Although some patients with cervical cancer respond well to therapy, others show minimal response and develop recurrence after treatment. A better understanding of the molecular features that distinguish and drive the variable responses to therapy is needed to improve patient stratification and treatment. In this issue of Cancer Research, Sandoval and colleagues conduct integrated multiomic analyses of longitudinal patient cohorts to characterize the molecular and cellular reprogramming induced by chemoradiation therapy (CRT). The analyses show that treatment fundamentally reshapes the tumor microenvironment, inducing a shift from lymphoid-dominant to myeloid-dominant immune infiltration. The authors also identify the induction of MDM2-dependent DNA damage response specifically in tumor cells. Leveraging both treatment-naïve and CRT-exposed patient-derived xenografts, they demonstrate that MDM2 inhibition enhances radiation response, with the greatest efficacy in therapy-resistant tumors. These findings identify MDM2 as a rational, therapy-induced target emerging from unbiased analysis. As the field moves toward integrating targeted therapies and immunotherapy with standard chemoradiation, this study underscores the importance of understanding when, where, and in whom to intervene. See related article by Sandoval et al., p. 1639.

Definitive chemoradiation has been the standard of care for locally advanced cervical cancer for almost 25 years, but despite advances in radiation therapy and brachytherapy techniques and approaches, survival outcomes generally remain poor. Two recent prospective randomized phase III trials, CALLA and Keynote A18, have explored the addition of concurrent and adjuvant immunotherapy to chemoradadiation for treatment intensification. Herein we explore how different high-volume insitutions have subsequently approached incorporation of immunotherapy into the management of locally advanced cervical cancer. Future studies and more long-term outcome data are warranted to better delineate which patients will derive the most benefit from first-line immunotherapy.

In 2016, McCluggage and colleagues first defined mesonephric-like adenocarcinoma (MLA) of the uterus and extra-uterine sites. Following this initial description, the World Health Organization officially recognized MLA as a type of uterine and ovarian carcinoma and subsequent studies have further refined the morphologic definition, immunohistochemical profile, molecular underpinnings, and clinical behavior in this rare entity. A consortium of pathologists, gynecologic oncologists, medical oncologists, radiation oncologists, as well as basic science collaborators with expertise in MLA was convened to develop consensus regarding the pathologic diagnosis, and to identify unanswered questions and priority areas for research. Here, we review the current understanding of MLA from a pathologic, molecular, and clinical standpoint.

PURPOSE:Determine if molecular classification using mismatch repair (MMR) and p53 protein expression predicts recurrence-free survival (RFS) and overall survival (OS) in endometrial cancer (EC) patients treated with chemotherapy and radiation (CRT) versus chemotherapy (CT). METHODS:GOG-0258, a phase III randomized trial (NCT00942357), compared CRT to CT. Immunohistochemistry assessed MMR and p53 status. Kaplan-Meier curves and adjusted Cox models analyzed survival outcomes by molecular subtype. RESULTS:ECs classified as deficient MMR (dMMR) (27 %), p53 abnormal (p53abn) (24 %), and p53 wild type (p53wt) (49 %). p53abn were more frequent in patients that were older, Black, and had serous histology (p < 0.001). Median follow up was 113 months. Five-year RFS and OS were worse with p53abn (29 % [Hazard Ratio (HR) = 3.39 (95 % Confidence Interval (CI): 2.34-4.91)] and 39 % [HR = 4.64 (95 % CI: 3.16-6.79)] compared to those with p53wt (referent) (p < 0.001). The five-year RFS and OS for dMMR cancers were (58 % [HR = 1.30 (95 % CI: 0.85-1.97)] and 77 % [HR = 1.53 (95 % CI: 0.99-2.36)] compared to those with p53wt (69 % and 85 %). After adjusting for age, gross residual disease, and treatment, p53wt improved RFS with CRT compared to CT in an exploratory analysis (77 % vs 60 %; HR = 0.54 (95 % CI: 0.32-0.94). The 5-year and 10-year OS rates were similar in CRT compared to CT in all subgroups. CONCLUSION:Molecular classification appears to be predictive and prognostic, with worse survival in those with p53abn tumors. In an exploratory analysis, p53wt appears to predict improved RFS, favoring CRT over CT. There was no difference in treatment efficacy based on molecular subtype for OS.

Cervical cancer is the second highest incident cancer among women. Radiation therapy is a common non-surgical treatment. Proper segmentation of cervical tumor and healthy tissue, such as the bladder and rectum, is critical for complete cancer elimination, minimal healthy tissue toxicity, and a positive patient outcome. Deep learning via convolutional neural network (CNN) models has become a breakthrough in automating and standardizing tumor segmentation for more accurate treatment planning. Models come in a diverse array of architecture, each bringing their own strengths and weaknesses. Hybrid models integrate the predictive power of multiple models, providing more accurate segmentation. In this study, we developed two hybrid-based models for cervical cancer using Kolmogorov-Arnold Convolutions (Hybrid-ConvKAN) and multilayer perceptrons (Hybrid-MLP) that combines the outputs of Deeplabv3+, 3D Unet and a custom 2D model. The two models automatically segment 11 organs (cervix-uterus, vagina, bladder, rectum, sigmoid, bowel bag, spinal cord, femoral heads, kidneys), CTVp (uterus and parametria) and CTVn (nodal) from CT images. The 11 organs and CTVs were delineated from 157 patients with 223 CT scans divided into 149 training, 36 validation and 38 test CTs. An additional 30 external CT scans were used for testing our proposed model. The two models use Adam optimizer and a custom loss function (cross entropy and dice loss). Performance was measured using the dice similarity coefficient (DSC), surface DSC at 2 mm (sDSC2mm), precision, and recall. From the experiments, Hybrid-ConvKAN segmented the 11 OARs and CTVs more accurately compared with the individual models and Hybrid-MLP. The average DSC for Hybrid-ConvKAN was 0.91 (range: 0.82-0.94) for organs, 0.83 for CTVp (range: 0.79-0.87) and 0.81 for CTVn (range: 0.77-0.84). The comparison methods were ranged from 0.73 and 0.92 for organs, and 0.64 and 0.84 for CTVs. The proposed Hybrid-ConvKAN model is promising for implementing dose stratification during the treatment.

PURPOSEThis study investigates the interplay between T-cell receptor (TCR) immune characteristics and microbiome profiles to explore the relationship between immune diversity and microbial composition in cervical samples from Ethiopia.METHODSCervical specimens were collected from patients at Tikur Anbessa Specialized Hospital in Addis Ababa, and rural Butajira, south-central Ethiopia. Patient data, including age, human papillomavirus status, pathology, and TCR immune characteristics, were analyzed with a focus on the interactions between TCR profiles and microbiome compositions in malignant samples.RESULTSThree distinct TCR profiles were identified: Group 1 (TCR active) exhibited features of active immune engagement, including high diversity, clonal expansion, and repertoire richness. Group 2 (TCR restricted) showed reduced TCR diversity and expansion, suggesting a restricted repertoire. Group 3 (TCR balanced) had moderate diversity and clonal activity. TCR repertoire groups were linked with microbial diversity, with Group 1 (TCR active) showing the highest number of microbes (high operational taxonomic units and microbial diversity). Maximum TCR clonal expansion positivity associated with microbial richness, while Group 3 (TCR balanced) was linked to reduced microbial alpha diversity. Taxonomic analysis revealed specific organisms enriched in TCR repertoire group.CONCLUSIONVariations in TCR profiles are linked to distinct microbial environments in cervical cancer with greater microbial richness in patients with greater maximum productive frequency. These findings underscore the interplay between TCR diversity, microbiome composition, and malignancy, offering insights into the potential implications for microbiome-targeted therapies and prognostic biomarkers in cervical cancer.

PURPOSECervical cancer remains a significant public health concern globally and particularly in sub-Saharan Africa, where high rates of HIV infection exacerbate cervical cancer incidence. Understanding the cervical microbiome and its role in cancer progression is essential, especially in regions where both cervical cancer incidence and HIV prevalence are high. This study aimed to characterize the cervical microbiome in women living with HIV (WLWH) and HIV-negative women with squamous cell carcinoma of the cervix in Botswana, compare the microbiome between before and after chemoradiation therapy (CRT) in WLWH, and assess the prognostic value of specific microbial taxa for overall survival (OS) in WLWH.PATIENTS AND METHODSCervical samples were collected from women with cervical cancer presenting to one hospital in 2018-2019. Patients' clinical data, including HIV status, were recorded. Microbial composition was analyzed using 16S rRNA gene sequencing. Microbiome diversity and composition were evaluated using alpha and beta diversity metrics. Differential microbial abundance was analyzed using linear discriminant analysis effect size. The association between microbial taxa and OS was explored using Cox proportional hazards regression.RESULTSWLWH (n = 42) had a significantly lower Pielou evenness index than HIV-negative women (n = 11; 0.6 v 0.7, P = .02), suggesting a more imbalanced microbiome in WLWH. WLWH had higher levels of Parvimonas and members of the Corynebacteriaceae and Micrococcaceae families, suggesting a shift toward a more pathogenic microbiome. In WLWH, CRT did not significantly alter overall microbial diversity. However, Lactobacillus and Sutterella were enriched before treatment, reflecting a less pathogenic microbiome, whereas Ruminococcus and Phascolarctobacterium and the families Caulobacterales and Flavobacteriia were enriched after treatment, reflecting microbial adaptations to the altered immune and treatment environment. Notably, higher levels of Flavobacteriia after CRT were independently associated with worse OS in WLWH.CONCLUSIONMicrobiome profiles differ between WLWH and HIV-negative women with cervical cancer in Botswana. The microbiome might have prognostic significance. Future research is needed to better understand the significance of the microbiota in cervical cancer progression and treatment outcomes and the potential role of microbiome-targeted interventions.

Pelvic exenteration (PE) is a radical surgical approach designed for the curative treatment of advanced pelvic malignancies, requiring en-bloc resection of multiple pelvic organs. While the procedure is radical, it has shown promise in enhancing long-term survival and is now comparable in surgical mortality to elective resections for primary pelvic cancers. Imaging plays a crucial role in preoperative planning, with MRI, CT, and PET/CT being pivotal in assessing the extent of cancer and formulating a surgical roadmap. This paper presents clinical practice guidelines for imaging in the context of PE, developed jointly by ESGAR, SAR, ESUR, and the PelvEx Collaborative. These guidelines aim to standardize imaging protocols and reporting to improve the preoperative assessment and facilitate decision-making in the multidisciplinary treatment of pelvic cancers. Our recommendations underscore the importance of a multidisciplinary approach and the need for clear and precise imaging reports to optimize patient care. Our recommendations underscore the importance of a multidisciplinary approach and the need for clear and precise imaging reports to optimize patient care.

Purpose MRI-only based treatment planning workflow for gynecological brachytherapy can eliminate post-operative CT, optimize efficiency, reduce costs, and improve patient outcomes. The current study focusses the utility of commercially available needle MRI line markers (Orion, C4 Imaging, Houston, Texas) for Proguide needle digitization in hybrid gynecological applicators and in-house CISS MRI protocol specifically developed to maximize MR-marker signals . The study examines the dosimetric implications of MRI-only hybrid applicator reconstruction in comparison to conventional CT based reconstruction. Materials and Methods Seven clinical HDR -PDR brachytherapy cases were analyzed for gynecologic malignancies, utilizing two Geneva and five Venezia hybrid applicators, with three to six needles per case. Post-implant imaging included CT (Portable Airo® TruCT, Siemens Somatom Edge) with x-ray catheters and CT markers placed in intracavitary channels and needles, followed by CISS/Fiesta-C and T2-weighted MR images (T2 MRI) with intracavitary MRI line markers (Elekta, Stockholm, Sweden)and needle MRI line markers (C4 Orion) placed in intracavitary channels and needles. MRI was performed on a 1.5T scanner (Siemens Magnetom Sola) for two Venezia cases and on a 3T scanner (Siemens Magnetom Vida) for three Venezia and two Geneva cases. CT-based treatment planning was performed on Oncentra TPS (Elekta), using 3D applicator models for intracavitary channels and manual digitization for needles. The institutional workflow includes CT-MRI registration, with HR-CTV delineation using T2 MRI and OAR delineation on CT, followed by CT-based treatment planning in the Oncentra. Retrospective MRI-only based hybrid applicator reconstruction utilized intracavitary (Elekta) and needle (C4 Orion) MRI line markers in CISS/Fiesta-C MRI. No other changes of contouring and planning were performed. Both MRI line markers presented hyper signal intensity in CISS MRI sequence for 3D Applicator model and manual needle digitization (The dosimetric impact of MRI-only based hybrid-applicator reconstruction were quantified. Dosimetric evaluation compared the relative mean differences in HR-CTV dose coverage metrics (D90 and D98) and D2cc dose constraints for OAR’s between MRI-only based and conventional CT-based reconstruction plans. Results The mean percentage dose difference for HR-CTV D90 and D98 of MRI guided relative to CT-based planning was 0.6% ± 1.6% and -2% ± 3.9%, respectively. The mean percentage difference in dose for D2cc to the bladder, bowel, rectum, and sigmoid was 2.1% ± 6.5%, 3.5% ± 4.7%, -1.9% ± 3.6%, and -1.6% ± 4%, respectively. The p-values of the statistical test for HR-CTV D90 and D98 were 0.33 and 0.15, while for D2cc to the bladder, bowel, rectum, and sigmoid, the p-values were 0.45, 0.16, 0.31, and 0.50, respectively. The dosimetric differences between MRI-only and CT-based planning did not demonstrate statistical significance (p>0.05). Conclusions The Elekta MRI line markers and Orion MRI positive contrast line markers generated considerably hyper signal intensity in CISS MRI image for catheter visualization and facilitated MRI-only hybrid applicator reconstruction. MRI-only based hybrid applicator reconstruction plan yielded statistically comparable plans having dosimetrically equivalent to conventional CT-based plans. The current preliminary data results are demanded to be validated through statistically meaningful large datasets.

Purpose. We investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities. Methods. Non -Hispanic Black and non -Hispanic White (hereafter known as Black and White) patients with stage I -IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC). Results. This study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p < 0.0001). After balancing the selected demographic, socioeconomic and clinical factors, survival in Black vs. White patients was no longer different in those with SCC (AHR = 1.01, 95% CI 0.97-1.06) or AC (AHR = 1.09, 95% CI = 0.96-1.24). In SCC, the largest contributors to survival disparities were neighborhood income and insurance. In AC, age was the most significant contributor followed by neighborhood income, insurance, and stage. Diagnosis of AC (but not SCC) at >= 65 years old was more common in Black vs. White patients (26% vs. 13%, respectively). Conclusions. Histology matters in survival disparities and diagnosis at >= 65 years old between Black and White cervical cancer patients. These disparities were largely explained by modifiable factors. (c) 2024 Elsevier Inc. All rights reserved.

Endometrial cancer (EC) is the most common gynaecological cancer among women in high-income countries, with both incidence and mortality continuing to increase. The complexity of the management of patients with EC has evolved with greater comprehension of the underlying biology and heterogeneity of this disease. With a growing number of novel therapeutic agents available, emerging treatment regimens seem to have the potential to help to address the concerning trends in EC-related mortality. In this Review, we describe the epidemiology, histopathology and molecular classification of EC as well as the role of the new (2023) International Federation of Gynecologists and Obstetricians (FIGO) staging model. Furthermore, we provide an overview of disease management in the first-line and recurrent disease settings. With increasing use of molecular profiling and updates in treatment paradigms, we also summarize new developments in this rapidly changing treatment landscape.

Abstract Objective Cervical cancer is a leading cause of cancer-related deaths in women worldwide, leading to over 340,000 deaths in 2022. The majority of cervical cancers are caused by the persistent infection of high-risk human papillomavirus (HPV). In the United States, Hispanic women are at increased risk of cervical cancer development and are more likely to die of the disease in certain geographical locations. Furthermore, prior research implicated an association between the vaginal microbiota and the risk of HPV infection and cervical dysplasia. This descriptive study aims to explore the vaginal microbiome profiles of Hispanic or Latino women at risk for HPV-induced cervical dysplasia or with cervical dysplasia residing in Houston and in Puerto Rico. MethodsCervical swab samples were collected from Hispanic patients in Houston IRB 2019-1059 (N = 93) and Puerto Rico IRB 1050411 (N = 118) during routine clinical visits on a prospective collection protocol. Swabs were acquired at the patient’s initial visit and subjected to 16S V4 rRNA gene sequencing for microbiome profiling. Through HPV genotyping via PCR, patients were categorized into three groups: having HPV 16, other high-risk HPV types (18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), and “other”, comprised of low-risk HPV types, HPV negative, or unknown HPV status. Alpha and beta diversity were assessed using QIIME2. Microbiome composition was evaluated across different locations, HPV status, and disease status, followed by exploring alpha diversity between locations and disease status. The taxa species classification was performed using a custom classifier trained via a cervicovaginal-specific database. Samples were assigned to vaginal community state types (CSTs) using VALENCIA. Results Within the study cohort, 72% (N = 152) were classified as high-risk normal, and 28% (N = 59) had cervical dysplasia. HPV 16 was detected in 12% (N = 26), other high-risk HPV types in 33% (N = 70), while 55% (N = 115) of patients were classified as “other”. At the species level, the vaginal microbiota is dominated by Lactobacillus crispatus, Lactobacillus iners, and Trichomonas vaginalis as the top three abundant, regardless of the patient’s location, HPV status, and disease status. Alpha diversity between locations was 2.2 (1.4) for Houston and 1.6 (1.3) for Puerto Rico, as demonstrated by the Shannon Diversity Index. Alpha diversity was also observed between disease status, with a mean Shannon Diversity Index of 1.9 (1.4) for high-risk normal and 1.9 (1.1) for cervical dysplasia. The top three vaginal community state types were IV-B (32%), I (27%), and III (23%) for Houston, while the top three for Puerto Rico were III (34%), IV-B (31%), and I (21%). Conclusion The study examines the vaginal microbiome profiles of Hispanic women in Houston and Puerto Rico who are at risk for HPV-induced cervical dysplasia or already have cervical dysplasia. These findings provide insights into the vaginal microbiome composition, which plays a crucial role in cervical cancer development. Citation Format: D'Shaunique Walters, Molly El Alam, Timothy Harris, Tatiana Cisneros, Nadim Ajami, Jagannadha Sastry, Josefina Romaguera, Filipa Godoy-Vitorino, Stephanie Dorta-Estremera, Ann Klopp, Lauren Colbert. Descriptive study of the vaginal microbiome in Hispanic populations in Houston and Puerto Rico with high-risk normal and cervical dysplasia [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C082.

PurposeCervical cancer patients undergoing chemoradiation have high symptom burden. We performed an analysis of prospectively collected patient-reported outcomes(PROs) to determine characteristics predictive of poor treatment experience.MethodsBetween 2021-2023, we prospectively collected PROs from cervical cancer patients undergoing definitive chemoradiation. EORTC-QLQ-C30 and EORTC-QLQ-CX24 were completed at baseline(BL) and at the end of treatment(EOT). Poor treatment experience was defined as EOT poor health-related quality of life (HRQOL), low physical function, or significant overall symptom burden. Predictive factors analyzed included demographic, clinical, disease-specific factors, and baseline financial toxicity, depression, social function, and emotional function. ROC analysis provided appropriate predictive cut-off values. Univariable(UVA) and multivariable(MVA) linear regression analyses were performed.ResultsFourty-nine patients completed BL and EOT questionnaires. Median age was 43 (range, 18-85). Most patients (59%) had stage III disease. Baseline financial toxicity ≥66.7, depression ≥66.7, social function ≤50 and emotional function ≤58 on the EORTC linear transformed scale of 0-100 were significant predictors for poor treatment experience (p≤0.04) based on ROC analysis. On MVA poor BL social function was associated with reduced EOT HRQOL (β-9.3,_95%CI_-16.1_to_-2.6,_p<0.008), decreased physical function (β-24.4,_95%CI_-36.3_to_-12.6,_p<0.001), and high symptom burden_(β26.9,_95%CI_17.5_to_36.3,_p<0.001). Earlier disease stage predicted for decreased symptom burden_(β-6.7,_95%CI_-13.1_to_-0.3,_p=0.039). BL financial toxicity was a significant predictor on UVA (p=0.001-0.044) and showed a significant interaction term on MVA (p=0.024-0.041) for all three domains of poor treatment experience. Demographic and treatment-related factors were not predictive.ConclusionCervical cancer patients with poor baseline social function or high financial toxicity were at-risk for increased symptom burden and poor HRQOL. Screening for these factors provides an opportunity for early intervention to improve treatment experience.

Purpose: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials. Methods: Patients diagnosed with stage IVB cervical cancer during 2013–2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates. Results: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. Age, insurance, facility type, sites of distant metastasis, and type of first-line treatment were independently associated with using IMT. In propensity-score-balanced patients, the median survival was 18.6 vs. 13.1 months for with vs. without IMT (p < 0.001). The AHR was 0.72 (95% CI = 0.64–0.80) for adding IMT overall, 0.72 for IMT + CT, 0.66 for IMT + CT + EBRT, and 0.69 for IMT + CT + EBRT + ICBT. IMT-associated survival improvements were suggested in all subgroups by age, race/ethnicity, comorbidity score, facility type, tumor grade, tumor size, and site of metastasis. Conclusions: IMT was associated with a consistent survival benefit in real-world patients with stage IVB cervical cancer.