David M. Gershenson

Phase II Trial of Ribociclib Plus Letrozole in Women With Recurrent Low-Grade Serous Carcinoma of the Ovary, Fallopian Tube, or Peritoneum: A GOG Partners Trial (GOG 3026)

PURPOSE Low-grade serous carcinoma (LGSOC) of the ovary, fallopian tube, or peritoneum is a hormonally driven, relatively chemoresistant malignancy with limited treatment options in the recurrent setting. Given frequent estrogen receptor (ER) expression and dysregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6)–p16–Rb pathway, features shared with hormone receptor–positive breast cancer, dual endocrine, and CDK4/6 inhibition is a biologically rational strategy. This phase II trial evaluated ribociclib plus letrozole in recurrent LGSOC. METHODS This open-label, single-arm, multicenter phase II study enrolled women with measurable, recurrent LGSOC. Patients received ribociclib (600 mg orally, once daily, days 1-21 of a 28-day cycle) and letrozole (2.5 mg orally, once daily). The primary end point was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary end points included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Of 74 patients screened, 51 were enrolled and 49 treated. The confirmed ORR was 30.6% (90% CI, 19.9 to 43.2), including one complete and 14 partial responses. Among responders, the median duration of response was 21.2 months. The CBR was 84% (90% CI, 72.5 to 91.6). The median PFS was 14.5 months (90% CI, 10.1 to 28.8), and the median OS was 44.5 months (90% CI, 31.8 to not reached). The most common grade ≥3 adverse event (AE) was neutropenia (47%), managed with dose modifications. Three grade 5 events (6%) occurred but were unrelated to treatment. Treatment discontinuation because of AEs occurred in 4%. No dose-limiting toxicities were observed. CONCLUSION Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

Molecular Profiling and Tumor Biomarker Analysis of GOG281/LOGS: A Positive Late-Phase Trial of Trametinib for Recurrent/Persistent Low-Grade Serous Ovarian Carcinoma

Abstract Purpose: Low-grade serous ovarian carcinoma (LGSOC) is a distinct form of ovarian cancer characterized by younger patient age and relative chemoresistance. The GOG281/LOGS trial (NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared with physician’s choice standard-of-care (SOC) in patients with LGSOC with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival (PFS) in the trametinib-treated arm. Experimental Design: Two hundred and sixty patients with recurrent/persistent LGSOC were enrolled and randomly assigned in GOG281. We performed molecular analysis of 170 patients with available tumor specimens, comprising whole-exome sequencing and phospho-ERK (pERK) IHC, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort (n = 170) were comparable with those of the total trial cohort. Results: High tumor pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs. 5.6 months, log-rank P < 0.0001; test for interaction P = 0.023). Tumors harboring canonical RAS–RAF–MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs. 8.3%; Barnard’s P = 0.0004; test for interaction P = 0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P = 0.719). KRAS amplification (n = 5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n = 25 without KRAS/NRAS/BRAF mutation or KRAS copy number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss (49% of cases) was associated with lower pERK expression (P = 0.021). Conclusions: This exploratory analysis suggests that pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

Repurposing Food and Drug Administration-approved cancer therapies: exploring endocrine and targeted pathways in low-grade serous ovarian cancer treatment

Low-grade serous ovarian cancer is a rare epithelial ovarian cancer with limited responsiveness to conventional chemotherapy, particularly, in advanced or recurrent settings. Low-grade serous ovarian cancer is characterized by an indolent growth pattern and a high prevalence of mitogen-activated protein kinase pathway alterations (KRAS, BRAF, NRAS) and hormone receptor positivity, highlighting the potential for targeted therapies. MEK inhibitors (eg, trametinib, binimetinib) specifically target the mitogen-activated protein kinase pathway, whereas endocrine therapies and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors exploit hormone-driven pathways. This review explores the repurposing of the therapeutic potential of both MEK inhibitors and breast cancer therapies, as endorsed by the National Comprehensive Cancer Network, to improve outcomes in low-grade serous ovarian cancer. This review synthesizes evidence supporting the repurposing of MEK inhibitors and breast cancer therapies (endocrine therapies, CDK4/6 inhibitors, and mammalian target of rapamycin inhibitors) as treatment approaches for low-grade serous ovarian cancer. Trametinib significantly improved progression-free survival in the GOG 281 trial, establishing MEK inhibition as a key therapeutic option. In addition, molecular similarities in estrogen receptor/progesterone receptor, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin, and CDK4/6 pathways between low-grade serous ovarian cancer and breast cancer provide a strong rationale for therapeutic crossover. Endocrine therapies demonstrated efficacy in low-grade serous ovarian cancer, particularly when combined with targeted agents to address resistance mechanisms. CDK4/6 inhibitors showed promise by blocking cell cycle progression and enhancing the response to endocrine therapies. In addition, mammalian target of rapamycin inhibitors have yielded clinical benefits in selected patients, emphasizing the importance of biomarker-driven treatment. Repurposing MEK inhibitors and endocrine-based approaches is shaping the treatment landscape for low-grade serous ovarian cancer, particularly in recurrent or advanced cases with limited treatment options. However, the variability in pathway alterations necessitates precise molecular profiling and optimized combination strategies. Future studies leveraging patient-derived models and advanced profiling techniques are critical for refining these approaches. These efforts may help expand National Comprehensive Cancer Network-endorsed options, and provide new hope for patients with hormone-sensitive low-grade serous ovarian cancer.

TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors

To evaluate survival outcomes among patients with adult-type granulosa cell tumors who have telomerase reverse transcriptase (TERT) promoter mutations. This is a retrospective cohort study using the MD Anderson Rare Gynecologic Malignancy Registry. Patients with adult granulosa cell tumors who underwent molecular testing for TERT promoter and FOXL2 c.C402G mutations were included. We used descriptive statistics to compare demographic and clinical variables and estimated progression-free and overall survival with Kaplan-Meier curves. Cox proportional hazards regression and log-rank tests were employed for comparisons, with multivariable analyses adjusting for various factors. Among 70 patients, 28 (40%) had TERT+ tumors. The median age at diagnosis was 40 years (range 12-71) for TERT- patients and 46 years (range 25-76) for TERT+ patients. At diagnosis, 22 (63%) of 35 TERT- patients were stage I, 10 (29%) stage II, and 3 (9%) stage III, while in the TERT+ group, 17/23 (74%) were stage I, 3 (13%) stage II, and 3 (13%) stage II. Univariable analysis showed no difference in time from diagnosis to first recurrence (p=0.19) and from first recurrence to second recurrence (p=0.24) based on tumor TERT status. The median time from first to second recurrence in the TERT- group was 27.3 months (95% CI 14.1 to 40.0) and in the TERT+ group was 14.8 months (95% CI 8.1 to 21.0). There was no observed difference in overall survival between the groups (HR=0.53; 95% CI 0.19 to 1.45; p=0.21).Multivariable analysis adjusting for age at diagnosis, TERT promoter mutation status, systemic chemotherapy, and stage demonstrated a significant difference in progression-free survival based on TERT mutation status (HR=2.89; 95% CI 1.32 to 6.36). After adjustment for covariates, patients with adult granulosa cell tumors and TERT+ tumors had shorter progression-free survival after first recurrence. TERT promoter mutations may identify a subset of patients with recurrent adult granulosa cell tumors and less favorable outcomes.

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer

There are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib has demonstrated efficacy and a consistent safety profile in two clinical trials in recurrent low grade serous ovarian cancer, and a lower discontinuation rate due to adverse events compared with historical rates for standard of care. To compare the progression-free survival of the combination of avutometinib with defactinib versus investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer. Combination treatment with avutometinib-defactinib will significantly improve progression-free survival compared with investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer. GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 is a phase 3, randomized, international, open-label study designed to compare avutometinib with defactinib versus investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer who have progressed on a previous platinum-based therapy. On confirmation of disease progression using a blinded independent central review, patients on the investigator's choice of treatment arm may cross over to the avutometinib-defactinib arm. Patients must have recurrent low grade serous ovarian cancer (KRAS mutant or wild-type) and have documented progression (radiographic or clinical) or recurrence of low grade serous ovarian cancer after at least one platinum-based chemotherapy regimen. Unlimited additional previous lines of therapy are allowed, including previous MEK/RAF inhibitor. Patients will be excluded if they have co-existing high grade ovarian cancer or had previous treatment with avutometinib, defactinib, or any other FAK inhibitor. Progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded-independent central review. Approximately 270 patients will be randomized in a 1:1 fashion to either the combination avutometinib with defactinib arm (n∼135) or the investigator's choice of treatment arm (n∼135). The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031. ClinicalTrials.gov NCT06072781.

Clinical and Genomic Landscape of RAS Mutations in Gynecologic Cancers

Abstract Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications. Experimental Design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan–Meier method, and multivariable analysis was performed using the Cox proportional hazard model. Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and lower grades (grade 1/2, 43.2% vs. 8.1%, all P < 0.0001). The highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n = 9/9), mesonephric-like ovarian (83.3%, n = 5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival [hazard ratio (HR) = 1.3; P = 0.001]. Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN (28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS + MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy [8.4 years [(95% confidence interval (CI), 5.5–12.0) vs. 5.5 years (95% CI, 4.6–6.6); HR = 0.67; P = 0.031], this effect did not persist in multivariable analysis. Conclusions: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

Impact of adjuvant chemotherapy on the overall survival of patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery

To investigate the use and outcomes of adjuvant chemotherapy for patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery. Patients diagnosed between 2010 and 2015 with International Federation of Gynecology and Obstetrics stage II-IV low-grade serous ovarian carcinoma who underwent primary debulking surgery with known residual disease status and had at least 1 month of follow-up were identified in the National Cancer Database. Adjuvant chemotherapy was defined as receipt of chemotherapy within 6 months of surgery. Overall survival was evaluated using the Kaplan-Meier method and compared with the log-rank test. A Cox model was constructed to control for a priori-selected confounders. A systematic review of the literature was also performed. In total, 618 patients with stage II-IV low-grade serous ovarian carcinoma who underwent primary cytoreductive surgery were identified; 501 (81.1%) patients received adjuvant chemotherapy, while 117 (18.9%) patients did not. The median follow-up of the present cohort was 47.97 months. There was no difference in overall survival between patients who did and did not receive adjuvant chemotherapy (p=0.78; 4-year overall survival rates were 77.5% and 76.1%, respectively). After controlling for patient age, medical co-morbidities, disease stage, and residual disease status, administration of adjuvant chemotherapy was not associated with better overall survival (HR=0.87, 95% CI 0.55 to 1.38). Based on data from three retrospective studies, omission of adjuvant chemotherapy following cytoreductive surgery was not associated with worse progression-free survival benefit (HR=1.25, 95% CI 0.80 to 1.95) for patients with stage III-V low-grade serous ovarian carcinoma. Adjuvant chemotherapy may not be associated with an overall survival benefit for patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery.

Survival outcomes in patients with recurrent mixed sex cord-stromal tumors of the ovary

Mixed sex cord-stromal tumors of the ovary contain combinations of granulosa cell tumor components-either adult or juvenile subtypes-and/or Sertoli-Leydig cell tumor elements. The objective of this study is to evaluate survival outcomes in recurrent mixed sex cord-stromal tumors. This is a retrospective cohort study of recurrent mixed ovarian sex cord-stromal tumors identified through the MD Anderson Rare Gynecologic Malignancy Registry between 2000 and 2025. Comparative cohorts with recurrent, histologically uniform adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors were included. Demographic and clinical characteristics were compared using descriptive statistics. Progression-free survival after first recurrence and overall survival from first recurrence were assessed using Kaplan-Meier methods and compared using log-rank tests. Sixteen patients with recurrent mixed ovarian sex cord-stromal tumors were identified: 6 (37.5%) with adult granulosa cell plus Sertoli-Leydig cell tumors, 4 (25%) with juvenile granulosa cell plus Sertoli-Leydig cell tumors, and 6 (37.5%) with adult plus juvenile granulosa cell tumors. When comparing adult granulosa cell tumors to adult plus juvenile granulosa cell tumors, significant differences in median progression-free survival-2 (21.2 vs 8.7 months, p = .03) and overall survival (181.9 vs 83.8 months, p = .001) were observed. No significant differences in progression-free survival-2 (p = .7) or overall survival (p = .8) were noted between juvenile granulosa cell tumors and adult plus juvenile granulosa cell tumors. Among tumors with molecular testing results, 25% (1 of 4) of adult plus juvenile granulosa cell tumors, 25% (1 of 4) of adult granulosa cell plus Sertoli-Leydig cell tumors, and 33% (1 of 3) of juvenile granulosa cell plus Sertoli-Leydig cell tumors were positive for the c.C402G FOXL2 mutation. Recurrent adult plus juvenile granulosa cell tumors may exhibit more aggressive clinical behavior than uniform adult granulosa cell tumors, aligning more closely with juvenile granulosa cell tumors in recurrence outcomes.

Low-grade serous ovarian cancer: expert consensus report on the state of the science

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade serous carcinoma diagnosis and treatment, a panel of experts convened for a workshop in October 2022 to develop a consensus document addressing pathology, translational research, epidemiology and risk, clinical management, and ongoing research. In addition, the patient perspective was discussed. The recommendations developed by this expert panel-presented in this consensus document-will guide practitioners in all settings regarding the clinical management of women with low-grade serous carcinoma and discuss future opportunities to improve research and patient care.

Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors

Abstract Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. After read alignment and quality-control filtering, DESeq2 was used to identify differentially expressed genes (DEG) between primary and recurrent tumors. Functional enrichment pathway analysis and gene set enrichment analysis was performed using “clusterProfiler” and “GSVA” R packages. TME composition was investigated through the analysis and integration of multiple published RNA-seq deconvolution algorithms. TME analysis results were externally validated using data from independent previously published RNA-seq datasets. A total of 31 DEGs were identified between primary and recurrent aGCTs. These included genes with known function in hormone signaling such as LHCGR and INSL3 (more abundant in primary tumors) and CYP19A1 (more abundant in recurrent tumors). Gene set enrichment analysis revealed that primarily immune-related and hormone-regulated gene sets expression was increased in recurrent tumors. Integrative TME analysis demonstrated statistically significant depletion of cancer-associated fibroblasts in recurrent tumors. This finding was confirmed in multiple independent datasets. Implications: Recurrent aGCTs exhibit alterations in hormone pathway gene expression as well as decreased infiltration of cancer-associated fibroblasts, suggesting dual roles for hormonal signaling and TME remodeling underpinning disease relapse.

Novel therapeutics in low-grade serous ovarian cancer

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-type

Gain-of-Function Chromatin Remodeling Activity of Oncogenic FOXL2C134W Reprograms Glucocorticoid Receptor Occupancy to Drive Granulosa Cell Tumors

Abstract Adult type ovarian granulosa cell tumors (AGCT) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a forkhead box family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence–specific chromatin remodeling activity in FOXL2. FOXL2C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduced viability, and dexamethasone rescued this effect. Combinatorial drug–drug interaction experiments demonstrated that dexamethasone antagonizes the potency of paclitaxel, a chemotherapy agent frequently used in the treatment of AGCT. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2C134W and creates a potentially targetable synergy with glucocorticoid signaling. Significance: Glucocorticoids promote granulosa cell tumor growth via epigenetic coregulation with the disease driver FOXL2C134W, providing mechanistic insight into disease oncogenesis and uncovering a potential treatment strategy.

A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer

This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with defactinib versus Investigator's choice of treatments (ICT) in subjects with recurrent LGSOC who have progressed on a prior platinum-based therapy.