Hahn Andrew W, Tidwell Rebecca S, Pilie Patrick G, Yu Yao, Liu Jingjing, Surasi Devaki Shilpa, Titus Mark, Zhang Jianhua, Venkatesh Neha, Panaretakis Theocharis, Gregg Justin R, Zurita Amado J, Siddiqui Bilal A, Corn Paul G, Subudhi Sumit K, Msaouel Pavlos, Koutroumpakis Efstratios, Huff Chad D, Aparicio Ana, McQuade Jennifer L, Frigo Daniel E, Logothetis Christopher J
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Prostate Cancer Prostatic Dis. 2024 Jul 17. doi: 10.1038/s41391-024-00870-8.
Androgen signaling is central to prostate cancer and men's health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC).
A post-hoc analysis was done of NCT02703623 where men with mCRPC (n = 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma.
Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3 rs12529, CYP17A1 rs6162, SRD5A2 rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p = 0.02), visceral adipose tissue index (VATi, p = 0.03), and BMI (p = 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r = 0.47) and SATi (r = 0.48).
Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.
雄激素信号传导对于前列腺癌和男性健康至关重要。先前的数据表明，体脂增加在局限性前列腺癌中不利，但与转移性疾病男性的良好预后相关。了解肥胖与前列腺癌之间的生物学联系可能会优化雄激素合成抑制剂（ASI）的治疗指数。我们假设宿主肥胖和雄激素合成与转移性去势抵抗性前列腺癌（mCRPC）男性使用ASI的疗效和毒性有关。
对NCT02703623进行事后分析，其中mCRPC男性（n = 186）接受醋酸阿比特龙、泼尼松和阿帕鲁胺（AAPA）治疗8周，满意反应定义为前列腺特异性抗原（PSA）下降>50%。在基线CT扫描上测量身体成分。对种系DNA进行全外显子测序（WES），重点关注类固醇生成基因中的变异。在治疗前血浆中测量脂肪因子水平。
参与雄激素合成的3个基因（AKR1C3 rs12529、CYP17A1 rs6162、SRD5A2 rs523349）中的种系多态性与仅接受雄激素剥夺治疗（ADT，在接受AAPA之前）时基线身体成分的差异相关。皮下脂肪组织指数（SATi，p = 0.02）、内脏脂肪组织指数（VATi，p = 0.03）和体重指数（BMI，p = 0.04）升高与对AAPA的满意反应相关。瘦素与VATi（r = 0.47）和SATi（r = 0.48）呈正相关。
雄激素合成中的遗传多态性与接受ADT后身体成分的差异相关，作为身体成分毒性的候选标志物值得进一步研究。皮下和内脏肥胖增加与对ASI的反应改善相关。
