Andrea R. Hagemann

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.

Multiomic Characterization of Pre- and Post-Neoadjuvant Chemotherapy–Treated Ovarian Cancer Reveals Mediators of Tumorigenesis and Chemotherapy Response

Abstract High-grade serous ovarian cancer (HGSC) accounts for more than 200,000 deaths each year. Despite recent advances in treating HGSC with neoadjuvant chemotherapy, the majority of patients ultimately develop chemotherapy resistance. HGSC is characterized by TP53 mutations and widespread copy-number alterations and occurs frequently in the setting of deleterious germline BRCA1/2 variations, but many cases lack putative driver mutations. In this study, we performed whole-exome, whole-genome, and whole-transcriptome sequencing along with mass spectrometry to characterize the molecular landscape of HGSC in 22 paired samples obtained before and after neoadjuvant chemotherapy. Responsiveness to chemotherapy was determined for each patient. Evidence at the DNA, RNA, and protein level revealed numerous defects in cell–cell and cell–matrix interactions, as well as disruption of cell polarity and cytoskeletal regulation in HGSC, indicating that defects in epithelial integrity were present in the majority of patients with HGSC. Nonresponsive HGSC harbored subclones with putative survival mutations. Additionally, ineffective nonsense-mediated decay resulted in the persistence of transcripts with frameshift mutations that were translated into aberrant proteins detectable in HGSC samples. Together, these findings suggest that HGSC may arise through defects in the maintenance of epithelial integrity that lead to the shedding of malignant cells throughout the peritoneum, and the presence of resistant subclones prior to chemotherapy may decrease the chemosensitivity of patients. Significance: Comprehensive longitudinal characterization of ovarian cancer identifies pathways that promote tumorigenesis and provides insights into regulators of chemotherapy response, which could help develop strategies to improve outcomes for patients.

Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins

Abstract Ovarian cancer is the leading cause of gynecologic cancer–related deaths. The propensity for metastasis within the peritoneal cavity is a driving factor for the poor outcomes associated with this disease, but there is currently no effective therapy targeting metastasis. In this study, we investigate the contribution of stromal cells to ovarian cancer metastasis and identify normal stromal cell expression of the collagen receptor, discoidin domain receptor 2 (DDR2), that acts to facilitate ovarian cancer metastasis. In vivo, global genetic inactivation of Ddr2 impairs the ability of Ddr2-expressing syngeneic ovarian cancer cells to spread throughout the peritoneal cavity. Specifically, DDR2 expression in mesothelial cells lining the peritoneal cavity facilitates tumor cell attachment and clearance. Subsequently, omentum fibroblast expression of DDR2 promotes tumor cell invasion. Mechanistically, we find DDR2-expressing fibroblasts are more energetically active, such that DDR2 regulates glycolysis through AKT/SNAI1 leading to suppressed fructose-1,6-bisphosphatase and increased hexokinase activity, a key glycolytic enzyme. Upon inhibition of DDR2, we find decreased protein synthesis and secretion. Consequently, when DDR2 is inhibited, there is reduction in secreted extracellular matrix proteins important for metastasis. Specifically, we find that fibroblast DDR2 inhibition leads to decreased secretion of the collagen crosslinker, LOXL2. Adding back LOXL2 to DDR2 deficient fibroblasts rescues the ability of tumor cells to invade. Overall, our results suggest that stromal cell expression of DDR2 is an important mediator of ovarian cancer metastasis. Implications: DDR2 is highly expressed by stromal cells in ovarian cancer that can mediate metastasis and is a potential therapeutic target in ovarian cancer.

RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

Abstract Purpose: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. Experimental Design: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. Results: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P < 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78–1.0; P < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33–0.85; P < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25–0.75; P = 0.003) than RAD51-High status. Conclusions: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.

Cost-Effectiveness of Combined Minimally Invasive Hysterectomy and Bariatric Surgery in Women With Morbid Obesity and Endometrial Hyperplasia or Early-Stage Endometrial Cancer

We studied the cost-effectiveness of simultaneous bariatric surgery and minimally invasive hysterectomy (MIH) (combined surgery) in comparison to MIH alone in endometrial cancer (EC) survivors with obesity-related disease (ORD). Cost-effectiveness analysis. Hypothetical cohort of women aged 50 to 69 with obesity (BMI ≥ 30 kg/m Combined surgery vs MIH alone. We constructed a decision-analytic model with lifetime horizon to compare life expectancy and lifetime healthcare costs between patients with combined surgery and those with MIH alone. Utility weights, a measure of health states that affect quality of life, from published studies were used to calculate quality-adjusted life years (QALYs). Lifetime healthcare costs associated with ORD and costs for MIH and surgical complications were obtained from published studies. Costs for combined surgery were obtained from a single institution. All costs were evaluated from the healthcare sector perspective and presented in US dollars at the 2022 price level. Future costs and QALYs were discounted to present values using an annual rate of 3%. For the 50 to 59 age group, QALYs for combined surgery were 14.8 compared with 11.0 for MIH alone. The lifetime healthcare cost for patients with combined surgery was $186 124 compared with $335 995 for MIH alone. For the 60 to 69 age group, QALYs for combined surgery were 12.0 compared with 7.9 for MIH alone. The lifetime healthcare cost for patients with combined surgery was $155 451 compared with $273 403 for MIH alone. Combined surgery yielded higher QALYs and lower costs than MIH alone. For women with endometrial intraepithelial neoplasia or early-stage EC with obesity and ORD, combined surgery may represent a cost-saving and QALYs-improving option for treatment. However, barriers to this approach may be insurmountable.