Andrew W Hahn, Rebecca S Tidwell, Patrick G Pilie, Yao Yu, Jingjing Liu, Devaki Shilpa Surasi, Mark Titus, Jianhua Zhang, Neha Venkatesh, Theocharis Panaretakis, Justin R Gregg, Amado J Zurita, Bilal A Siddiqui, Paul G Corn, Sumit K Subudhi, Pavlos Msaouel, Efstratios Koutroumpakis, Chad D Huff, Ana Aparicio, Jennifer L McQuade, Daniel E Frigo, Christopher J Logothetis
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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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":20727,"journal":{"name":"Prostate Cancer and Prostatic Diseases","volume":null,"pages":null},"PeriodicalIF":5.1000,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Body composition as a determinant of the therapeutic index with androgen signaling inhibition.\",\"authors\":\"Andrew W Hahn, Rebecca S Tidwell, Patrick G Pilie, Yao Yu, Jingjing Liu, Devaki Shilpa Surasi, Mark Titus, Jianhua Zhang, Neha Venkatesh, Theocharis Panaretakis, Justin R Gregg, Amado J Zurita, Bilal A Siddiqui, Paul G Corn, Sumit K Subudhi, Pavlos Msaouel, Efstratios Koutroumpakis, Chad D Huff, Ana Aparicio, Jennifer L McQuade, Daniel E Frigo, Christopher J Logothetis\",\"doi\":\"10.1038/s41391-024-00870-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Androgen signaling is central to prostate cancer and men's health. 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引用次数: 0
摘要
背景:雄激素信号对前列腺癌和男性健康至关重要。先前的数据表明,增加体内脂肪不利于局部治疗,但却与男性转移性疾病的良好预后有关。了解脂肪与前列腺癌之间的生物学联系可优化 ASI 的治疗指数。我们假设,宿主脂肪和雄激素合成与 ASI 对转移性耐受性前列腺癌(mCRPC)患者的疗效和毒性有关:对NCT02703623进行了事后分析,mCRPC男性患者(n = 186)接受了为期8周的醋酸阿比特龙、泼尼松和阿帕鲁胺(AAPA)治疗,PSA下降>50%即为满意反应。通过基线CT扫描测量身体成分。进行了种系 DNA WES 检测,重点是类固醇生成基因的变异。对治疗前血浆中的脂肪因子水平进行了测量:结果:3个参与雄激素合成的基因(AKR1C3 rs12529、CYP17A1 rs6162、SRD5A2 rs523349)的种系多态性与单用ADT时(接受AAPA治疗前)基线身体成分的差异有关。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)的升高与对 AAPA 的满意反应相关。瘦素与VATi(r = 0.47)和SATi(r = 0.48)呈正相关:结论:雄激素合成的遗传多态性与暴露于 ADT 后身体成分的差异相关,值得作为身体成分毒性的候选标记进一步研究。皮下和内脏脂肪含量升高与 ASI 反应改善有关。
Body composition as a determinant of the therapeutic index with androgen signaling inhibition.
Background: 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).
Methods: 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.
Results: 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).
Conclusion: 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.
期刊介绍:
Prostate Cancer and Prostatic Diseases covers all aspects of prostatic diseases, in particular prostate cancer, the subject of intensive basic and clinical research world-wide. The journal also reports on exciting new developments being made in diagnosis, surgery, radiotherapy, drug discovery and medical management.
Prostate Cancer and Prostatic Diseases is of interest to surgeons, oncologists and clinicians treating patients and to those involved in research into diseases of the prostate. The journal covers the three main areas - prostate cancer, male LUTS and prostatitis.
Prostate Cancer and Prostatic Diseases publishes original research articles, reviews, topical comment and critical appraisals of scientific meetings and the latest books. The journal also contains a calendar of forthcoming scientific meetings. The Editors and a distinguished Editorial Board ensure that submitted articles receive fast and efficient attention and are refereed to the highest possible scientific standard. A fast track system is available for topical articles of particular significance.