use in men with poorly differentiated cancer was associated with improved prostate cancer-specific survival (59.8% vs 54.3%; HR, 0.84; 95% CI, 0.70-1.00; P = .049) but not overall survival (17.3% vs 15.3%; HR, 0.92; 95% CI, 0.84-1.01).ConclusionPrimary androgen deprivation therapy is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management.

Project description:IMPORTANCE:One in 6 American men will be diagnosed as having prostate cancer during their lifetime. Although there are no data to support the use of primary androgen-deprivation therapy (ADT) for early-stage prostate cancer, primary ADT has been widely used for localized prostate cancer, especially among older patients. OBJECTIVE:To determine the long-term survival impact of primary ADT in older men with localized (T1/T2) prostate cancer. DESIGN, SETTING, AND PARTICIPANTS:This was a population-based cohort study of 66,717 Medicare patients 66 years or older diagnosed from 1992 through 2009 who received no definitive local therapy within 180 days of prostate cancer diagnosis. The study was conducted in predefined US geographical areas covered by the Surveillance, Epidemiology, and End Results (SEER) Program. Instrumental variable analysis was used to assess the impact of primary ADT and control for potential biases associated with unmeasured confounding variables. The instrumental variable comprised combined health services areas with various usage rates of primary ADT. The analysis compared survival outcomes in the top tertile areas with those in the bottom tertile areas. MAIN OUTCOMES AND MEASURES:Prostate cancer-specific survival and overall survival. RESULTS:With a median follow-up of 110 months, primary ADT was not associated with improved 15-year overall or prostate cancer-specific survival following the diagnosis of localized prostate cancer. Among patients with moderately differentiated cancers, the 15-year overall survival was 20.0% in areas with high primary ADT use vs 20.8% in areas with low use (difference: 95% CI, -2.2% to 0.4%), and the 15-year prostate cancer survival was 90.6% in both high- and low-use areas (difference: 95% CI, -1.1% to 1.2%). Among patients with poorly differentiated cancers, the 15-year cancer-specific survival was 78.6% in high-use areas vs 78.5%, in low-use areas (difference: 95% CI, -1.8% to 2.4%), and the 15-year overall survival was 8.6% in high-use areas vs 9.2% in low-use areas (difference: 95% CI, -1.5% to 0.4%). CONCLUSIONS AND RELEVANCE:Primary ADT is not associated with improved long-term overall or disease-specific survival for men with localized prostate cancer. Primary ADT should be used only to palliate symptoms of disease or prevent imminent symptoms associated with disease progression.

Dataset Information

Persistence of senescent prostate cancer cells following prolonged neoadjuvant androgen deprivation therapy.

Purpose

Methods and materials

Results

Conclusions

Publications

Persistence of senescent prostate cancer cells following prolonged neoadjuvant androgen deprivation therapy.

Similar Datasets

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