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Jaesung (Peter) Choi
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Reena Desai
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Yu Zheng
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Mu Yao ANZAC Research Institute, Discipline of Endocrinology, Department of Anatomical Pathology, University of Sydney, Sydney, New South Wales 2139, Australia

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Qihan Dong ANZAC Research Institute, Discipline of Endocrinology, Department of Anatomical Pathology, University of Sydney, Sydney, New South Wales 2139, Australia

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Geoff Watson ANZAC Research Institute, Discipline of Endocrinology, Department of Anatomical Pathology, University of Sydney, Sydney, New South Wales 2139, Australia

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David J Handelsman
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Ulla Simanainen
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Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4 was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

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Neha Venkatesh Baylor College of Medicine, Houston, TX, USA

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Rebecca S Tidwell Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Yao Yu Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Ana Aparicio Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Amado J Zurita Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Sumit K Subudhi Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Bilal A Siddiqui Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Sagar S Mukhida Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Justin R Gregg Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Paul G Corn Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Efstratios Koutroumpakis Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Jennifer L McQuade Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Daniel E Frigo Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Patrick G Pilie Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Chad Huff Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Christopher J Logothetis Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Andrew W Hahn Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Hormone therapy (HT) to treat prostate cancer is reported to cause adverse changes in body composition. Clinically, interpatient body composition changes are heterogeneous, but the biological and clinical determinants of body composition toxicity are unknown. Herein, we test the hypothesis that inherited polymorphisms in steroidogenic genes are associated with differential changes in body composition after HT. Men with biochemically recurrent prostate cancer (BCR) who received 8 months of LHRH analog (LHRHa) +/− abiraterone acetate (AAP) were eligible if they had: i) CT imaging of L3 prior to and after treatment; and ii) nucleated cells collected. Cardiometabolic co-morbidities were retrospectively extracted. Body composition was measured using an AI-based segmentation tool. Germline DNA whole exome or genome sequencing was performed. In 162 men treated with 8 months of HT, median skeletal muscle mass (SMMi) loss was 6.6% and subcutaneous adipose gain was 12.3%. Men with type 2 diabetes had higher losses of SMMi after treatment (−11.1% vs −6.3%, P = 0.003). For the 150 men with germline NGS, SRD5A2 rs523349 genotype was associated with differential loss in skeletal muscle density after HT, (−1.3% vs −7.1%, P = 0.04). In addition, the HSD3B1 rs104703 genotype was associated with decreased baseline visceral adipose tissue (63.0 cm2/m2 vs 77.9, P = 0.05). In men with BCR, HT induced notable loss of skeletal muscle and increased subcutaneous adipose tissue. An inherited polymorphism in SRD5A2 and T2DM was associated with differential skeletal muscle toxicity. These findings suggest that inherited polymorphisms may contribute to the body composition toxicity observed with HT.

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Xiangqian Zheng Thyroid Neck Oncology Department, Tianjin Medical University Cancer Institute & Hospital, Tianjin, Tianjin, China

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Meiyu Fang Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

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Yun Fan Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

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Yuping Sun Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China

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Meili Sun Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China

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Ankui Yang Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

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Bin Zhang Head and Neck Surgery Department, Beijing Cancer Hospital, Beijing, Beijing, China

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Qinjiang Liu Head and Neck Surgery, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China

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Hui Liu Head and Neck Oncology Surgical Department, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, China

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Xiaohong Zhou Head and Neck Surgery, Chongqing Cancer Hospital, Chongqing, Chongqing, China

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Tao Huang Breast and Thyroid Surgery, Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China

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Jianwu Qin Head and Neck Surgery, Henan Cancer Hospital, Zhengzhou, Henan, China

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Zhaohui Wang Head and Neck Surgery Department, Sichuan Cancer Hospital & Institute, Chengdu, Sichuan, China

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Mengmeng Qin Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, Jiangsu, China

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Zhenwei Shen Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, Jiangsu, China

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Sheng Yao Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, Jiangsu, China

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Jason Yang Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, Jiangsu, China

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Yu Wang Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China

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Ming Gao Thyroid Neck Oncology Department, Tianjin Medical University Cancer Institute & Hospital, Tianjin, Tianjin, China
Department of Breast and Thyroid Surgery, Tianjin Union Medical Center, Tianjin, Tianjin, China

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Pralsetinib has demonstrated efficacious activity in various solid tumors, including medullary thyroid cancer (MTC), as observed in the phase 1/2 global ARROW study (BLU-667-1101; NCT03037385). We evaluated the safety and efficacy of pralsetinib in Chinese patients with advanced RET-mutant MTC. In the extension cohort of ARROW, adult patients with advanced MTC, who had not received systemic therapy (except for cytotoxic chemotherapy), were treated with pralsetinib (400 mg once daily, orally). The primary endpoints were blinded independent central-reviewed (BICR) objective response rate (ORR) and safety. Between October 9, 2019, and April 29, 2020, 34 patients were enrolled at 12 centers across China. Among them, 28 patients tested positive for RET mutations in the central laboratory, and 26 of these, with measurable disease at baseline per BICR, were included in the analysis set for tumor response. As of April 12, 2021 (data cutoff), the ORR was 73.1% (95% CI: 52.2–88.4), and the median duration of response was not reached. The most common (≥15%) grade ≥3 treatment-related adverse events (TRAEs) in the 28 patients with RET-mutant MTC were neutrophil count decreased (8/28, 28.6%), blood creatine phosphokinase increased (6/28, 21.4%), and lymphocyte count decreased (5/28, 17.9%). Serious TRAEs were reported by six patients (21.4%), with the most common event being pneumonia (3/28, 10.7%). No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, as well as a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.

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