OBJECTIVE:The primary aim of this study was to determine if metformin, an oral biguanide administered with first-line chemotherapy and continued as maintenance therapy, improves progression-free survival (PFS) for patients with advanced-stage ovarian cancer. METHODS:Patients with pathologically confirmed advanced-stage ovarian cancer undergoing primary debulking or neoadjuvant platinum-based chemotherapy followed by surgery were eligible to participate. Patients were randomized 1:1 to receive platinum/taxane-based chemotherapy with metformin 850 mg orally twice per day or placebo, followed by maintenance therapy (metformin or placebo) for two years from the date of randomization. RESULTS:108 evaluable patients were enrolled; 54 were randomly assigned to metformin, and 54 to placebo. Sixty-six percent (n = 71) received neoadjuvant therapy, 31 % (n = 33) primary debulking surgery, and 88 % (n = 93) had tumors of high-grade serous histology. The primary endpoint, PFS, was not significantly different between the treatment groups (1-sided p-value = 0.31; adjusted hazard ratio [HR] = 0.87, 95 % confidence interval [CI]: 0.56-1.36). Median PFS was 15.4 months (95 % CI: 11.2-23,5) for metformin and 14.3 months (95 % CI: 11.6-18.0) for placebo. Overall survival (OS) was not significantly different (2-sided p-value = 0.21; adjusted HR = 1.49, 95 % CI: 0.86-2.59), with a median of 40.7 months (95 % CI: 28.0-48.2) for metformin versus 43.8 months (95 % CI: 35.3-57.2) for placebo. The addition of metformin was well tolerated, and there were no differences in toxicity between the two groups. CONCLUSION:Although it was well-tolerated, adding metformin to first-line platinum/taxane-based therapy does not improve PFS or OS for patients with newly diagnosed advanced stage ovarian cancer.

High-grade serous carcinoma (HGSC) is the most common ovarian cancer subtype, typically diagnosed at late stages with poor prognosis. Understanding early molecular events driving HGSC progression is crucial for timely detection and development of effective treatment strategies. We performed and integrated spatial cell-type resolved proteomics and paired transcriptomics across 25 women with precursor lesions of the fallopian tube and/or HGSC. Epithelial cell signatures revealed early activation of SUMOylation machinery, increased ATR and Wnt signaling, and enhanced MHC-I antigen presentation along the disease trajectory. The stroma exhibited extracellular matrix remodeling and interferon-mediated inflammation. Serous tubal intraepithelial carcinomas (STICs) in cancer patients contained a pro-coagulative signature and reduced APOA1/2 compared to STICs in individuals without cancer. We functionally established important roles of epithelial-derived TRIP13 and SUMOylation, and cancer-associated fibroblast-derived SULF1 and BGN in HGSC progression. These findings provide unique molecular insights into HGSC pathogenesis and identify potential new therapeutic targets for intervention.

Gravid hysterectomy is a management option for providing abortion care in the setting of placenta accreta spectrum. However, performing a gravid hysterectomy requires significant multidisciplinary coordination to ensure a safe outcome for the pregnant individual. In this Narrative Review, we review the limited data surrounding gravid hysterectomy, perioperative considerations for conducting a gravid hysterectomy, a case of perioperative outcomes for a patient who underwent a gravid hysterectomy, and recommendations for future directions in research and clinical innovations in the management of placenta accreta spectrum and procedural abortion care.

Objectives:To characterize stage I-III Grade 3 endometroid endometrial cancer (Gr3 EEC) by molecular subtype and human epithelial growth factor receptor 2 (HER2) status and explore differences in characteristics by race. Methods:We identified patients with a diagnosis of stage I-III Gr3 EEC from a single-institution health system cancer registry and pathologically confirmed the diagnosis. Review of the electronic health record was performed as needed to confirm patient characteristics. Next-generation sequencing (NGS) and immunohistochemical staining (IHC) for HER2 was performed on all primary tumors. Results:Thirty-four primary cases remained classified as stage I-III Gr3 EEC after pathologic review and exclusion of cases lacking in-house primary tumor for re-review. Fifteen were categorized as microsatellite unstable (MSI; 44 %), 10 as copy number high (CNH; 29 %), six as polymerase E mutant (POLEmut; 17.6 %) and three as copy number low (CNL; 8.8 %). Thirteen patients were Black, 18 were White, and 3 had a race of "other and/or unknown". HER2 status by IHC in the primary tumor was 0 (n = 7; 20.5 %), 1+ (n = 11; 32 %), 2+ (n = 14; 41 %), 3+ (n = 1; 3 %). There was no difference in the distribution of TCGA subtype or HER2 status by race. Conclusion:In stage I-III stage Gr3 EEC HER2 positivity (3 + ) was uncommon, but expression at the 2 + level was frequent, and did not differ by race. In this limited sample, there were no differences in distribution of TCGA subtype amongst patients with grade 3 EEC. Other causes should be explored to explain reported differences in outcomes in EEC by race.

OBJECTIVE:To identify associations between race, neighborhood disadvantage, and outcomes in women with stage I-III endometrioid endometrial cancer (EEC) treated at a tertiary referral center. METHODS:This retrospective tumor registry study included patients with stage I-III EEC between 1/2006 and 12/2022. Progression-free (PFS) and overall survival (OS) were analyzed by race and neighborhood disadvantage, stratified by Area Deprivation Index (ADI; national quartile). RESULTS:Of 797 patients included, 112 (14 %) resided in the least disadvantaged quartile, 267 (34 %) in the second ADI quartile, 248 (31 %) in the third ADI quartile, and 170 (21 %) in the most disadvantaged quartile. A greater proportion of Black than White patients lived in the most disadvantaged areas (39 % vs 16 %, p < 0.01). In adjusted Cox-proportion model for PFS, older age, higher grade, higher stage and living in the least disadvantaged areas were associated with a higher risk of progression, however, in adjusted model for OS, only higher stage and older age were associated with a higher risk of death. Race was not associated with PFS or OS. CONCLUSIONS:In women with Stage I-III EEC treated at a single tertiary referral center, we did not find differences in outcomes when analyzed by ADI or race. Given previously reported racial disparities in outcomes for women with EEC, our data may reflect increased resources available to patients with access to a tertiary center regardless of residence. Future studies should focus on broader geographic areas and more individual measurements of vulnerability.

PURPOSE:Increasing genomics-based evidence suggests that synchronous endometrial and ovarian cancer (SEOC) represents clonally related primary and metastatic tumors. A systematic analysis of the global protein landscape of SEOCs, heretofore lacking, could reveal functional and disease-specific consequences of known genetic alterations, the directionality of metastasis, and accurate histologic markers to distinguish SEOCs from single-site tumors. EXPERIMENTAL DESIGN:We performed a systematic proteogenomic analysis of 29 patients diagnosed with SEOC at three international gynecologic oncology treatment centers (Chicago, Vancouver, and Tübingen). For direct comparison with single-site tumors, we included 9 patients with single-site endometrioid ovarian and 26 patients with single-site endometrioid endometrial cancer (EEC). For all 64 patients, we performed sequencing of a 275-gene cancer panel combined with compartment-resolved mass spectrometry-based proteomics of consecutive tissue sections to compare global (6,000+ proteins), tumor, and stromal proteomes. RESULTS:DNA-based panel sequencing confirmed that most SEOCs are clonally related. Global proteome profiling uncovered pronounced differences between SEOCs and single tumors and underscored the importance of the stromal proteome in defining and identifying SEOCs. We identified molecularly unique SEOC stromal proteomes, which were globally more related to single endometrial cancers. We finally derived a proteomic predictor distinguishing SEOCs from single-site ovarian and uterine tumors. CONCLUSIONS:The integrated proteogenomic data show that SEOCs are distinguishable from endometrioid endometrial or endometrioid ovarian cancer. Based on their proteogenomic similarity to EECs, we conclude that most SEOCs represent primary EECs that have metastasized to the ovary.

Abstract Background: Low-grade serous ovarian cancer (LGSC) is a rare subtype of epithelial ovarian cancer, accounting for 5% of all cases. These cancers are marked by resistance to cytotoxic chemotherapy and frequently exhibit MAP kinase (MAPK) pathway mutations. LGSC is thought to arise either de-novo, or develop from its putative precursor, serous borderline tumor (SBT). Herein, we sought to characterize the genomic and immune landscape of LGSC and SBT. Methods: De-identified records of 6,605 patients with ovarian cancer were retrospectively analyzed. Selection criteria included a histologic diagnosis of low-grade serous ovarian cancer (LGSC) and serous borderline ovarian tumor (SBT). Tumor sequencing was performed via the Tempus xT assay, a targeted, tumor-normal-matched DNA panel that detects single-nucleotide variants, insertions and/or deletions, and copy number variants in 648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Tumor mutational burden (TMB), microsatellite instability (MSI) status and immunologic markers including PD-L1 status were also assessed in this cohort. The prevalence of individual gene alterations were described and compared by Chi-squared/Fisher’s Exact tests and adjusted for multiple testing using false discovery rate methods. Results: A total of 132 LGSC and SBT samples were included in the analysis (LGSC, n = 108; SBT, n = 24). The median age at diagnosis was 55 years in LGSC and 57 years in SBT. Approximately 51% (n=55) of LGSC and 75% (n=18) of SBT had MAPK pathway-related gene mutations (p=0.032). Notably, BRAF mutations were significantly more prevalent in SBT compared to LGSC cases (46% vs. 8%, q=0.001). The most common BRAF mutation was BRAF V600E, accounting for 82% of BRAF-mutated SBT and 50% of BRAF-mutated LGSC. In contrast, 11% of LGSC patients carried an NRAS mutation compared to 4% in SBT, although this result did not approach statistical significance. ATM (8.3%) was the most common non-MAPK altered gene in SBT, whereas CREBBP (3.7%) and HNF1B (3.7%) alterations were the most frequently altered non-MAPK genes in LGSC. Median TMB was the same in both LGSC and SBT (1.17 mutations/Mb) and 100% of patients in both cohorts with MSI results were MSI-low or MSI-stable. Approximately 3.6% of LGSC cases and 10% of SBT cases with available PD-L1 testing results were PD-L1 positive. Conclusions: In our cohort, SBT and LGSC share a similar microsatellite stable status, low PD-L1 expression and a high percentage of MAP kinase pathway mutations. The higher incidence of BRAF mutations in SBT and increased frequency of NRAS mutations in LGSC suggest that MAPK pathway gene mutations may differentially impact propensity for tumor behavior and malignant potential. Citation Format: Rahul Krishnan, Agnes Bilecz, Paula Herbst, Aasa Shimizu, Lisa Schweizer, Ellen Jaeger, Jen Godden, Melissa Stoppler, Diane Yamada, Ernst Lengyel. Characterizing the genomic and immunologic landscape of serous borderline tumors and low-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A107.

IntroductionPrimary lymphomas of the gynecologic tract are a rare pathology that may present with typical gynecologic symptoms. Unlike other gynecologic malignancies, surgical management is not considered an essential part of the treatment regimen for gynecologic lymphomas but may be required for diagnosis. The purpose of this series is to report on symptom presentation and management from the gynecologic specialist’s perspective.MethodsRecords from an institutional pathology database identified patients diagnosed with primary gynecologic lymphoma between 1993 and 2023.ResultsEight patients were identified for this series. Patients presented with pelvic pain, abnormal vaginal bleeding, and/or a mass on pelvic exam. The majority were diagnosed with lymphoma only after surgical resection. The most common pathology was diffuse large B-cell lymphoma (DLBCL). Seven of the eight patients received chemotherapy, which was administered by a medical oncologist.ConclusionsOur series highlights the presentation, diagnostic workup, and management of gynecologic lymphomas with attention to the role of surgical management and intraoperative pathologic evaluation as well as medical treatment of these cancers after surgical debulking.

Supplementary Figure S1. Sequencing of HGSOC reveals conserved mutational signatures and TP53 mutations. Supplementary Figure S2. Distribution of mutations and mutational signatures in HGSOC. Supplementary Figure S3. Genomic instability is a core feature of ovarian cancer that frequently involves DNA-damage repair genes. Supplementary Figure S4. Annotated dendrograms of HGSOC metastatic trajectories. Supplementary Figure S5. Ex vivo model of metastasis to the fallopian tube. Supplementary Figure S6. In vitro model of HGSOC-fallopian tube adhesion.

Epithelial serous borderline tumors (SBT) are non-invasive neoplastic ovarian lesions that may recur as chemo-resistant low-grade serous cancer (LGSC). While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood. Here, we integrate cell-type resolved spatial proteomics and transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastases in both stroma and tumor. The transition occurs within the epithelial compartment through an intermediary stage with micropapillary features, during which LGSC overexpresses c-Met and several brain-specific proteins. Within the tumor microenvironment, interconnectivity between cancer and stromal cells, along with enzymes degrading a packed extracellular matrix, suggests functional collaboration among various cell types. We functionally validated 16 drug targets identified through integrated spatial transcriptomics and proteomics. Combined treatment targeting CDK4/6 (milciclib) and FOLR1 (mirvetuximab) achieved significant tumor reduction in vivo, representing a promising therapeutic strategy for LGSC.

Supplementary Figures S1-S3; Supplementary Table S1.

Background: Increasing evidence over the past two decades has implicated serous tubal intraepithelial carcinoma (STIC) of the fallopian tube (FT) epithelium as the putative precursor lesion for high-grade serous ovarian cancer (HGSC). Additional atypical lesions of the FT known as p53 signature lesions and serous tubal intraepithelial lesions (STIL) have been proposed as early precursors in the carcinogenic sequence based on morphology, histochemical and genetic studies. Little however is known about the molecular events that drive FT epithelial cells to transform into HGSC. Methods: To elucidate the molecular changes that underlie the progression from p53 signature to STIL to STIC, we performed spatial transcriptomics on formalin-fixed paraffin embedded (FFPE) tissue sections using the Nanostring GeoMx Whole Transcriptome Atlas panel (18,000 protein-encoding gene panel). Our study cohort consisted of 16 representative cases (3 p53 signature cases, 3 STIL cases, 3 STIC lesions, and 7 STIC cases with matched HGSC). Results: We characterized gene expression to a depth of over 9400 genes in these rare precursor cell populations. Our analysis demonstrated that by gene expression profiles, p53 signatures and STIL lesions bear close resemblance to normal FT secretory cells compared to FT ciliated cells or even STIC and invasive HGSC. We identify for the first time, several pathways altered in expression between normal fallopian tube epithelium and early p53 signature lesions including those related to signaling pathways (Trop-2), Wnt pathway (LGR5), identifying new pathways observed in the progression from normal FT cells to precursor intraepithelial lesion. Our data show that STIC lesions bear significant similarities to invasive HGSC by gene expression, especially compared to the earlier precursor lesions (p53 signature and STIL). We observed several alterations in cell-adhesion(EGR1) and signaling pathways, transcription factors (Trop-2) and metabolism that mark the transition from STIC to HGSC, representing possible mechanisms by which these intraepithelial lesions transform into disseminated invasive disease. Conclusion: Our data profile HGSC precursor lesions in high-depth with characterization of over 9400 genes providing new insight into the molecular alterations that characterize these intraepithelial lesions. Our future direction is to pair transcriptomics data with our established spatial proteomics platform (Deep Visual Proteomics) to measure matched spatial protein expression in our cohort. Citation Format: Rahul Krishnan, Lisa Schweizer, Agnes Bilecz, Aasa Shimizu, Rachelle Mendoza, Diane Yamada, Ricardo Lastra, Matthias Mann, Ernst Lengyel. Spatial transcriptomics of serous tubal intraepithelial carcinoma and its putative precursor lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6782.

Time toxicity is the time-related burden patients experience while tending to their healthcare needs. We sought to define treatment-related time burden for women with advanced or recurrent endometrial cancer to ascertain time-related quality of life (QOL) and relative time toxicity between treatment courses. Women diagnosed with advanced/recurrent endometrial cancer participated in a survey-structured interview about their treatment. Participants completed the EuroQOL-5D-5L survey to assess QOL and were queried about their treatment decision-making preferences. A retrospective chart review of patient interactions with the healthcare system was performed to calculate a measure for time toxicity, defined as the number of days spent at healthcare services away from home that were needed to treat their cancer during a specific treatment regimen. Healthcare services included infusion, lab collection, imaging, provider visits related to oncology and treatment care, and ancillary and emergency/inpatient services related to treatment. Days away from home were calculated by treatment regimen with a median number of days attributed per treatment cycle and attributed overall during each treatment course. Time spent on healthcare (T) was defined as % healthcare days/total days spent during treatment regimen represented as %. This value was correlated with QOL measures. To date, sixty women have been interviewed, reflecting an 86% participation rate. The median age of participants was 66 years, and 53% self-identified as White, 40% as Black, and 7% as other. Endometrioid adenocarcinoma was the most common histology (53%), followed by serous carcinoma (23%), clear cell carcinoma (9%), carcinosarcoma (9%), and others (6%). Twenty-eight (47%) participants had advanced endometrial cancer (Stage III or IV), and 32 (53%) had recurrent endometrial cancer. Fifty-two participants (87%) were on treatment at the time of the interview. Among these 53 participants, 16 (26.7%) were on immunotherapy, 16 (26.7%) were on cytotoxic chemotherapy, and the remaining were on a clinical trial (n = 9, 15%), hormones (n = 6, 10%), and radiation (n = 4, 6.7%). Patients on a clinical trial or undergoing radiation spent the highest proportion of days with healthcare needs (time spent on healthcare, T = 21%), followed by patients receiving cytotoxic chemotherapy (16%), immunotherapy (9%), and hormone therapy (5%). Time spent on healthcare significantly differed between the four largest groups represented (independent-samples median test = 12.14, P < 0.05). However, post-hoc analysis found only significant differences in time spent on healthcare between the clinical trial group and the groups who received hormones or immunotherapy, respectively (T = 20% vs 5% vs 9%, respectively, P < 0.05). A higher proportion of time spent on healthcare days (T) was correlated with lower QOL as measured by EQ-5D-5L health utility scores (r = 0.40, P < 0.01). Women with endometrial cancer spend significant time tending to their healthcare needs while on treatment, which correlates with worse QOL scores. This represents the first description of time spent on healthcare in a cohort of patients receiving treatment for advanced/recurrent endometrial cancer. Further work is needed to define time toxicity and investigate its effect on patient-centered outcomes.

TP53 mutations in the patient cohort.

Clear cell carcinomas of the vagina and cervix are rare. The most well-established risk factor for these cancers is exposure to diethylstilbestrol (DES) in utero. However, after the first case series describing the association of DES with clear cell carcinomas was published in 1970, DES use significantly declined. Clear cell carcinomas of the vagina and cervix have also been associated with non-DES-related urinary tract abnormalities or Mullerian anomalies. For girls and women diagnosed with clear cell carcinomas of the vagina or cervix, the mean age at diagnosis is 22 years old, and most patients are diagnosed between the ages of 15 and 30. Five-year survival rates are slightly better for women with DES-related clear cell carcinomas of the vagina or cervix as compared with those who were not exposed to DES. The staging systems and diagnostic work-up mirrors cervical and vaginal cancers of other histologic subtypes. Early stage disease is often managed surgically, with or without adjuvant therapy. Locally advanced disease is often managed with chemoradiation, and metastatic disease frequently requires chemotherapy. Depending on the disease burden and location, recurrent disease may be managed surgically, or with chemotherapy and/or radiation therapy. Although there are few data evaluating the use of targeted therapies or immunotherapy agents in clear cell carcinomas of the vagina and cervix, these agents may offer some clinical efficacy and are worth considering in women with these cancer types.

Newick trees and cophenetic correlation coefficients.

Supplementary Figures 1-4 from Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via α₅-Integrin, which Is a Therapeutic Target

Supplementary Table and Figure Legends

Single nucleotide variants and indels.