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Inherited Variants in Wnt Pathway Genes Influence Outcomes of Prostate Cancer Patients Receiving Androgen Deprivation Therapy.

ABSTRACT: Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT) has not been determined. Here, we comprehensively studied the contribution of common single nucleotide polymorphisms (SNPs) in Wnt pathway genes to the clinical outcomes of 465 advanced prostate cancer patients treated with ADT. Two SNPs, adenomatous polyposis coli (APC) rs2707765 and rs497844, were significantly (p ? 0.009 and q ? 0.043) associated with both prostate cancer progression and all-cause mortality, even after multivariate analyses and multiple testing correction. Patients with a greater number of favorable alleles had a longer time to disease progression and better overall survival during ADT (p for trend ? 0.003). Additional, cDNA array and in silico analyses of prostate cancer tissue suggested that rs2707765 affects APC expression, which in turn is correlated with tumor aggressiveness and patient prognosis. This study identifies the influence of inherited variants in the Wnt pathway on the efficacy of ADT and highlights a preclinical rationale for using APC as a prognostic marker in advanced prostate cancer.

SUBMITTER: Geng JH

PROVIDER: S-EPMC5187770 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Inherited Variants in Wnt Pathway Genes Influence Outcomes of Prostate Cancer Patients Receiving Androgen Deprivation Therapy.

Geng Jiun-Hung JH Lin Victor C VC Yu Chia-Cheng CC Huang Chao-Yuan CY Yin Hsin-Ling HL Chang Ta-Yuan TY Lu Te-Ling TL Huang Shu-Pin SP Bao Bo-Ying BY

International journal of molecular sciences 20161126 12

Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT) has not been determined. Here, we comprehensively studied the contribution of common single nucleotide polymorphisms (SNPs) in Wnt pathway genes to the clinical outcomes of 465 advanced prostate cancer patients treated with ADT. Two SNPs, <i>adenomatous polyposis coli</i> (< ...[more]

PMID: 27898031

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Project description:BackgroundAndrogen deprivation therapy (ADT) is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT.Methods/designA 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data.DiscussionMusculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant impact on reducing the risk of fracture, promoting physical function, and ultimately improving the health-related quality of life in men with prostate cancer receiving ADT.Trial registrationClinicalTrials.gov: NCT00834392.

Project description:BackgroundAndrogen deprivation therapy (ADT) worsens glycaemic control and cardiovascular outcomes. The prognostic value of visit-to-visit HbA1c variability (VVHV) has been unexplored in prostate cancer (PCa) patients receiving ADT.ObjectiveTo explore the effect of ADT on VVHV and the cardiovascular prognostic value of VVHV.Design setting and participantsPCa patients receiving ADT in Hong Kong between January 1, 1993 and March 31, 2021 were included in this retrospective cohort study. Those with fewer than three HbA1c results available within 3 yr after ADT initiation, <6 mo of ADT, missing baseline HbA1c, prior diagnosis of any component of major adverse cardiovascular events (MACEs), and MACEs occurring within 3 yr were excluded. Patients were followed up until September 31, 2021.Outcome measurements and statistical analysisThe outcome was MACEs (composite of heart failure, myocardial infarction, stroke, and cardiovascular mortality). VVHV was calculated from HbA1c levels within 3 yr after and, separately where available, before ADT initiation using coefficient of variation (CV; standard deviation [SD] divided by mean) and average real variability (ARV; average difference between consecutive measurements).Results and limitationsAltogether, 1065 patients were analysed (median age 74.4 yr old [interquartile range 68.3-79.5 yr]). In 709 patients with VVHV available before and after ADT initiation, VVHV increased after ADT initiation (p < 0.001), with 473 (66.2%) and 474 (66.9%) having increased CV and ARV, respectively. Over a median follow-up of 4.3 yr (2.8-6.7 yr), higher VVHV was associated with a higher risk of MACEs (adjusted hazard ratio [per SD] for CV 1.21 [95% confidence interval: 1.02, 1.43], p = 0.029; ARV 1.25 [1.06, 1.48], p = 0.008). Limitations included residual confounding and selection bias.ConclusionsIn PCa patients receiving ADT, VVHV increased after ADT initiation. Higher VVHV was associated with an increased risk of MACEs.Patient summaryIn prostate cancer patients receiving androgen deprivation therapy (ADT), glycaemic control is less stable after initiating ADT, which was associated with an increased cardiovascular risk.

Project description:PurposeAndrogen deprivation therapy may increase diabetes risk. As the benefits of primary androgen deprivation therapy for localized prostate cancer are controversial, and most prostate cancer survivors are of advanced age with comorbidities, it is important to determine if primary androgen deprivation therapy increases the risk of diabetes and to determine the susceptibility factors.Materials and methodsWe conducted a retrospective cohort study of 12,191 men diagnosed with incident localized prostate cancer during 1995 to 2008, age 35 to 100 years, and without diabetes or receipt of prostatectomy or radiation 1 year after diagnosis. Patients were enrolled in 1 of 3 managed health plans and followed through 2010. Primary androgen deprivation therapy was defined as androgen deprivation therapy within 1 year after diagnosis. Incident diabetes was ascertained using inpatient and outpatient diagnosis codes, diabetes medications and hemoglobin A1c values. We estimated primary androgen deprivation therapy associated diabetes risk using Cox proportional hazard models in conventional and propensity score analyses.ResultsDiabetes developed in 1,203 (9.9%) patients during followup (median 4.8 years) with incidence rates of 2.5 and 1.6 events per 100 person-years in the primary androgen deprivation therapy and nonprimary androgen deprivation therapy groups, respectively. Primary androgen deprivation therapy was associated with a 1.61-fold increased diabetes risk (95% CI 1.38-1.88). The number needed to harm was 29. The association was stronger in men age 70 or younger than in older men (HR 2.25 vs 1.40, p value for interaction=0.008).ConclusionsPrimary androgen deprivation therapy may increase diabetes risk by 60% and should be used with caution when managing localized prostate cancer. Because of the consistent association between androgen deprivation therapy and greater diabetes risk across disease states, we recommend routine screening and lifestyle interventions to reduce the risk of diabetes in men receiving androgen deprivation therapy.

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Inherited Variants in Wnt Pathway Genes Influence Outcomes of Prostate Cancer Patients Receiving Androgen Deprivation Therapy.

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Inherited Variants in Wnt Pathway Genes Influence Outcomes of Prostate Cancer Patients Receiving Androgen Deprivation Therapy.

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