Can we minimize androgen deprivation therapy-related quality of life effects in Māori & Pacific prostate cancer survivors using a genetic stratification?

Abstract

BACKGROUND: Androgen deprivation therapy (ADT) is an effective palliation treatment for men with advanced prostate cancer (PC). This is a common treatment received by the majority of PC survivors among New Zealand (NZ) Maori men due to their late presentation of the disease. However, ADT have well documented side effects that could alter the patient’s quality of life (QoL). ADT involves suppression of androgens produced either by the testes or the adrenal gland or both. Adrenal androgen production involves conversion of androstenedione to testosterone by the aldo-keto reductase 1C3 (AKR1C3) enzyme. We have previously reported that the AKR1C3 rs12529 G allele is associated with a lower prostate specific antigen (PSA) level, which is a downstream product of androgens binding to the androgen receptor. The AKR1C3 rs12529 G allele frequency is 14.2% higher among Māori, Pacific and East Asian men compared to Caucasians in our study cohort. Therefore, the current assessment is to evaluate whether genetic stratification with the AKR1C3 rs12529 polymorphism could support decision making on ADT to minimize QoL effects. METHODS: A patient cohort with confirmed clinical diagnoses of PC was recruited with written consent from 2006-2014 to Urology studies carried out at the Auckland Cancer Society Research Centre, University of Auckland, NZ. Recruitment was carried out at hospitals managed under three District Health Boards of Auckland, and private Urology clinics from Waikato District, in NZ. From May 2013, patients were invited to complete a questionnaire that contained options for selecting PC treatment type/s received and a QoL survey. The primary outcomes were the percentage scores under each QoL subscale assessed using the European Organisation for Research and Treatment of Cancer quality of life questionnaires (EORTC QLQ-C30 and PR25). Genotyping of these men for the AKR1C3 rs12529 single nucleotide polymorphism (SNP) was carried out using the Sequenom MassArray and iPlex system or the Applied Biosystem’s Taqman SNP genotyping procedure. Age at diagnosis, Gleason score and alcohol consumption were confounding variables between ADT and no ADT groups, and were corrected for subsequent analysis. Analysis of QoL scores were carried out against ADT duration or in association with the AKR1C3 rs12529 SNP using the Generalised Linear Model. P-values <0.05 were considered significant. FINDINGS: A total of 206 patients provided valid completed questionnaires and 191 patients were linked to the AKR1C3 rs12529 SNP genotype data. 36.4% of this cohort has received ADT either as a monotherapy or as a combined androgen blockage. 85.3% of ADT composed of anti-androgens (AA) either as a monotherapy or in combination with the luteinizing hormone- releasing hormone agonists. Increase in QoL subscales (95% CI) for insomnia [39.7 (1.9-77.4), p<0.05] and hormone treatment-related effects [36.1 (18.6-53.7), p<0.005] were recorded with long-term ADT as compared to no ADT. Hormone treatment-related effects showed an increase with ADT when associated with the AKR1C3 rs12529 G allele [4.9 (95% CI (1.1-8.6) p<0.02]. This increase among the rs12529 GG genotype (9.7) is therefore, equivalent to 59% of the mean hormone treatment-related symptom score of 16.5 (SD16.6) recorded in this study. INTERPRETATION: As 85.3% ADT recipients have used AA the current study is best interpreted as QoL effects of AAs. This study suggests a possibility for those stratified with the AKR1C3 rs12529 G allele to receive intermittent AA treatment to minimize QoL effects. If larger prospective studies can confirm these findings, PC survivors particularly those of Maori and Pacific ethnic groups may greatly benefit through optimal ADT options not only for their survival benefits, but also to better maintain their QoL.