bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivariate index assay MIA3G vs other assessment tools for the ovarian cancer risk assessment of indeterminate masses.
Authors: Ghosh Srinka , Pappas Todd C , Phan Ryan
Published: June 2023

e17609

Background: Estimated 10% of women with adnexal masses will undergo preventive surgery for ovary removal to mitigate malignancy risk. This is significant, compared to the 15% rate of ovarian cancer (OC) confirmed by pathology. On the other hand, a women’s lifetime risk of getting OC is estimated at 1 in 78, with death at 1 in 108. This predicament motivates a surveillance paradigm for assessment of malignancy risk. ROMA (Roche) is a multi-marker assay intended to assess the cancer risk of adnexal masses in women already scheduled for surgery. We recently characterized the clinical performance of MIA3G[1], to assess OC risk for women with adnexal mass clinically characterized as benign or indeterminate. Here we present the comparative analysis for MIA3G and ROMA in a multi-site study. Methods: MIA3G -a 7-biomarker assay with a DNN-based risk prediction algorithm – was tested for clinical management of women (median: 51yo, IQR:41-61) across 11 centers. Data is presented for 206 patients with adnexal mass (286 unique samples), who follow an admix of surgical and clinical management. The continuous MIA3G probabilistic scores and dichotomized risk classification were used for the analyses. The primary objective was to compare MIA3G with ROMA assays. The secondary objective was to validate – via a pair-wise approach – the correlation of the biomarkers, age and menopausal status(MENO) - with the predicted risk stratification. Results: MIA3G stratified 13% [CI:0.096-0.174] and 87% [CI:82.6-90.4] of the 286 samples as indeterminate and low risk of malignancy respectively (p-value<2.2e-16, Welch’s t-test). In comparison, ROMA stratified 11.3% with a high likelihood of finding a malignancy on surgery. In the pre-menopausal sub-cohort MIAG3 risk-stratified only 7% as indeterminates, whereas for ROMA and CA125 the analogous estimates increased to 15% and 20% respectively. For the post-menopausal population, the converse trend was observed. In MIAG3 with increasing risk, the inhibitive effect of APO was signaled (R2:-24%, p:0.0006) and potential implication of iron metabolism was observed in TFR (R2:-31%,p:9.76e-5). B2M indicated inflammation with increasing risk (R2:28%, p:0.052. In addition to being a clinical attribute, MENO status was confirmed with FSH and age (R2 >80%,p<2.2e-16). A strong correlation of risk with HE4 (R2:38%) and CA125 (R2:32%) was observed and a HE4-CA125 pairwise-correlation of >85% confirmed. Additionally, the positive association of PRE with APO( R2 :33%) and negative association with CA125 and HE4 (R2~:-20%) rounded out the comprehensive nature of the MIA3G assay for characterizing the nuanced evolution of the masses. Conclusions: This real-world study established the efficacy of MIA3G as the most clinically validated tool for the risk assessment of ovarian cancer of indeterminate masses. 1: DOI 10.3389/fmed.2023.1102437.
The predictive value of CA-125 for radiologic evidence of metastatic disease in type 2 endometrial cancers.
Authors: Miller Madison Ellis , Pham Tra , Kole Monica , Elshaikh Mohamed A. , Dimitrova Irina
Published: June 2023

e17610

Background: Type 2 endometrial cancers encompass histologic variants that are more aggressive and have a higher incidence of extrauterine disease at the time of presentation than their type 1 counterparts. For high grade endometrial carcinomas, current National Comprehensive Cancer Network (NCCN) guidelines propose the "consideration of chest, abdomen and pelvis CT to evaluate for metastatic disease." We sought to investigate the predictive value of serum CA-125 for radiographic evidence of metastatic disease in patients with type 2 endometrial cancers. Methods: An IRB-approved, retrospective study investigating patients diagnosed with endometrial cancers between 2000-2020 at an urban, multi-site health system was conducted. Only patients with type 2 endometrial cancers and both pre-operative computed tomography scans of the chest, abdomen, and pelvis (CT CAP) and serum CA-125 results were included. A Youden’s index was used to calculate the optimal CA-125 cutoff. The sensitivity and specificity of CA-125 in predicting radiographic evidence of extrauterine disease was then calculated using this pre-determined CA-125 cutoff. Results: In total, 2,227 patients diagnosed with endometrial cancer (types 1 and 2) between 2000-2020 were identified. 1,932 cases were excluded due to low grade disease and/or the absence of pre-operative imaging and CA-125 results. Ultimately, 295 cases were included in analyses. A receiver operating characteristic (ROC) curve was used to generate Youden’s index which established the optimal CA-125 cutoff as 68 U/mL (P=0.0005). Using this cutoff, the specificity and sensitivity were determined to be 92.45% and 63.86%, respectively. The positive predictive value was 76.81% and the negative predictive value was 86.73%. Conclusions: According to current NCCN guidelines, pre-operative imaging and CA-125 should be considered if extrauterine disease is suspected in the setting of endometrial cancer. Although the role of serum CA-125 in monitoring clinical response is well documented, the utility of this test in stratifying patients who should undergo further radiologic evaluation is uncertain. Our results suggest that a CA-125 cutoff of > 68 U/mL is predictive of radiographic evidence of metastatic disease and, thus, can be used to determine which patients should receive pre-operative CT CAP.
The association of progesterone receptor and abnormal p53 expression in endometrioid endometrial cancer.
Authors: Chang Ting-Chang , Wu Ren-Chin , Jung Shih-Ming , Ueng Shir-Hwa , Chang Wei-Yang , Chou Hung-Hsueh , Huang Kuan-Gen , Huang Huei-Jean , Chao Angel , Tang Yun-Hsin , Lynn Perera , Lai Chyong-Huey
Published: June 2023

e17611

Background: Based on the TCGA endometrial cancer study results, a clinically applicable classification that identifies distinct subgroups with prognostic signature, the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), has been built and validated. It shows that those with abnormal expression of p53 (p53abn) are the group with the worst prognosis. We attempted to explore the association of p53abn and progesterone receptor (PR) in endometrioid endometrial cancer. Methods: We included 397 consecutive endometrial cancer cases of endometrioid histology with adequate tumor tissue in the formalin-fixed, paraffin-embedded (FFPE) block and available follow-up information. This study was granted by Chang Gung Medical Foundation IRB 201702242B0D001. Sanger sequencing to assess the POLE exonuclease domain hotspot mutations of exon 9-14 and immunohistochemical staining on FFPE tumor tissue sections for p53, ER, PR, and mismatch repair proteins were performed. Immunohistochemical p53 expression of cancer cell nucleus was recorded as completely negative (0%), weakly positive (1-59%), and diffusely strong positive (>60%). Tumors with weak positive p53 staining were defined as p53 wild type (p53wt), while the other two were defined as p53 abnormal (p53abn). PR scores were calculated by multiplying the average staining intensity by the tumor cell nucleus stained percentage. We arbitrarily defined a progesterone receptor score of 100 or higher as positive (PR+). Progression-free and endometrial cancer-specific overall survivals starting at the date of diagnosis were evaluated using Kaplan-Meier method and compared by log-rank test between groups. Results: PR was positive in 82% of all studied cases. Of the 48 cases with p53abn tumor, 35(73%) were PR (+). With a median follow-up of 74 months, the progression-free survival and cancer-specific survival of patients with PR+ tumors (N = 310) were 93% and 96.8%, respectively, compared with 75% and 85.7% of those with PR- tumors (N = 70) (both p < 0.001, log-rank test). Among those with P53abn, PR expression was associated with a favorable progression-free survival ( p = 0.081) and better cancer-specific survival ( p = 0.044). POLEmut, POLE mutated; dMMR, deficient mismatch repair PR+, progesterone receptor score ≥100, ER+, estrogen receptor score ≥100; p53abn, abnormal p53 expression. MMR was undetermined in 32 cases, PR in 17 cases, ER in 17 cases, and p53 was undetermined in 10 cases. POLE status was detected in all cases. Cases with POLE wild type, proficient mismatch repair, progesterone score < 100, estrogen score < 100 and wild type p53 were not listed in this table. Conclusions: Our study showed that incorporating PR into prognostic molecular markers for endometrioid endometrial cancer might provide further risk stratification. [Table: see text]
Development and validation of prediction models for coexisting adnexa malignancy in patients with endometrial cancer using machine learning algorithm: A population-based cohort study.
Authors: Wang Qiannan , Song Kun
Published: June 2023

e17617

Background: As the rate of ovarian conservation in endometrial cancer patients declined over the course of a decade, the study was to build and validate prediction models based on machine learning algorithms using preoperative predictors to evaluate the risk of coexisting adnexa malignancy, in order to guide decision-making for patients and clinicians before the surgery. Methods: Patients surgically treated for endometrial cancer from 30 medical center which forming the Chinese Endometrial Carcinoma Consortium (CECC) between 2010 and 2019 were enrolled. These patients were randomly divided at ratio of 7:3 into development cohort and validation cohort. Preoperative clinical and histopathological features were included as predictors, and least absolute shrinkage and selection operator (LASSO) was used for selecting candidate predictors. Machine learning (ML) algorithms including logistic regression (LR) analysis, support vector machine (SVM), random forest (RF), AdaBoost, decision tree (DT), naïve Bayes (NB), and multilayer perceptron (MP) were applied to develop the models. The best final model was selected by integrating area under the receiver operating characteristic curve (AUC) value as well as the relative sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy into account. Results: Among 3108 patients in the study cohort, 212 (6.7%) coexisted with adnexal malignancy. Data from 2226 female patients were divided into the cohort for model development. Ultimately the model included 10 predictors selected by LASSO: personal cancer history, age, CA-125, neutrophil lymphocyte ratio (NLR), tumor grade, myometrial involvement, cervix involvement, lymph node involvement, adnexal involvement, and extrauterine involvement. Among all ML algorithms, LR model outperformed the other algorithms, with an AUC of 80% and an accuracy of 85% in the validation cohort. Further evaluation proved that the model was well-calibrated and showed satisfied clinical utility. Based on LR, an online calculator was created for enhancing the clinical interpretability. Conclusions: This model provides individualized estimates of risk of adnexa malignancy in patients with endometrial cancer, with all model inputs available at the time before the surgery. A prospective feasibility study will be needed prior to implementation in the clinic.
Comparing sentinel lymphadenectomy and complete lymphadenectomy among obese patients (BMI >30) undergoing minimally invasive hysterectomy for early-stage endometrial cancer: An ACS-NSQIP database study.
Authors: Hollingsworth Jessie , Beier Matthew , Adkoli Anusha , Stephenson Ruth
Published: June 2023

e17618

Background: In patients with endometrial cancer, lymph node assessment is used for staging and adjuvant treatment planning. Sentinel lymphadenectomy (SLN) is an acceptable alternative to complete lymphadenectomy due to decreased risk of major complications. As obesity increases in the United States, so does the rate of endometrial cancer. Complete staging may be more challenging in obese patients. Our goal was to evaluate the relative use and complication rates of sentinel versus complete lymphadenectomy among obese patients undergoing minimally invasive hysterectomy (MIH) for early-stage endometrial cancer. Methods: The National Surgical Quality Improvement Program (NSQIP) database was queried for patients diagnosed with stage I to III endometrial carcinoma between 2015 and 2020 who underwent MIH, identified by Current Procedural Terminology (CPT) code. Extent of lymphadenectomy was also identified using CPT codes. Relative utilization of sentinel versus complete lymphadenectomy was evaluated over the study period. Propensity scores were used to control for potential confounders, and complication rates were compared between propensity matched cohorts of sentinel versus complete lymphadenectomy. Major and minor complications were defined by the Clavien-Dindo scale. Results: From 2015 to 2020 a total of 11,844 obese (BMI > 30) patients underwent MIH for stage I to III endometrial cancer. Of these 7,067 (59%) had a lymph node assessment. Sentinel lymphadenectomy was completed in 3,845 patients, and complete lymphadenectomy was completed in 3,222 patients. Over the five-year period, the utilization of SLN increased for obese and non-obese patients. Prior to 2018, complete lymphadenectomy was performed more often. After 2018, SNL was more common. After propensity matching, there was no increased risk of death (OR 0.67, 95% CI 0.06-5.8, p = 1.0), infection (OR 0.86, 95% CI 0.69-1.1, p = 0.20), thrombo-embolic events (OR 0.77, 95% CI 0.51-1.1, p = 0.21), major complications (OR 0.84, 95% CI 0.66-1.1, p 0.15), or minor complications (OR 0.87, 95% CI 0.69-1.1, P = 0.22) in obese patients who underwent SLN compared to complete lymphadenectomy. Conclusions: The average BMI of patients who underwent MIH over the study period was 35. After controlling for comorbidities and other baseline characteristics, there were no significant differences in complication rates between sentinel and complete lymphadenectomy in obese patients. With the adoption of SLN, more patients may be adequately staged, providing more prognostic information and targeted therapies. These results suggest that sentinel lymphadenectomy is a technically feasible and safe staging procedure in obese patients.
Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for human uterine sarcoma cells.
Authors: Omran Mervat Mostafa , Vafaei Somayeh , Al-Hendy Ayman , Yang Qiwei
Published: June 2023

e17620

Background: Uterine sarcoma is strongly associated with poor prognosis, high rates of recurrence, and metastasis. However, the molecular mechanisms underlying the origin and development of uterine sarcoma and treatment options are limited. Enhancer of zeste homolog 2 (EZH2) and histone deacetylase (HDACs) play an important role in cancer progression. This study aimed to assess the effect of targeting both EZH2 and HDACs on the phenotype of uterine sarcoma (US) cells. Methods: Tazemetostat (EPZ-6438, E7438), a potent, and selective EZH2 inhibitor, was first approved by the US Food and Drug Administration (FDA) in 2020. Entinostat (MS-275, SNDX-275) is one of the strong inhibitors for HDAC1 and HDAC3, Vorinostat is used to treat cutaneous T-cell lymphoma, Tucidinostat (Chidamide, HBI-8000, CS-055) is a low nanomolar inhibitor of HDAC1, 2, 3, and 10. Uterine sarcoma cell line (MES-SA) was treated with different concentrations (1.56-200 mM) of Tazemetostat and/or Entinostat, Vorinostat, Tucidinostat (Chidamide). for 24, 48, 72 h, respectively. Further mechanistic confirmation was carried out on best combination in both 2D and 3D culturing using IHC and real time PCR. Results: Our data showed that Entinostat synergistically (with a combination index 0.539) augments the cytotoxic activity of Tazemetostat in both 2D and spheroids in vitro model systems. The IC50 values for Tazemetostat were significantly reduced to 4.5 mM after combination treatment with 6.25 mM Entinostat for 48 h. Entinostat enhanced the antiproliferative effect of Tazemetostat with a decrease in the expression of proliferative markers Ki67(P < 0.0001) and PCNA (P < 0.01). Furthermore, combination treatment significantly increased US cell apoptosis, concomitantly with increased both BAX and Caspase-3 levels and decreased Bcl-2 (P < 0.0001) using 2D and spheroid in vitro model (P < 0.001). The finding was confirmed by IHC analysis in the US cell-derived spheroids. Conclusions: Our studies demonstrate that Entinostat, in combination with Tazemetostat proves significantly superior to either single treatment. Dual targeting EZH2 and HDACs may provide a promising treatment option for this aggressive cancer disease.
Study of endometrial carcinoma on correlation between molecular typing and lymph node metastasis and construction of prediction model.
Authors: Jiang Quanhong , Han Qiuyue , Song Kun , Chu Ran , Zhao Yong , Zhang Zhaoyang , Li Zhuang
Published: June 2023

e17621

Background: TCGA molecular typing was proposed by The Cancer Genome Atlas (TCGA) in 2013 and recommended by the fifth edition of WHO, which has a strong prognositic value and is included in the risk stratification system, clinical diagnosis and treatment decision-making system of endometrial cancer (EC) patients. Meanwhile, Lymph node management in patients with EC is still controversial. Lymph node dissection (LND) and sentinel lymph node biopsy (SLNB) have their own advantages and limitations. This study attempts to establish a predictive model for lymph node metastasis (LNM) in patients with EC based on molecular typing and other clinical features and establish risk stratification, in order to provide a feasible method for predicting LNM in EC. Methods: In this study, SPSS19, R 4.2.1 and python 3.6 were used to establish a nomogram and evaluate it through a number of indicators, and the model was repeatedly verified by machine learning algorithms. With LNM as the outcome, risk stratification was set through the cut-off value of nomogram score to guide clinical treatment. Finally, an online LNM prediction website was designed to help patients. Results: A total of 325 EC patients were included, 35 (10.8%) with LNM and 290 (89.2%) without LNM. CA125 and cervical involvement were significantly correlated with LNM (p < 0.001), molecular typing, neutrophil to lymphocyte ratio (NLR), menstrual status were associated with LNM (p < 0.05). Lasso analysis screened out four independent factors: molecular typing, CA125, cervical involvement and menstrual status. The nomogram model was established by logistics regression (LR), with the prediction accuracy of the training set and validation set of 0.890 and 0.886, respectively. Machine learning algorithms in the training set also validates the model. Meanwhile, a risk stratification is established by the cut-off value of nomogram. We define high-risk group of LNM with more than the cut-off value and LND is recommended, while below the value is low-risk group and SLNB is recommended. Conclusions: We have established a nomogram clinical prediction model incorporating four factors, practicing stratified medical treatment about LND and SLNB, and formed a website for LNM prediction, genuinely providing patients recommendations.
A novel prognostic model for high-grade endometrial cancer using combined neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR).
Authors: Zhang Zhaoyang , Chu Ran , Kong Beihua , Chen Gang , Li Yang , Song Kun
Published: June 2023

e17622

Background: Endometrial carcinoma (EC) as a common malignant tumor of the female reproductive system, posing a serious threat to the health of women. Compared to low-grade EC, high-grade EC has more rapid progression and a worse prognosis. Among the high-grade EC, grade3 endometrioid carcinoma, serous carcinoma, and clear cell carcinoma were the most common. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are potential biomarkers of the systemic inflammatory response, and the correlation with prognosis of high-grade EC remains unclear. We want to evaluate the predictive significance of NLR and PLR in the prognosis of high-grade endometrial carcinoma and to establish a predictive model combining clinical factors. Methods: This multicenter retrospective cohort study included 910 high-grade epithelial endometrial carcinoma patients from the Chinese Endometrial Carcinoma Consortium database who underwent initial surgical treatment between January 1, 2005, and December 31, 2019. Univariable Cox survival analysis(the 2-sided Log-rank test) was used to assess each factor. Then the least absolute shrinkage and selection operator (LASSO) method was used to select the independent risk factors for DFS (disease-free survival) and OS (overall survival) from the outcomes of the univariate analysis to proceed with model fitting. Cox proportional hazard regression models were developed to predict the risk of recurrence and death at 3, 5, and 10 years, and the models were validated and calibrated. The area under the curve was used to measure the predictive performance of the model. The decision curve analysis was used to explore the clinical net benefit of the nomograms. Results: NLR and PLR were risk factors for recurrence, and NLR was a risk factor for death. We established models for predicting death and recurrence. In the training cohort, the AUC of recurrence model at 3, 5 and 10-year was 0.85, 0.85 and 0.86. And for the death model, the AUC at 3, 5 and 10-year was 0.83, 0.84 and 0.86. In the validation cohort, the AUC of recurrence model at 3,5 and 10-year was 0.72, 0.77 and 0.77. And for death model was 0.72, 0.81 and 0.84. Kaplan–Meier survival analysis showed a significant difference between low-risk and high-risk groups. The calibration curve also revealed excellent predictive accuracy both in the training and validation cohort. Conclusions: NLR and PLR are risk factors affecting the prognosis of high-grade endometrial carcinoma patients. Combining NLR/PLR and clinicopathological factors, we established a novel and more comprehensive prognostic model for patients to achieve risk stratification. This prognosis predictive model has the potential to offer risk scores and precise risk stratification for patients with high-grade endometrial cancer.
Real world evidence on long-term survival of patients with endometrial cancer in Germany: Analysis of population-based cancer registry data on 49808 women.
Authors: Chinczewski Lukas , Zocholl Dario , Wagner Alexandra , Chekerov Radoslav , Braicu Elena Ioana , Sehouli Jalid
Published: June 2023

e17623

Background: Endometrial cancer (EC) is the most common gynecological cancer worldwide. The understanding of clinicopathological characteristics has changed within the last years. Limited data are available regarding the long-term survival of EC patients. Methods: Clinical data and survival data for patients with EC diagnosed in Germany between 2010 and 2020 were gathered from the German national center for population-based cancer registry. Differentiated by histological subtype, 5- and 7-year survival rates were calculated. Results: 49,808 patients with newly diagnosed EC between 2010 and 2020 were included in the analysis. Median age at diagnosis was 68.1 years (IQR 59.0;76.4). 5-year and 7-year overall survival was 67.5% and 56.7%, respectively, and decreased with increasing FIGO-stage: 83.7% and 72.6% for FIGO IA, 71.0% and 56.3% for FIGO IB, 59.8% and 47.3% for FIGO II, 48.2% and 38.7% for FIGO IIIA , 32.5% and 20.7% for FIGO IIIB, 40.0% and 30.6% for FIGO IIIC, 13.3% and 8.2% for FIGO IVA, 16.4% and 13.9% for FIGO IVB, respectively. Regarding histological subtype, endometrioid carcinoma showed the best 5-year and 7-year overall survival rates with 72.5% and 61.3%, respectively, followed by clear cell carcinoma with 41.2% and 34.0%, serous carcinoma with 35.5% and 24.8%, and lastly carcinosarcoma with 28.5% and 23.0%. Of 3,765 patients with known cause of death, 53.8% were due to endometrial cancer. 19.0% died of cardiovascular disease and 18.8% of other malignancies. Conclusions: Our data represents deeper insight in the characterization of long-term survival patients of this tumor entity.
3D genomics identify alternate mechanisms of homologous recombination deficiency in uterine sarcoma.
Authors: Chiang Sarah , Hensley Martee Leigh , Vasudevaraja Varshini , Tran Ivy , Yang Yiying , Stewart Colin JR , Park Kay J , Ellenson Lora H , Sikkink Kristin , Schmitt Anthony , Snuderl Matija
Published: June 2023

e17624

Background: Uterine sarcomas are rare tumors with diverse morphologic appearances, genetic underpinnings, and clinical behavior. Molecular characterization of these tumors by next generation sequencing (NGS) has improved disease classification and prognostication, but its impact on therapeutic selection remains limited. Analysis of 3D genomics datasets has recently been shown to detect large complex structural variants (SV) and chromatin architecture in normal and diseased human tissues. We applied genome-wide chromosome conformation capture (Hi-C) techniques in a variety of uterine sarcomas to identify novel therapeutic targets. Methods: Formalin-fixed paraffin-embedded tissue from 48 primary or recurrent uterine sarcomas were subjected to Hi-C to identify chromosomal rearrangements. The cohort included leiomyosarcoma (LMS, n = 7), adenosarcoma (AS, n = 7), endometrial stromal sarcoma (n = 7; high grade (HGESS), n = 4; low grade (LGESS), n = 3), sarcoma not otherwise specified (n = 17; high grade (HGNOS), n = 10, low grade (LGNOS), n = 7), undifferentiated uterine sarcoma (UUS, n = 6) and heterologous sarcoma (n = 2). Tumors were previously subjected to targeted DNA (n = 10) and/or RNA (n = 26) NGS with no therapeutic targets identified and only BCOR internal tandem duplication detected in a HGESS. Results: Hi-C detected SV in 73% of uterine sarcomas (n = 35/48), including those previously negative by targeted RNA NGS (n = 25/26). Homologous recombination repair (HRR) gene alterations were detected by Hi-C in 42% of tumors (n = 20/48), including AS (n = 5/7), HGESS (n = 2/4), LGESS (n = 1/3), LMS (n = 2/7), UUS (n = 2/6), heterologous sarcoma (n = 1/2), HGNOS (n = 3/10) and LGNOS (n = 1/7). SV included gene (gene to gene, n = 3; gene to non-coding DNA, n = 8) and proximity (n = 13) fusions disrupting HRR genes ( ATM, BRIP1, CDK12, CHEK1, CHEK2, NBN, PARP3, RAD51B, RAD51C, RAD51D) with enrichment for RAD51B fusions (50%, n = 10/20). Among all tumors with HRR gene alterations detected by Hi-C, only one uterine sarcoma harbored a missense ATM mutation by targeted DNA NGS (n = 1/5). Conclusions: Molecular characterization of uterine sarcomas by Hi-C may uncover HRR gene alterations not currently detectable by targeted DNA and RNA NGS. Homologous recombination deficiency (HRD) is not limited to LMS and may frequently result from SV, particularly between HRR gene to non-coding DNA in a variety of uterine sarcomas. These alternate mechanisms for HRD may serve as a potential therapeutic biomarker for HRD-targeted therapy in uterine sarcoma.
Risk reclassification of endometrial cancer according to molecular profiling: UK single centre experience.
Authors: Kebaier Ep Chaabouni Narda , Vroobel Katherine , Attygalle Ayoma , Proszek Paula , Lalondrelle Susan , Taylor Alexandra , George Angela Joy
Published: June 2023

e17628

Background: Endometrial cancer (EC) ranks second among gynaecological malignancies worldwide. Traditionally, adjuvant treatment recommendation was based on risk stratification based on clinicopathological data. The Cancer Genome Atlas (TCGA) defined four distinct and prognostically significant molecular subgroups. Recent international guidelines recommend integrating molecular classification into risk stratification. The aim of our study was to evaluate the distribution of molecular groups in our population and its impact on treatment decision. Methods: Retrospective cohort study including all newly diagnosed endometrial cancer cases treated at the Royal Marsden Hospital between July 2020 and May 2022. Tumour specimens underwent next generation sequencing (NGS) of a two hundred gene panel including POLD1, POLE; MMR proteins and TP53; concordance for the latter two assessed also by immunohistochemistry (IHC). Risk stratification according to ESMO guidelines and following molecular classification was reviewed for each case and its potential impact on treatment decision. Results: 121 patients were included. POLE mutated tumours comprised 14 cases (11.6%), MSI hypermutated 24 cases (19.8 %), copy number high 36 cases (29.8%), copy number low 45 cases (37.2%) and 2 cases (1.6%) where classified as NOS (not otherwise specified). According to clinicopathological data, 39 tumours were categorised as low risk, 14 tumours as intermediate risk, 15 tumours as high-intermediate risk, 39 tumours as high risk and 14 were advanced/metastatic. According to final prognostic group when molecular profile was integrated 8.3 % (n = 10) of cases were reclassified: 8 cases were down staged (2 high, 3 high-intermediate, 3 intermediate) to low-risk category due to POLE mutations. 2 cases were upstaged from high-intermediate to high-risk category (copy number high tumours). There were no shifts noted in the low risk (based on clinicopathological data) prognostic group. One further case in the high-risk category (stage III, gr3 endometrioid tumour with substantial LVSI) was found to be POLE mutated and may be reclassified as low risk. For the 10 cases that were reclassified, adjuvant treatment recommendations may have been adjusted according to the most recent ESMO guidelines. Conclusions: Molecular classification refines traditional risk classification of EC and may change treatment recommendation in a non-negligible proportion of patients. Efforts should be made to implement molecular analysis in routine clinical practice to guide appropriate treatment.
Preclinical testing of farletuzumab ecteribulin (FZEC [MORAb-202]) and MORAb-109, folate receptor α and mesothelin targeting antibody-drug conjugates (ADCs), in rare gynecologic cancers.
Authors: Vandenberg Cassandra J. , Rybinski Katherine , Nesic Ksenija , Lim Ratana , Neagle Chloe , Ho Gwo-Yaw , Ratnayake Gayanie , Papenfuss Anthony T. , Furuuchi Keiji , Barker Holly E. , Scott Clare L.
Published: June 2023

e17634

Background: Rare gynecologic cancers, such as ovarian carcinosarcoma (OCS), uterine serous carcinoma (USC) and ovarian clear cell adenocarcinoma (OCCA), have limited treatment options and molecular alterations that drive cell proliferation and drug resistance, resulting in poor overall survival. The anti-microtubule agent (AMA) paclitaxel is used in first-line treatment of most gynecologic cancers; however, the AMA eribulin is known to have additional anticancer properties (Goto et al. Anticancer Res 38:2929, 2018; Ho et al. Cancer Res 82:4457, 2022). Eribulin ADCs have been developed for targeted delivery to limit toxicity and maximize response. FZEC is an anti-folate receptor α (FRA)-eribulin ADC (Shimizu et al. Clin Cancer Res 27:3905, 2021) and MORAb-109 targets eribulin to mesothelin (MSLN; Albone et al. Annals Oncol 31:S491, 2020). Here we provide preclinical data to support clinical trials of FZEC and MORAb-109 in rare gynecologic cancers. Methods: Fresh tumor tissue from patients consented to the WEHI Stafford Fox Rare Cancer Program was used to establish a cohort of patient-derived xenograft (PDX) models of high-grade serous ovarian carcinoma (HGSOC), OCS, USC and OCCA. PDX models were screened for FRA and MSLN expression by IHC and quantified by HALO software, and 15 models were selected for in vivo testing. Tumor-bearing mice were treated with eribulin (1 mg/kg TIW 3 wks), FZEC (12.5 mg/kg Q14Dx3) or MORAb-109 (25 mg/kg Q14Dx3) and compared to standard of care treatments. Results: About 80% of HGSOC PDX models were FRA positive with no difference between models from chemonaïve samples vs multiple lines of prior treatment. FRA expression was frequent in USC and OCCA models, with MSLN seen in a smaller subset. Despite most (80%) models being cisplatin refractory, 11/15 responded to eribulin with the 4 non-responders having high MDR1 expression and being from previously treated patients. Overall, responses to FZEC and MORAb-109 appeared to correlate with FRA and MSLN expression; importantly, some models with moderate to high target antigen expression showed deeper and more durable responses to FZEC and MORAb-109 compared to eribulin. Conclusions: Responses to FZEC and MORAb-109 correlated with FRA and MSLN expression, with equivalent or better activity compared to eribulin in target-positive PDX models of HGSOC, USC and OCCA. [Table: see text]
Nominating molecular/immunologic drivers of central nervous system (CNS) metastases in squamous cell carcinoma of the head/neck (SCCHN).
Authors: Kacew Alec , Wotman Michael , Quinn Charles T , MacConaill Laura E , Egloff Ann Marie , Jones Stephanie M , Pfaff Kathleen L. , Rodig Scott J. , Sehgal Kartik , Haddad Robert I. , Posner Marshall R. , Hanna Glenn J.
Published: June 2023

e18002

Background: In the ~1% of patients with SCCHN who experience CNS metastases, median overall survival (mOS) is <1 year. We investigated whether molecular/immunologic features distinguish SCCHN cases that metastasize to the CNS. Methods: We performed a case-control study on a convenience sample of individuals with SCCHN treated at two academic institutions. Next generation targeted sequencing and/or immunoprofiling of primary and metastatic tumor sites were performed. Results: We identified 39 patients with SCCHN (21 with CNS metastases (cases), 18 without (controls)). Median age at diagnosis 60, 79% male, 46% current/former smokers, 51% oropharyngeal primary, 51% HPV+/31% HPV-/18% not tested (NT) across all cases, and 69% stage III or IV disease at diagnosis. HPV+ frequency trended higher among cases (52%+, 14%-, 33% NT) vs. controls (50%+, 50%-, 0% NT) (p=0.08). mOS from diagnosis was 34.4 months (95% CI 14.5-41.0) in cases and 44.4 months (95% CI 19.0-82.3) in controls. Genomic data was available for 18 (86%) cases and 12 (67%) controls. Most common mutations in cases were KMT2D (39%) and NOTCH1 (39%). There were no genes for which alteration frequency differed significantly between groups. Tumors of 18 (86%) cases and 18 (100%) controls underwent immunoprofiling. Mean PD-1 density at the tumor-stroma interface (TSI), CPS, and TPS were higher in controls (Table). In cases, TSI PD-1 density tended to be higher at primary sites than at sites of CNS metastases. No significant difference was seen in CD8 or FOXP3 staining. Conclusions: SCCHN with CNS metastases shows markers of lower immunogenicity at both the primary site and site of CNS metastasis vs. other SCCHN tumors, regardless of HPV status. This suggests that localized tumors with low immune infiltration and poor responsiveness to immunotherapy may be at higher risk of CNS metastasis and could imply reduced benefit from immunotherapy for patients with CNS metastases. [Table: see text]
Mechanisms of sensitivity to platinum-based chemotherapy in PD-1 blockade-refractory head and neck cancer.
Authors: Burkitt Kyunghee
Published: June 2023

e18003

Background: Our clinical observation from recurrent/metastatic head and neck patients who treated with platinum based combination after progression on pembrolizumab showed a striking response rate of 80% (8 out of 10 patients), this impressive ORR is dramatically higher than the historical ORR of 27% in the first-line setting. Our mouse model of ‘immune-cold’ head and neck cancer is developed to investigate the mechanism of sensitivity to platinum- based chemotherapy in PD-1 blockade-refractory head and neck cancer. Methods: For ‘immune-cold’ syngeneic model of HNSCC, C57BL/6 mice were injected with 5 × 104 MOC2 tumor cells in the right flank. After 11 days, mice with palpable tumors were randomized and treated concurrently with 4 groups (n = 5 per group): control, anti–PD1 antibody (200 mcg three times/week × 3 cycles), cisplatin (3mg/kg) +paclitaxel (5mg/kg) once a week x 3 cycles, or anti-PD1 antibody (200 mcg three times/week × 1 cycle) followed by cisplatin (3mg/kg) + paclitaxel (5mg/kg) once a week x 2 cycle. Cisplatin + paclitaxel arm received total of 4 cycles of treatment, while PD-1 followed by cisplatin and paclitaxel arm received total of 3 cycles of cisplatin and paclitaxel, this schedule was set up to maintain every 3 week regimen with same duration of treatment time to mimic patient’s treatment schedule in clinic setting. Tumor volume was measured 3 times per week. Results: Our initial pilot mouse model study showed similar tumor response seen in patient population. Starting on D24, average tumor size of PD1 inhibitor followed by cisplatin+paclitaxel group is significantly decreased compared to PD1 inhibitor or cisplatin+paclitaxel group and the difference is statistically significant. Most of mice in control and PD1 inhibitor group died at day 24 due to tumor progression. Our IHC data showed that the expression levels of immune markers such as CD8+, CD4+ and PDL1 in tumors treated with PD1 inhibitor followed by cisplatin and paclitaxel were increased, compared to almost no or scant expression (CD8+, CD4+) and lower expression (PDL1) in tumors treated with cisplatin and paclitaxel alone. With our expansion cohort, we will be further exploring key changes in immune signatures using both peripheral blood samples and tumor blocks for flow cytometry (myeloid/lymphoid subtypes, alterations in cytokine expression and circulating tumor DNA levels) and RNA sequencing analysis. Conclusions: We successfully established an ‘immune-cold’ mouse model of head and neck and reproduced similar tumor response seen in clinic. Preliminary data showing increased expression of immune makers such as CD8+, CD4+ and PDL warrants further investigation on tumor immune microenvironment remodeling as a potential mechanism of sensitivity to platinum-based chemotherapy in PD-1 blockade-refractory head and neck cancer.
The changes of HER3 expression in head and neck cancer patients treated with induction chemotherapy.
Authors: Kim Joori , Kim Jeong-Oh , Lee Youn Soo , Shin Jung-Young , Kim Min Young , Lee Mi-Ran , Kim Seoree , Fujita-Sato Saori , Kobayashi Maki , Kakegawa Tomoya , Kang Jin Hyoung
Published: June 2023

e18004

Background: Erb-b2 receptor tyrosine kinase 3 (HER3) is broadly expressed in various types of cancer and is associated with poor prognosis. Recent evidence supports HER3 plays a role in acquired resistance to chemotherapy. The change of HER3 expression by chemotherapy in head and neck squamous cell carcinoma (HNSCC) remains unclear. Methods: We evaluated 95 patients with locally advanced HNSCC who had received induction chemotherapy (ICT) between 2009 and 2019. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. H-score of membrane staining was evaluated. Results: Median age of patients was 64 years, and 85% were male. Primary locations included oropharynx (54.8%), hypopharynx (21.5%), oral cavity (17.2%), and salivary gland (6.5%). Mean H-score of HER3 in tumor tissues was 77.6 ± 7.9. H-score of HER3 in HPV-positive tumors was higher than HPV-negative tumors (p = 0.019), which was more pronounced in oropharynx and hypopharynx tumors. While, H-score of HER3 in adjacent normal tissues of these tumors did not significantly differ. Compared with the non-smokers, tumor tissues of current or ex-smokers demonstrated higher H-score of HER3 (p = 0.033), independent of tumor location. In contrast, in adjacent normal tissues, no significant differences of H-score of HER3 were observed depending on the smoking status. The H-score higher than 100 was defined as HER3-high group. Among oropharynx and hypopharynx tumors with positive correlation between H-score of HER3 and HPV status (n = 56), HER3-high group was significantly correlated with HPV positivity (p = 0.009) and good response to ICT (p = 0.035). Good clinical response was also strongly related to HPV-positivity (p = 0.001). In addition, there was a tendency for longer overall survival in HER3-high group than low HER3 expression group (93 vs. 70 months, p = 0.053). The paired tumor samples collected at pre- and post-ICT (n = 21) were analyzed. HER3 expressions in adjacent normal tissue were higher at post-ICT compared to pre-ICT (p = 0.003), and these results were more pronounced in the non-smoking group, but no differences were found according to HPV-status. Conclusions: Taken together, our results showed that H-score of HER3 was significantly higher in both HPV-positive and smoking group. Interestingly, high HER3 expression in oropharynx and hypopharynx tumors was associated with HPV positivity and good clinical response to ICT. Additional analysis of tumor immune microenvironment in tumor tissues are underway.
A phase II study cohort of penpulimab plus anlotinib in patients with recurrent or metastatic non-squamous cell carcinomas of head and neck.
Authors: Zhang Changgong , Sun Yan , Wang Jun , Liu Zhigang , Su Haichuan , Chen Jianhua , Tian Youxin , Wu Huijuan , Gao Liying , Shi Yuankai
Published: June 2023

e18013

Background: Recurrent or metastatic non-squamous cell carcinoma of head and neck (R/M non-SCCHN) lack effective systemic treatment. The feasibility of the combination of immune checkpoint inhibitor and anti-angiogenic agents in the treatment of R/M non-SCCHN was unknown. Penpulimab is a novel anti-programmed cell death-1 (PD-1) antibody with complete elimination of FcγR binding activity. Anlotinib is a multi-kinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. ALTN-AK105-II-01 is a single-arm, multi-cohort, multi-center phase II study to investigate the efficacy and safety of penpulimab plus anlotinib in the treatment of various advanced cancers. Here we report the results of the cohort 2 for patients (pts) with R/M non-SCCHN. Methods: Eligible pts were aged 18 years or older and diagnosed with histologically confirmed R/M non-SCCHN. Other inclusion criteria included ECOG PS 0-1 and having at least one measurable lesion according to RECIST 1.1, and anti-angiogenic agents or immune checkpoint inhibitor treatment-naïve. Pts were given penpulimab 200mg intravenously on day 1 and oral anlotinib 12mg once daily from day 1 to day 14 every 3 weeks until disease progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: From May 21, 2020 to October 14, 2020, 21 pts were enrolled in 7 centers in China. The most common site of primary tumor was salivary gland (15/21, 71.4%) and the most common pathological types included adenoid cystic carcinoma (7/21, 33.3%) and duct carcinoma (4/21, 19.0%). 15 pts (71.4%) had distant metastatic lesions and 12 pts (57.1%) had prior chemotherapy history. As of October 20, 2022 (data cut-off), 4 pts achieved confirmed partial response and the ORR was 19.0%. Stable disease (SD) was observed in 17 pts and the DCR was 100%. The median follow-up for PFS was 14.2 months (95%CI: 7.8, 20.6), 9 pts suffered disease progression and the median PFS was 10.6 months (95%CI: 0.0, 22.4). 14 pts (66.7%) experienced at least one ≥grade 3 treatment-related adverse events (TRAEs) and the most common ≥grade 3 TRAEs was hypertension (15.0%). No treatment-related death was reported. Conclusions: The combination of penpulimab and anlotinib showed encouraging efficacy and favorable safety profile in R/M non-SCCHN and is worthy of further investigation. Clinical trial information: NCT04203719 .
Patterns and outcomes of palliative radiation therapy with immunotherapy in locally recurrent head and neck squamous cell carcinoma.
Authors: Roof Logan , Buchberger David , Yalamanchali Anirudh , Campbell Shauna , Miller Jacob , Koyfman Shlomo A. , Woody Neil McIver , Geiger Jessica Lyn , Yilmaz Emrullah
Published: June 2023

e18015

Background: Immune checkpoint inhibitors (ICI) have been shown to improve outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Radiation therapy (RT) is commonly incorporated into R/M HNSCC treatment for symptom management and disease control. RT is a potential immunostimulatory treatment modality that may enhance the antitumor activity of ICI; however, ideal sequencing of RT and ICI in the palliative treatment setting is not defined. The objective of this study was to describe the patterns and outcomes of RT and ICI in locally recurrent HNSCC. Methods: All adults (≥ 18 years) with HNSCC who received palliative ICI for R/M disease from 2015-2021 were identified from the institutional electronic medical record via ICD codes under an IRB approved protocol. Patients who received ICI for non-HNSCC, had synchronous primary tumors, or had history of hematologic malignancy or immunodeficiency were excluded. Patients without documentation of clinical outcomes after palliative RT were excluded. Retrospective data were collected and underwent descriptive analysis. Results: We identified 26 patients who received palliative ICI and RT for locally recurrent HNSCC. Twelve underwent palliative RT while on ICI. In this group, there were 0 patients with complete response (CR), five with partial response (PR), two with stable disease (SD), and four with progression of disease (PD) in the target lesion. There were 10 grade 3 events. Fourteen patients had RT separately from ICI: 6 before and 8 after receiving ICI. In this group, there was one patient with CR, six with PR, one with SD, and six with PD in the target lesion. There were 3 grade 3 events. Most common grade 3 events in both groups were: dysphagia, mucositis, and voice change. The most common modalities of RT were SBRT, IMRT, and 3D conformal; 7 patients underwent SBRT, 19 underwent IMRT/3D conformal, with similar responses in target lesions. Conclusions: These data suggest that concurrent ICI and palliative RT for locally recurrent HNSCC is effective in the target lesions, but has an increase in toxicities. Although there was a small number of patients who underwent concurrent ICI and RT, the disease control rate (DCR) in this group was 58%, which is promising. Similarly, the DCR for patients receiving ICI and RT separately was 57%. Further study on the optimal type and sequence of palliative RT in this patient population is warranted.