Role of Androgen Receptor in Prostate Cancer: A Review

Kazutoshi Fujita,Norio Nonomura 대한남성과학회 2019 The World Journal of Men's Health Vol.37 No.3

Androgen receptor (AR) is a steroid receptor transcriptional factor for testosterone and dihydrotestosterone consisting of four main domains, the N-terminal domain, DNA-binding domain, hinge region, and ligand-binding domain. AR plays pivotal roles in prostate cancer, especially castration-resistant prostate cancer (CRPC). Androgen deprivation therapy can suppress hormone-naïve prostate cancer, but prostate cancer changes AR and adapts to survive under castration levels of androgen. These mechanisms include AR point mutations, AR overexpression, changes of androgen biosynthesis, constitutively active AR splice variants without ligand binding, and changes of androgen cofactors. Studies of AR in CRPC revealed that AR was still active in CRPC, and it remains as a potential target to treat CRPC. Enzalutamide is a second-generation antiandrogen effective in patients with CRPC before and after taxane-based chemotherapy. However, CRPC is still incurable and can develop drug resistance. Understanding the mechanisms of this resistance can enable new-generation therapies for CRPC. Several promising new AR-targeted therapies have been developed. Apalutamide is a new Food and Drug Administration-approved androgen agonist binding to the ligand-binding domain, and clinical trials of other new AR-targeted agents binding to the ligand-binding domain or N-terminal domain are underway. This review focuses on the functions of AR in prostate cancer and the development of CRPC and promising new agents against CRPC.

Genomic Profiling of Prostate Cancer: An Updated Review

Hatano Koji,Nonomura Norio 대한남성과학회 2022 The World Journal of Men's Health Vol.40 No.3

Understanding the genomic profiling of prostate cancer is crucial, owing to the emergence of precision medicine to guide therapeutic approaches. Over the last decade, integrative genomic profiling of prostate tumors has provided insights that improve the understanding and treatment of the disease. Minimally invasive liquid biopsy procedures have emerged to investigate cancer-related molecules with the advantage of detecting heterogeneity as well as acquired resistance in cancer. The metastatic castration-resistant prostate cancer (mCRPC) tumors have a highly complex genomic landscape compared to primary prostate tumors; a number of mCRPC harbor clinically actionable molecular alterations, including DNA damage repair (e.g., BRCA1/2 and ATM) and PTEN/phosphoinositide 3-kinase signaling. Heterogeneity in the genomic landscape of prostate cancer has become apparent and genomic alterations of TP53, RB1, AR, and cell cycle pathway are associated with poor clinical outcomes in patients. Prostate cancer with mutant SPOP shows a distinct pattern of genomic alterations, associating with better clinical outcomes. Several genomic profiling tests, which can be used in the clinic, are approved by the U.S. Food and Drug Administration, including MSK-IMPACT, FoundationOne CDx, and FoundationOne Liquid CDx. Here, we review emerging evidence for genomic profiling of prostate cancer, especially focusing on associations between genomic alteration and clinical outcome, liquid biopsy, and actionable molecular alterations.

Favorable Outcome in Elderly Asian Patients with Metastatic Renal Cell Carcinoma Treated with Everolimus: The Osaka Urologic Oncology Group

Inamoto, Teruo,Azuma, Haruhito,Nonomura, Norio,Nakatani, Tatsuya,Matsuda, Tadashi,Nozawa, Masahiro,Ueda, Takeshi,Kinoshita, Hidefumi,Nishimura, Kazuo,Kanayama, Hiro-Omi,Miki, Tsuneharu,Tomita, Yoshihi Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.4

Background: In clinical trials with no upper age limit, the proportion of older patients is usually small, probably reflecting the more conservative approach adopted by clinicians when treating the elderly. An exploratory analysis of elderly patients in the RECORD-1 Trial showed that patients ${\geq}$ 65 y.o. had superior median PFS than overall RECORD-1 population (5.4 months and 4.9 months, respectively). We investigated the efficacy, relative benefit and safety of Everolimus (EVE) as sequential therapy after failure of VEGFr-TKI therapy for older patients with metastatic renal cell cancer (mRCC), in daily practice. Materials and Methods: 172 consecutive IRB approved patients with mRCC (median age 65, M:F 135/37, 78% clear cell) who received salvage EVE at 39 tertiary institutions between October 2009 and August 2011 were included in this analysis. Some 31% had progressed on sunitinib, 22% on sorafenib, 1% on axitinib, 41% on sequential therapy, and 5% had received other therapy. Patients with brain metastases were not included and 95% of the patients had a ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0 or 1. Previous radiotherapy was an exclusion criterion, but prior chemotherapy was permitted. Adequate organ function and hematologic parameters were mandatory. EVE administration was approved by the institutional review board at each participating institution and signed informed consent was obtained from all patients. Results: Median time of the whole cohort to last follow-up was 3.5 months (range 0.4-15.2 months). Forty four percent were continuing to take EVE at last followup. There were 86 (50%) patients ${\geq}$ 65 y.o. and 86 (50%) <65 y.o. The percentage of patients who showed PR/SD was higher in the older group than in the younger one (5.9%/61.2% vs 1.2%/46.5%, respectively). Median survival of older patients was also significantly longer (3.5 +/- 0.31 vs 3.1 +/- 0.34, hazard ratio=0.45, CI; 0.255-0.802). Analysis using Cox regression model adjusted for gender, PS, number of metastases, site of metastases, histology, smoking history and age detected an association between age and PFS (p=0.011). The frequency of adverse events in elderly patients treated with EVE was no greater than that in younger patients, although such toxicity may have had a greater impact on their quality of life. Conclusions: Older patients should not generally be excluded from accepted therapies (mTOR inhibitors after failure of VEGFr-TKI therapy) for mRCC.

Erectile Dysfunction in Germ Cell Tumor Survivors

Okada Koichi,Fujita Kazutoshi,Fukuhara Shinichiro,Kiuchi Hiroshi,Uemura Motohide,Imamura Ryoichi,Nonomura Norio 대한남성과학회 2021 The World Journal of Men's Health Vol.39 No.3

Purpose: Germ cell tumors (GCTs) are the most common malignant neoplasms in adolescents and young adults, and most patients with these tumors can be completely cured. Therefore, maintaining quality of life (QOL) is important. Erectile dysfunction (ED) is one factor that reduces the QOL of GCT survivors. We aimed to clarify the relationship between ED and age, follow-up period, serum levels of hormones, and treatment methods for GCT survivors. Materials and Methods: We evaluated ED using the Sexual Health Inventory for Men questionnaire (SHIM) and measured serum levels of hormones in survivors after GCT treatment. The relationships between the SHIM score responses and age, serum levels of hormones, follow-up period, and treatment methods were assessed using a logistic analysis. Results: Fifty-two GCT survivors were enrolled and 46 survivors completed the SHIM. The median age, follow-up period, and SHIM score were 38 years, 35 months, and 18, respectively. Regarding the SHIM scores, 85% had scores <22 and 46% had scores <17. The percentage of SHIM scores <17 was 69% in patients with under 2 years of follow-up. It significantly improved to 33% in patients with over 2 years of follow-up. The multivariate analysis identified the follow-up period as an independent factor for SHIM scores <17. Age, serum levels of hormone, and treatment method were not significant factors for SHIM scores <17. Conclusions: Improvement of SHIM score can be expected after GCT treatment regardless of age, serum levels of hormone, and treatment method.