Ovarian Adult-Type Granulosa Cell Tumor: Focusing on Endocrine-Based Therapies

Abstract

FOXL2 mutation is diagnostic, and, if pathology is in doubt, it should be performed.• Surgical resection and staging is key to assess prognosis.• Platinum-based adjuvant chemotherapy such as with carboplatin plus paclitaxel is a reasonable step for women diagnosed with distant recurrences or poor prognostic initial features. However, evidence for improved outcome is lacking. • Hormone-based therapies, especially with aromatase inhibitors, have shown activity and future studies may lead to further insight on the relationship of inhibition of hormonal pathways and tumor progression.Adult-typegranulosa cell tumors (GCTs), although rare, are the most commonly diagnosed neoplasms arising in the endocrine-active ovarian stroma. They are characterized by excessive production of estrogens, antimullerian hormone and inhibins. In 2009, a specific mutation in FOXL2 was identified to be pathognomonic of GCTs. How dysregulation of this transcription factor, resulting in upregulation of aromatase, leads to unchecked proliferation, and progression to a malignancy, remains unclear. The key pathological and clinical feature of GCTs that affects their usually favorable outcomes is a diagnosis of greater than Stage 1 disease at presentation. Chemotherapy is given as adjuvant upon an advanced stage diagnosis; however, its effect on survival upon recurrence is modest. On the other hand, aromatase inhibitors also lead to tumor regression and are suitable for long-term maintenance.

Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer

“…Estrogen-targeting therapies have shown marked promise in the treatment of GCTs [ 87 ]. In early studies prior to the use of aromatase inhibitors, tamoxifen produced a response rate (8%) and stable disease rate (32%) comparable to those obtained with epithelial ovarian cancer subtypes [ 87 ]. However, it is the aromatase inhibitors that are of great interest here.…”

“…However, it is the aromatase inhibitors that are of great interest here. As mentioned above, one of the consequences of the FOXL2 mutation is an increase in aromatase activity in malignant granulosa cells, and this, leads through an undefined mechanism, to sensitivity to aromatase inhibitors [ 87 ]. In a review summarizing the use of the aromatase inhibitors as single agents, 25 cases with known outcomes are described.…”

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord–Stromal Tumors: A Contemporary Review

“…A more recent review in 2018 provided an updated meta-analysis including 12 different combinations of non-AI hormonal therapies (including GnRH agonists/antagonists, tamoxifen, progesterone, and diethylstilbestrol-DES), among 50 patients. The pooled analysis found clinical benefit for 33 of 50 patients and at least partial response in 17 patients [143]. The same review also compiled data for AI specifically, including letrozole, anastrozole, and exemestane.…”

“…In this data set of 25 patients, 7 experienced complete response, 5-partial response, and 7-disease stability for a total of 19 patients with clinical benefit. Given the favorable side effect profile, the authors concluded that AI may be an alternative to chemotherapy [143].…”

“…There has been considerable interest surrounding AI given the data above and that FOXL2 is also known to activate aromatase [143]. The phase 2 PARAGON trial, which investigated anastrozole in a variety of gynecologic cancers, included a cohort of 41 postmenopausal recurrent granulosa cell tumor patients with estrogen receptor-positive disease.…”