Novel therapeutics in low-grade serous ovarian cancer

Abstract

Low-grade serous ovarian cancer is a rare subtype of epithelial ovarian cancer clinically characterized by younger age at diagnosis, relative chemoresistance, and prolonged survival compared with its high-grade serous counterpart. It is molecularly characterized by estrogen and progesterone receptor positivity, aberrations in the MAPK (mitogen-activated protein kinase) pathway, and wild-typeTP53expression pattern. As research into low-grade serous ovarian cancer as a distinct entity has been able to accelerate independently, we have learned more about its unique pathogenesis, oncogenic drivers, and opportunities for novel therapeutics. In the primary setting, cytoreductive surgery in combination with platinum-based chemotherapy remain the standard of care. However, low-grade serous ovarian cancer has demonstrated relative chemoresistance in the primary and recurrent settings. Endocrine therapy is also commonly utilized in the maintenance and recurrent settings and is being evaluated in the adjuvant setting. Given the many similarities of low-grade serous ovarian cancer to luminal breast cancer, many recent studies have utilized similar therapeutic strategies including endocrine therapy combinations with CDK (cyclin-dependent kinase) 4/6 inhibitors. Additionally, recent trials have investigated combination therapies targeting the MAPK pathway, including MEK (mitogen-activated protein kinase kinase), BRAF (v-raf murine sarcoma viral oncogene homolog B1), FAK (focal adhesion kinase), and PI3K (phosphatidylinositol 3-kinase) inhibition. In this review, we will outline these novel therapeutic strategies for low-grade serous ovarian cancer.

Characterization and prognostic impact of ACTBL2-positive tumor-infiltrating leukocytes in epithelial ovarian cancer

“…Kurman et al postulated a dualistic model, claiming that LGSC is a separate tumor entity due to specific histological characteristics and substantial molecular differences 7 , 30 , 60 . Patients with LGSC are characterized by a younger age at diagnosis and a better overall survival despite showing a relative resistance against platinum-taxane-based therapy due to its lower mitotic rate, warranting alternative and subtype-specific treatment strategies 61 , 62 . Since the majority of LGSC shows a positive estrogen receptor expression, hormone-based maintenance therapy revealed a promising effect on median progression-free survival compared to patients only undergoing clinical observation 63 .…”

“…Since the majority of LGSC shows a positive estrogen receptor expression, hormone-based maintenance therapy revealed a promising effect on median progression-free survival compared to patients only undergoing clinical observation 63 . Other therapeutic options include the use of CDK4/6 inhibitors 61 and MEK inhibitor Trametinib for recurrent disease since the MAP-kinase pathway was shown to be a crucial part of LGSC pathogenesis 64 , 65 . To date, comprehensive analyses regarding the tumor microenvironment of LGSC considering the use and efficacy of immune checkpoint inhibition are missing, presumably because of its comparably rare occurrence.…”

Systematic Review of the Survival Outcomes of Neoadjuvant Chemotherapy in Women with Malignant Ovarian Germ Cell Tumors

“…Chemosensitivity is an important factor in NACT for EOC, and HGSC shows a good response (65–80%) to platinum-based chemotherapy [ 51 , 52 ]. Nevertheless, CCC, MOC, and LGSC are considered less chemoresponsive (10–30%) than conventional platinum-based chemotherapy [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. Differences in chemosensitivity based on the histological type of the tumor may result in different outcomes stemming from NACT for EOC.…”

Exploring novel approaches in the systemic therapy of low-grade serous carcinoma of the ovary: a literature review

“…In metastatic luminal breast cancer, the role of CDK 4/6 inhibitors in combination with endocrine therapy is well established, with phase 3 studies demonstrating significant improvements in PFS and OS ( 59 ). As LGSC presents similarities to hormone receptor-positive breast cancer ( 60 ), studies are being developed to evaluate the efficacy of this combination in this scenario.…”