Obese patients with castration‐resistant prostate cancer may be at a lower risk of all‐cause mortality: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Vidal, Adriana C.; Howard, Lauren E.; Hoedt, Amanda M. De; Kane, Christopher J.; Terris, Martha K.; Aronson, William J.; Cooperberg, Matthew R.; Amling, Christopher L.; Freedland, Stephen J.

doi:10.1111/bju.14193

Cited by 15 publications

(4 citation statements)

References 20 publications

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“…Although validation studies in human PCa remain to be done, these studies clearly place tumor lipids as potential drivers of aggressive PCa. Interestingly, AR signaling is known to be decreased in obesity [88], and obese patients with CRPC seem to have better overall survival [89]. These seemingly conflicting results clearly represent the difficulty in understanding how systemic lipid metabolism affects cancer outcomes in humans.…”

Section: Therapeutic Opportunities Targeting Lipid Metabolism and mentioning

confidence: 99%

Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy

Stoykova¹,

Schlaepfer²

2019

IJMS

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Prostate cancer (PCa) is the most common cancer in men, and more than 10% of men will be diagnosed with PCa during their lifetime. Patients that are not cured with surgery or radiation are largely treated with endocrine therapies that target androgens or the androgen receptor (AR), a major driver of PCa. In response to androgen deprivation, most PCas progress to castrate resistant PCa, which is treated with anti-androgens like enzalutamide, but tumors still progress and become incurable. Thus, there is a critical need to identify cellular pathways that allow tumors to escape anti-androgen therapies. Epidemiological studies suggest that high-fat diets play important roles in PCa progression. Lipid metabolism rewires the PCa metabolome to support growth and resistance to endocrine therapies, although the exact mechanisms remain obscure. Therapeutic effects have been observed inhibiting several aspects of PCa lipid metabolism: Synthesis, uptake, and oxidation. Since AR remains a driver of PCa in advanced disease, strategies targeting both lipid metabolism and AR are starting to emerge, providing new opportunities to re-sensitize tumors to endocrine therapies with lipid metabolic approaches.

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Section: Therapeutic Opportunities Targeting Lipid Metabolism and mentioning

confidence: 99%

Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy

Stoykova¹,

Schlaepfer²

2019

IJMS

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“…Interestingly, notwithstanding the population-level evidence that appears to support a straightforward link between obesity and prostate cancer, emerging evidence suggests a much more nuanced relationship. BMI correlates with more aggressive prostate cancer; however, patients with BMI greater than 30 actually have better outcomes [ 97 , 98 ]. Evidence regarding more advanced, metastatic castration-resistant prostate cancer is complex with data both supporting and refuting a correlation between BMI and prostate cancer risk [ 98 , 99 , 100 , 101 , 102 ].…”

Section: Discussionmentioning

confidence: 99%

Adipose Tissue-Derived Extracellular Vesicles Contribute to Phenotypic Plasticity of Prostate Cancer Cells

Mathiesen¹,

Haynes²,

Huyck³

et al. 2023

IJMS

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Metastatic prostate cancer is one of the leading causes of male cancer deaths in the western world. Obesity significantly increases the risk of metastatic disease and is associated with a higher mortality rate. Systemic chronic inflammation can result from a variety of conditions, including obesity, where adipose tissue inflammation is a major contributor. Adipose tissue endothelial cells (EC) exposed to inflammation become dysfunctional and produce a secretome, including extracellular vesicles (EV), that can impact function of cells in distant tissues, including malignant cells. The aim of this study was to explore the potential role of EVs produced by obese adipose tissue and the ECs exposed to pro-inflammatory cytokines on prostate cancer phenotypic plasticity in vitro. We demonstrate that PC3ML metastatic prostate cancer cells exposed to EVs from adipose tissue ECs and to EVs from human adipose tissue total explants display reduced invasion and increased proliferation. The latter functional changes could be attributed to the EV miRNA cargo. We also show that the functional shift is TWIST1-dependent and is consistent with mesenchymal-to-epithelial transition, which is key to establishment of secondary tumor growth. Understanding the complex effects of EVs on prostate cancer cells of different phenotypes is key before their intended use as therapeutics.

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“…17 Multiple epidemiologic studies have shown increased incidence of prostate cancer 18 or more aggressive behavior of disease in patients who have higher BMI. 19,20 However, in studies of patients with advanced prostate cancer, a higher BMI is associated with increased survival, 7 and in mCRPC it appears to have a protective effect. 15,21 For example, in the CHAARTED study, men with metastatic hormone-sensitive prostate cancer with low or normal BMI showed evidence of more advanced cancer and a poorer baseline quality of life when compared to overweight or obese men.…”

Section: Discussionmentioning

confidence: 99%

“…4 Furthermore, obesity has been implicated in the development of high-grade prostate cancer and death from prostate cancer. 5,6 However, once prostate cancer has metastasized and has become castration-resistant, some studies have identified obesity to have a protective effect on survival, 7 and in prior studies of veterans with mCRPC, obesity was associated with longer survival. 8 Diabetes mellitus is a major comorbid condition that can affect outcomes of cancer treatment and is often associated with body mass index (BMI).…”

Section: Introductionmentioning

confidence: 99%

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration‐resistant prostate cancer treated with abiraterone or enzalutamide

Govindan,

Cheranda,

Riekhof

et al. 2023

The Prostate

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BackgroundAbiraterone acetate and enzalutamide are two common therapies for metastatic castration‐resistant prostate cancer (mCRPC) that have shown improved overall survival (OS). The drugs have different mechanisms of action with limited comparative trials to evaluate treatment in patients with comorbidities such as obesity and diabetes. This is important since abiraterone requires the co‐administration of prednisone. We assessed the relationship between body mass index (BMI), hemoglobin A1c (HbA1c), treatment, and survival in mCRPC.MethodsVeterans treated with abiraterone or enzalutamide within the Veterans Health Administration between September 10, 2014 and June 2, 2017 with BMI and HbA1c were identified. Additional variables included age, baseline prostate‐specific antigen at first treatment for mCRPC, race, and the Charlson comorbidity index. Differences in survival were compared using the Kaplan–Meier method. Cox proportional hazards regression modeling was used to assess the association between initial treatment, BMI, and HbA1c while adjusting for confounding variables.ResultsA total of 5231 patients were identified with a mean age of 75.2 years and 1241 (23.7%) were of black race. BMI was associated with OS with longest median survival of 29.8 months in BMI ≥ 30 (n = 1903), 23.9 months in BMI 25–30 (n = 1879), 15.9 months in BMI 18.5–25 (n = 1336), and 9.2 months in BMI < 18.5 (n = 113, p < 0.001). In a multivariable model compared to normal BMI, increased mortality was observed in BMI < 18.5 (adjusted hazard ratio (aHR) = 1.583, 95% confidence interval [CI]: 1.29–1.94) and a decreased mortality in BMI 25–30 (aHR = 0.751, 95% CI: 0.69–0.81) and BMI > 30 (aHR = 0.644, 95% CI: 0.59–0.70). In 3761 patients with BMI > 25, there was longer OS in patients treated with enzalutamide (28.4 months, n = 1615) compared to abiraterone (25.8 months, n = 2146, p = 0.002). In 1470 patients with BMI < 25, there was no difference in OS between patients treated with enzalutamide (16.0 months, n = 597, p = 0.513) or abiraterone (16.1 months, n = 873). In 1333 veterans with HbA1c ≥ 6.5%, initial prescription of enzalutamide was associated with longer OS compared with abiraterone (24.4 vs. 20.5 months, p = 0.0005). In 2088 patients with HbA1c < 6.5%, there was no difference in OS in patients who were initially prescribed enzalutamide versus abiraterone (25.7 vs. 23.5 months, p = 0.334).ConclusionsIn veterans with mCRPC, increased BMI was associated with longer survival. Veterans with BMI > 25 had longer survival with enzalutamide compared to abiraterone. In patients with HbA1c ≥ 6.5%, enzalutamide was associated with longer survival compared to abiraterone. These results may facilitate prognostication of survival and improve treatment selection based on patient comorbidities.

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Obese patients with castration‐resistant prostate cancer may be at a lower risk of all‐cause mortality: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Abstract: Amongst patients with non-mCRPC obesity was associated with better overall survival. Although this result mirrors evidence from men with mCRPC, obesity was not associated with prostate cancer outcomes. Larger studies are needed to confirm these findings.

Cited by 15 publications

References 20 publications

Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy

Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy

Adipose Tissue-Derived Extracellular Vesicles Contribute to Phenotypic Plasticity of Prostate Cancer Cells

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration‐resistant prostate cancer treated with abiraterone or enzalutamide

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