Objectives: There remains a need to develop targeted therapies for recurrent AGCT that produce measurable tumor responses. The FOXL2C134W mutation is identified in nearly all AGCT. In a genetically engineered mouse model utilized by Cluzet et al., tumorigenesis was associated with the inactivation of p53 and Rb pathways, increased circulating androgens, estradiol, and antimullerian hormone along with decreased FOXL2 abundance [1]. By examining the pathways involved in granulosa cell development, including limitations on GnRH-induced apoptosis, aromatase induction, and increased androgen expression, a novel treatment regimen is proposed for recurrent AGCT: bicalutamide (androgen receptor antagonist), exemestane (aromatase inhibitor), and leuprolide acetate (gonadotropin-releasing hormone receptor agonist) to block excess steroidogenesis seen in AGCT. Methods: Six patients identified at our institution with recurrent AGCT and tumor AR positive (by Leica IHC-AR27 antibody) were treated with bicalutamide 50mg PO once daily, Exemestane 25mg PO once daily, and Leuprolide acetate 3.75mg IM every four weeks. All patients were heavily pre-treated, with two to seven prior lines of therapy and had undergone two to seven surgeries. Prior treatment lines consisted of prior chemotherapy, hormonal therapy, and targeted therapies, including bevacizumab and everolimus. Patients were monitored for toxicities and for response to treatment via surveillance exams, inhibin B levels and CT scans. Results: Based on RECIST v1.1 criteria, of the six patients receiving bicalutamide, exemestane, and leuprolide acetate, two patients had a partial response, four patients had stable disease and one patient had progressive disease. Strong AR expression in 95% of cells was identified in the tumors of patients who had a partial response. This drug combination has been well-tolerated. There has been one hospitalization for disease-related complications; no other grade 3 or higher toxicities reported thus far. Conclusions: Based on the response of our institutional cohort and the rationale behind the antiandrogen/aromatase inhibitor/GnRH agonist combination in recurrent AGCT, this regimen of bicalutamide/exemestane/leuprolide acetate is a promising treatment. An NRG concept has been submitted to proceed with a single-arm, multicenter phase II study of this regimen in patients who meet the criteria of recurrent AGCT, AR expression, measurable disease, and one prior line of therapy. Objectives: There remains a need to develop targeted therapies for recurrent AGCT that produce measurable tumor responses. The FOXL2C134W mutation is identified in nearly all AGCT. In a genetically engineered mouse model utilized by Cluzet et al., tumorigenesis was associated with the inactivation of p53 and Rb pathways, increased circulating androgens, estradiol, and antimullerian hormone along with decreased FOXL2 abundance [1]. By examining the pathways involved in granulosa cell development, including limitations on GnRH-induced apoptosis, aromatase induction, and increased androgen expression, a novel treatment regimen is proposed for recurrent AGCT: bicalutamide (androgen receptor antagonist), exemestane (aromatase inhibitor), and leuprolide acetate (gonadotropin-releasing hormone receptor agonist) to block excess steroidogenesis seen in AGCT. Methods: Six patients identified at our institution with recurrent AGCT and tumor AR positive (by Leica IHC-AR27 antibody) were treated with bicalutamide 50mg PO once daily, Exemestane 25mg PO once daily, and Leuprolide acetate 3.75mg IM every four weeks. All patients were heavily pre-treated, with two to seven prior lines of therapy and had undergone two to seven surgeries. Prior treatment lines consisted of prior chemotherapy, hormonal therapy, and targeted therapies, including bevacizumab and everolimus. Patients were monitored for toxicities and for response to treatment via surveillance exams, inhibin B levels and CT scans. Results: Based on RECIST v1.1 criteria, of the six patients receiving bicalutamide, exemestane, and leuprolide acetate, two patients had a partial response, four patients had stable disease and one patient had progressive disease. Strong AR expression in 95% of cells was identified in the tumors of patients who had a partial response. This drug combination has been well-tolerated. There has been one hospitalization for disease-related complications; no other grade 3 or higher toxicities reported thus far. Conclusions: Based on the response of our institutional cohort and the rationale behind the antiandrogen/aromatase inhibitor/GnRH agonist combination in recurrent AGCT, this regimen of bicalutamide/exemestane/leuprolide acetate is a promising treatment. An NRG concept has been submitted to proceed with a single-arm, multicenter phase II study of this regimen in patients who meet the criteria of recurrent AGCT, AR expression, measurable disease, and one prior line of therapy.
Search from 250 M+ research papersSearch from 250 M+ research papers
Open Access
Oct 1, 2022
Duc Thanh Le + 4
