Dataset Information

Glutamine and Cholesterol Plasma Levels and Clinical Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Taxanes.

ABSTRACT: Altered metabolism is a hallmark of cancer. Malignant cells metabolise glutamine to fulfil their metabolic needs. In prostate cancer, androgen receptor signalling promotes glutamine metabolism, which is also involved in cholesterol homeostasis. We aimed to determine whether the plasma glutamine levels correlate with the blood lipid profile, clinical characteristics and outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) undergoing taxanes. We retrospectively assessed the glutamine and glutamate levels in plasma samples by a bioluminescent assay. Pre-treatment glutamine, glutamate, cholesterol and triglycerides levels were correlated with patients' clinical characteristics, taxanes response and clinical outcomes. Seventy-five patients with mCRPC treated with taxanes were included. The plasma glutamine levels were significantly higher in patients that received abiraterone or enzalutamide prior to taxanes (p = 0.003). Besides, patients with low glutamine levels were more likely to present a PSA response to taxanes (p = 0.048). Higher glutamine levels were significantly correlated with shorter biochemical/clinical progression-free survival (PSA/RX-PFS) (median 2.5 vs. 4.2 months; p = 0.048) and overall survival (OS) (median 12.6 vs. 20.3; p = 0.008). High cholesterol levels independently predicted early PSA/RX-PFS (p = 0.034). High glutamine and cholesterol in the plasma from patients with mCRPC were associated with adverse clinical outcomes, supporting the relevance of further research on metabolism in prostate cancer progression.

SUBMITTER: Marin-Aguilera M

PROVIDER: S-EPMC8507765 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ? 50% and ? 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.ClinicalTrials.gov identifier NCT01091103.

Project description:Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR]=1.61, 95% confidence interval [CI]=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95% CI 0.74-1.46, p=0.8) or PSA response (odds ratio=1.14, 95% CI=0.65-1.99, p=0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.16, 95% CI=0.06-0.46, p<0.001) and PFS (HR=0.31, 95% CI=0.12-0.80, p=0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR=1.93, 95% CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95% CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial. PATIENT SUMMARY: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker.

Project description:Metastatic castration resistant prostate cancer (mCRPC) is still the lethal stage for the whole spectrum of prostate cancer disease. Even though different treatment options have been introduced in the last decade with a significant survival improvement for this population, a lack of more reliable prognostic and predictive markers is still one of the main clinical challenges in management of mCRPC. The aim of this study was to investigate the correlation between Natural Killer cell activity (NKA) and both treatment effect and outcomes in patients with mCRPC treated with enzalutamide. A total of 87 patients with mCRPC treated with enzalutamide as the first line treatment were enrolled. NKA was estimated at baseline and prior to each treatment cycle. Endpoints included both treatment effect with biochemical response (BR), biochemical progression (BP) and radiological progression (RP), as well as outcome data with overall survival (OS), radiologic progression free survival (rPFS), and time to next treatment (TTT). At the time of BR, interferon-gamma (IFNγ) decreased significantly compared to levels detected at baseline (z-score = 2.33, p = 0.019). Regarding outcome data, the whole cohort was divided into four groups according to the change of IFNγ level during the first 3 cycles of enzalutamide treatment. In group 1 (n = 42) the IFNγ level remained within a normal range (≥ 250 pg/mL),while in group 2 (n = 7) it increased from an abnormal (< 250 pg/mL) to a normal level. In group 3 (n = 13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n = 17). Patients in group 2 showed the worst prognosis with shorter both rPFS and TTT (HR 4.30, p = 0.037; and HR 6.82, p = 0.011, respectively). In this study inverse correlations between NKA and both treatment response and outcomes was observed in mCRPC patients receiving enzalutamide, suggesting an unfavourable role of NK cells in the late stage of PCa.

Dataset Information

Glutamine and Cholesterol Plasma Levels and Clinical Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Taxanes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets