Journal Article

Sex hormones influence survival of patients with metastatic urothelial carcinoma undergoing immune checkpoint therapy

Pichler, Martin, Kocher, Florian, Lindner, Andrea Katharina, Seeber, Andreas, Toth, Bettina, Lackner, Felizian, Tymoszuk, Piotr, Hochleitner, Margarethe, Barth, Dominik Andreas, Pichler, Renate

2023

Overview

Introduction Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI. Material and methods Sex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17β-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks. Results Twenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders ( p  = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders ( p  = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS ( p  = 0.014 for LH, p  = 0.016 for LH/FSH ratio) and OS ( p  = 0.026 and p  = 0.018). In male patients, increased E2 levels were linked with improved PFS ( p  < 0.001) and OS ( p  = 0.039). Conclusion Increased LH and LH/FSH values in women as well as high E2 levels in men were significant predictors of better survival. Elevated LH/FSH ratio was predictive of better response to ICI in women. These results show first clinical evidence of the potential role of sex hormones as prognostic and predictive biomarker in mUC. Further prospective analyses are needed to corroborate our findings. Plain language summary Urothelial carcinoma (UC) presents as aggressive disease with a greater incidence in men, yet a more aggressive course of disease in women. Patients with metastatic UC receive a chemotherapy regimen as the gold standard, based on an included platin substance. In the case of having contraindications to chemotherapy, checkpoint immunotherapy, priming the immune system to the tumor, is the treatment of choice. Furthermore, immunotherapy is used as second line therapy in progressive disease after chemotherapy and as maintenance therapy in stable tumor conditions after completing the chemotherapy regimen. Evidence shows that sex hormones of the hypothalamus–hypophysis axis influence development and course of UC. The sex hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate estrogen (E2) production with a negative feedback function on the LH and FSH secretion. High levels of E2 present with a protective effect against UC. Sex has furthermore shown to predict potential response to immunotherapy. This study therefore focused on monitoring and correlating changes of sex hormone levels in 28 patients during therapy with checkpoint inhibitors. This first study assessing changes in sex hormones and the influence of baseline sex hormone values on survival in UC shows that responders to immunotherapy had significantly increased FSH levels. FSH furthermore increased in male patients receiving second line immunotherapy. High values of LH and a high LH/FSH ratio at baseline correlated with better overall survival in female patients. High E2 levels were indicative of better survival in male patients. The study results represent first suggestive prognostic and predictive results to the response of immunotherapy in UC. Highlights Increased LH and LH/FSH values in women as well as high E2 levels in men were significant predictors of better survival. Elevated LH/FSH ratio was predictive of better response to immunotherapy in women. First clinical evidence of the potential role of sex hormones as prognostic and predictive biomarkers in metastatic urothelial cancer.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 17β-Estradiol / Analysis / Androgens / Antimitotic agents / Antineoplastic agents / Biomedical and Life Sciences / Biomedicine / Bladder / Bladder cancer / Cancer / Cancer therapies / Carcinoma / Care and treatment / Chemotherapy / Clinical trials / Endocrinology / Estrogen / Estrogens / Females / Follicle-stimulating hormone / Glycoproteins / Gonadotropins / Histopathology / Hormone replacement therapy / Human Physiology / Immune checkpoint inhibitors / Immunotherapy / Luteinizing hormone / Metastases / Metastasis / Metastatic urothelial carcinoma / Monoclonal antibodies / Overall survival / Patient outcomes / Patients / Pembrolizumab / Prognostic / Prolactin / Remission (Medicine) / Sex hormones / Survival / Testosterone / Urothelial cancer / Urothelial carcinoma / Womens health