Kevin M. Elias

Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer

Abstract Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. Significance: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.

DNA Methylation Profiles of Ovarian Clear Cell Carcinoma

Abstract Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. Methods: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. Results: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10−4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10−6). Conclusions: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. Impact: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

Synthetic Lethality in Ovarian Cancer

AbstractOvarian cancers include several distinct malignancies which differ with respect to clinicopathologic features and prognosis. High-grade serous cancer is the most common histologic subtype and accounts for most ovarian cancer–related deaths. High-grade serous ovarian cancer (HGSOC) is treated with surgery and platinum-based chemotherapy, but most patients relapse and succumb to chemoresistant disease. The genetic concept of synthetic lethality, in which the synergy of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to overcome chemoresistance in ovarian cancer. Recent progress in understanding the genomic architecture and hereditary drivers of ovarian cancer has shown potential for synthetic lethality strategies designed around homologous DNA repair. Clinical trials have validated high response rates for PARP inhibitors in patients with BRCA1 or BRCA2 mutations. Here we discuss the biological rationale behind targeting BRCA–PARP synthetic lethality based on genetic context in ovarian cancer and how this approach is being assessed in the clinic. Applying the concept of synthetic lethality to target non–BRCA-mutant cancers is an ongoing challenge, and we discuss novel approaches to target ovarian cancer using synthetic lethality in combination with and beyond PARP inhibitors. This review will also describe obstacles for synthetic lethality in ovarian cancer and new opportunities to develop potent targeted drugs for patients with ovarian cancer.

Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Abstract Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental Design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838

Transforming treatment paradigms: Focus on personalized medicine for high‐grade serous ovarian cancer

AbstractHigh‐grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of ovarian cancer, accounting for approximately 70% of all ovarian cancer cases and contributing significantly to the high mortality rates associated with this disease. Because of the asymptomatic nature of early stage disease, most patients are diagnosed at advanced stages when the cancer has already spread into the abdominal cavity, requiring complex and intensive surgical and chemotherapeutic interventions followed by maintenance therapies. Although a minority of cases are associated with well defined genetic syndromes, specific risk factors and a clear etiology in many cases remain elusive. HGSOC tumors are characterized by a high frequency of somatic gene copy number alterations, often associated with defects in homologous recombination repair of DNA. All attempts to introduce an effective screening for HGSOC to date have been unsuccessful. This review elucidates the complexities surrounding HGSOC and encompasses its etiology, epidemiology, classification, pathogenesis, and the current array of treatment strategies. Understanding molecular underpinnings is crucial for the development of targeted therapies and personalized multimodal treatment approaches in centralized therapeutic structures. This review also examines the importance of the tumor microenvironment. In addition, the authors' objective is to underscore the critical importance of placing the patient's perspective and diversity at the forefront of therapeutic strategies, thereby fostering a genuinely participatory decision‐making process and ultimately improving patient quality of life.

Pembrolizumab in gestational trophoblastic neoplasia: Systematic review and meta-analysis with sub-group analysis of potential prognostic factors

To assess the performance of pembrolizumab for the treatment of Gestational Trophoblastic Neoplasia (GTN). The Medical Subject Headings related to immunotherapy/pembrolizumab and GTN were used alone or in combination to retrieve relevant articles. The authors searched in EMBASE, MEDLINE/PubMed, Elsevier's Scopus, and Web of Science until November/2024. The authors included any randomized controlled trials, cohort studies, case series, and case reports focusing on pembrolizumab treatment in GTN. Meta-analysis of proportions was carried out employing a random-effects model. The meta-analysis employed the inverse variance method, with the arcsine link function for the analysis of proportional data. All analyses were performed using Stata 18. For all analyses, a p-value < 0.05 indicated statistical significance. This study was registered on PROSPERO (CRD42023493329). A total of 550 studies were identified after a literature search among which 15 original studies were included in the systematic review and in the meta-analysis. Pembrolizumab induced complete sustained remission in 71.59% (95% CI 53.27‒84.78%; I Pembrolizumab seems an effective treatment for patients with high-risk GTN with chemoresistant or relapsed disease, including cases of PSTT/ETT, notwithstanding patient age, time to initiate immunotherapy and whether or not it was associated with chemotherapy.

Recurrence and resistance risk factors in low- risk gestational trophoblastic neoplasia

Gestational trophoblastic neoplasia (GTN) is a group of rare but highly curable pregnancy-related tumors, especially in low-risk cases. However, around 25% of patients with GTN develop either resistant or recurrent disease after initial chemotherapy. To enhance the understanding of the mechanisms driving treatment failures and to develop more personalized and effective therapeutic strategies, this review explored diverse factors influencing low-risk GTN prognosis. These factors include FIGO (International Federation of Gynecology and Obstetrics) risk score, histology, patient age, pregnancy type, human chorionic gonadotropin (hCG) levels, disease duration, tumor characteristics, metastasis, Doppler ultrasonography, and consolidation chemotherapy. Additionally, the review examined independent risk determinants for disease recurrence and resistance to single-agent chemotherapy in patients with low-risk GTN. In most previous studies on the risk factors related to low-risk GTN, resistance and recurrence have typically been examined independently, despite their overlapping and interrelated nature. Furthermore, they often involve small sample sizes, suffer from methodological shortcomings, and exhibit limited statistical power. Studies utilizing multivariate analysis have shown that independent risk determinants for resistance to firstline treatment include FIGO score, metastatic disease, pre-treatment hCG level, interval between antecedent pregnancy and GTN diagnosis, tumor size, uterine artery pulsatility index (UAPI), choriocarcinoma, lung metastases, lung nodule size, and clearance hCG quartile. The independent predictive factors associated with recurrence include lung metastases, lung nodule size, interval between antecedent pregnancy and chemotherapy, interval from first chemotherapy to hCG normalization, post-delivery low-risk GTN, number of chemotherapy courses to achieve hCG normalization, and number of consolidation chemotherapy cycles. However, while these identified predictive factors offer valuable guidance, the variability in definitions and populations across studies may have implications for the generalizability of their findings. A comprehensive approach using clear definitions and taking into account multiple predictive factors may be necessary for accurately assessing the risk of resistance and recurrence in patients with low-risk GTN.

Differences in Serum miRNA Profiles by Race, Ethnicity, and Socioeconomic Status: Implications for Developing an Equitable Ovarian Cancer Screening Test

Abstract Serum miRNAs are promising biomarkers for several clinical conditions, including ovarian cancer. To inform equitable implementation of these tests, we investigated the effects of race, ethnicity, and socioeconomic status on serum miRNA profiles. Serum samples from a large institutional biobank were analyzed using a custom panel of 179 miRNA species highly expressed in human serum, measured using the Abcam Fireplex assay via flow cytometry. Data were log-transformed prior to analysis. Differences in miRNA by race and ethnicity were assessed using logistic regression. Pairwise t tests analyzed racial and ethnic differences among eight miRNAs previously associated with ovarian cancer risk. Pearson correlations determined the relationship between mean miRNA expression and the social deprivation index (SDI) for Massachusetts residents. Of 1,586 patients (76.9% white, non-Hispanic), compared with white, non-Hispanic patients, those from other racial and ethnic groups were younger (41.9 years ± 13.2 vs. 51.3 ± 15.1, P &amp;lt; 0.01) and had fewer comorbidities (3.5 comorbidities ± 2.7 vs. 4.6 ± 2.8, P &amp;lt; 0.01). On logistic regression, miRNAs predicted race and ethnicity at an AUC of 0.69 (95% confidence interval, 0.66–0.72), which remained consistent when stratified by most comorbidities. Among eight miRNAs previously associated with ovarian cancer risk, seven significantly varied by race and ethnicity (all P &amp;lt; 0.01). There were no significant differences in SDI for any of these eight miRNAs. miRNA expression is significantly influenced by race and ethnicity, which remained consistent after controlling for confounders. Understanding baseline differences in biomarker test characteristics prior to clinical implementation is essential to ensure instruments perform comparably across diverse populations. Prevention Relevance: This study aimed to understand factors affecting miRNA expression, to ensure we create equitable screening tests for ovarian cancer that perform well in diverse populations. The goal is to ensure that we are detecting ovarian cancer cases earlier (secondary prevention) in women of all races, ethnic backgrounds, and socioeconomic means.