bluuebunny/crossref_metadata_2025 huggingface dataset:
Is laparoscopic approach feasible in early-stage ovarian cancer? A retrospective study in single tertiary center.
Authors: Chang Chen Bin
Published: June 2023

e17560

Background: Laparoscopic approach for early-stage ovarian cancer is a controversy. Current studies showed no negative impacts on these patients. However, some limitations were noted, such as small case numbers, heterogeneity, and retrospective study. Methods: We retrospectively reviewed our cases who was diagnosed as early-stage ovarian cancer and received staging surgery from 2009 through 2017. There patients were divided into two groups, via laparoscopic staging or laparotomy. The primary outcome was progression-free survival. The secondary outcomes were overall survival and intra-operative rupture rate. We performed the Kaplan-Meier method and chi-square test for analyzing survival outcome and factors, in order to evaluate impacts on different surgical methods. Results: Total 520 patients (2014 FIGO stage IA-IC3) were enrolled, including 355 patients who underwent open surgery and 165 patients who underwent laparoscopic surgery. The median follow-up time for survivors was 71(range,39.7-102.3）months. The progression-free survival was similar between two groups and all subgroups. The overall survival was also similar between two surgical methods and all subgroups, except subgroup of clear cell carcinoma. The p-value of overall survival in clear cell carcinoma patients was 0.05. However, the case numbers of clear cell carcinoma 81 in laparotomy group and 31 in laparoscopy group, respectively. The intra-operative rupture rate was increased in laparoscopic group. The relative risk and p-value were 1.139 and 0.043, respectively. Conclusions: Laparoscopic may be feasible in early-stage ovarian cancer in selected patients and expert surgeon due to higher intra-operative rupture rate. If clear cell carcinoma of ovary was highly suspected, the surgeon should be alerted because poorer overall survival in clear cell carcinoma of ovary patients was observed.
Can epigenetic treatments efficiently revoke the ability of 3D ovarian cancer cells to proliferate, migrate, and invade?
Authors: Kelly Rebeca , Aviles Diego , Warshal David Philip , Krill Lauren , Ostrovsky Olga
Published: June 2023

e17562

Background: 3D ovarian cancer propagation and metastasis arise not only from genetic mutations, but from aberrant epigenetic modifications known to involve mechanisms of DNA methylation and histone deacetylation. Clinically, cancer induces epigenetic aberrations in adipose-derived stem cells from omentum (O-ASCs), creating a tumorigenic microenvironment that supports chemoresistance and dissemination of disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we investigate whether these diet-derived compounds can suppress proliferation, migration and invasion of ovarian cancer in 3D-spheroids or 3D-organoids with O-ASCs when compared to synthetic Panobinostat (Pano) and cisplatin/paclitaxol (C/T). Methods: 3D ovarian cancer spheroids and organoids (30% O-ASCs) were treated with EGCG (10, 50 µm), I3C (50, 200 µm), Pano (5, 15 µm) and C/T. Percent growth was followed for 17 days and compared to an untreated control group. Post-treated cancer was then derived from 3D structures and tested for its ability to regrow (MTT assay), to form colonies (CFU), and to migrate and invade (CytoSelect Cell Migration and Invasion assay). Results: Our results show that higher doses of epigenetic regimens more efficiently suppress growth of 3D ovarian cancer when compared to the control and C/T groups (p<.05). Additionally, the synthetic epigenetic drug Pano also efficiently suppressed cancer as compared to control and C/T treated cells (p<.05). Given that experimental treatments efficiently down-regulated 3D cancer growth, follow up of post-treatment cancer recovery was analyzed through multiple biochemical and biological assays. 3D derived cells pre-treated with EGCG, I3C and Pano had significant lower proliferation capacity as compared to control or C/T as demonstrated by an MTT assay (p<.05). While all epigenetic treatments inhibited CFU in the spheroid derived group, EGCG was not able to fully inhibit CFU in the organoid group. Further, inhibition of CFU was not noted in the C/T pre-treated cells. Finally, the ability of cells to migrate and invade following treatment was more efficiently suppressed in cells derived from organoids. I3C and Pano significantly suppressed cancer migration, while EGCG and Pano suppressed invasion (p<.05). Conclusions: Diet-derived epigenetic treatments can reprogram epigenetic aberrations involved in mechanisms of proliferation, migration and invasion of 3D ovarian cancer. Our results suggest that these treatments not only suppress 3D cancer growth and post-treatment regrowth, but could be considered as adjuncts to standard chemotherapy, improving efficiency and patient outcomes.
Genetic counseling and testing for epithelial ovarian cancer in a diverse patient population.
Authors: Kim Kee-Hwan Michael , Hayek Judy , Acker Cheyenne , An Anjile , Zhang Peilin , Gorelick Constantine , Kanis Margaux Jenna
Published: June 2023

e17563

Background: According to the current American Society of Clinical Oncology (ASCO) guidelines, “all women diagnosed with epithelial ovarian cancer should be offered germline genetic testing for BRCA1, BRCA2, and other ovarian cancer susceptibility genes, irrespective of their clinical features or family history”. Test results have implications for surveillance, familial testing, and treatment. We investigated how genetic counseling and testing rates at a New York City tertiary care center with a large minority population compared with national rates, and if any disparities existed. Methods: This is a retrospective cohort study of patients with newly diagnosed epithelial ovarian, fallopian tube, peritoneal cancer between January 2014 and June 2022. Data were obtained from pathology and chemotherapy databases at the NewYork-Presbyterian Brooklyn Methodist Hospital. Variables including age, race, ethnicity, BMI, insurance, language, family history of cancer, date of diagnosis, stage, and genetic counseling/testing status were manually extracted. Descriptive statistics were used to characterize the variables of interest. Chi-square/Fisher’s exact tests were used to examine the association between genetic counseling/testing and categorical variables. Wilcoxon rank-sum/t-tests were used for association between continuous factors. The Mann-Kendall trend test was used to assess year-to-year trends. Results: 144 patients were identified. Mean age at diagnosis was 63 years (SD:13). This diverse cohort included 51% white, 36% black, 3.5% Asian, 9% other/unknown; 9% were of Hispanic ethnicity and 26% were non-English speaking. 104 (72%) patients received genetic counseling and 99 (69%) received subsequent genetic testing. 95% of those that underwent genetic counseling underwent subsequent testing. The genetic counseling and testing rates were not influenced by race, ethnicity, language, insurance type, BMI, family history of cancer. It was associated with significant difference by cancer stage (p < 0.01). There was a significant upward trend of proportion of patients that received genetic counseling from 47% in 2015 to 100% in 2022 (p < 0.01). Most genetic counseling was performed by a gynecologic oncologist (93%) as opposed to a genetic counselor (6.7%). Overall, 12 (8.3%) patients were BRCA+. Conclusions: Genetic counseling and testing rates within this diverse study population proved to be at least twice as high as the national average of 10-30%, with an increasing year-to-year trend. There were no disparities observed, in contrast to previously published data. BRCA mutation detection was in line with established prevalence within ovarian cancer, indicating adequate screening. Concentrated efforts on behalf of oncologists ensures excellent access to testing.
Comparison of BRCA genetic testing and subsequent treatment with PARP inhibitors (PARPi) for ederly vs non-elderly women with non-mucinous epithelial ovarian cancer (EOC): A large prospective cohort study from the Australian National Gynaecology Oncology Registry (NGOR).
Authors: Naidoo Mahendra , Scott Clare L. , McNally Orla , Rome Rob , Perera Sharnel , Zalcberg John Raymond
Published: June 2023

e17566

Background: The 5-year survival rate for elderly women (≥ 75 years) with ovarian cancer is 25%. Germline mutations in BRCA1/BRCA2 are identified in approximately 15% of newly diagnosed women with ovarian cancer and have implications for prognosis and predicted benefit of both platinum chemotherapy and PARPi therapy. Objectives: To compare differences in, and subsequent management of Elderly (aged ≥75 years) vs Non-elderly (aged <75 years) women with non-mucinous EOC who underwent germline and somatic BRCA1/BRCA2 testing across the Australian NGOR sites from 2017 – 2022. Methods: Clinical data were sourced from NGOR patient databases and assessed to confirm accuracy prior to analysis. Results: Data on 1579 eligible women between May 2017 and July 2022 across 21 hospitals were collected. Patient characteristics are summarised in Table 1. The rates of germline testing in Elderly women was 51% compared to 71% in Non-elderly women and this difference was statistically significant (p<0.001). The rates of somatic testing in Elderly women was 28% compared to 33% in Non-elderly women although this difference was not statistically significant (p=0.2). In Elderly women with either germline or somatic pathogenic BRCA mutations and Stage III/IV disease, 67% received PARPi within 8 weeks of chemotherapy completion compared to 53% in Non-elderly women. In a multi-variate analysis, the most significant characteristic associated with reduced germline testing was the ‘Elderly’ compared to ‘Non-elderly’ group (OR 0.41, 95% CI: 0.30-0.58, p < 0.001). Germline testing was more likely to be conducted in postcodes associated with higher Socioeconomic status (SES) quintiles 2-5 compared to quintile 1 (OR 2.06, 95% CI: 1.50-2.81, p< 0.001) and in those women receiving operative and chemotherapy treatment compared to chemotherapy alone (OR 1.84, 95% CI: 1.08-3.11, p=0.024). Conclusions: The rates of germline and somatic BRCA testing are lower than anticipated, particularly germline testing in Elderly women. Women known to have pathogenic germline or somatic BRCA mutations may have received PARPi at lower rates than expected. Further studies are required to understand the cause of such variations, including accounting for the advent of government funded BRCA testing, PARPi funding and correlating effects on survival. [Table: see text]
Demographic and socioeconomic factors in poorly differentiated Sertoli-Leydig cell tumors: A National Cancer Database analysis.
Authors: Cogua Laura
Published: June 2023

e17568

Background: Poorly differentiated Sertoli-Leydig cell tumor (PD-SLCT) is a rare and aggressive type of ovarian cancer. This cancer has a 5-year cancer-specific survival rate of 43.9% with a chance of early relapse of approximately 2-3 years following initial diagnosis. Given the rarity of the cancer, potential risk factors could offer providers and patients more information about the epidemiology. The National Cancer Database (NCDB) was analyzed to study the demographic factors in patients diagnosed with PD-SLCT. Methods: Cases of PD-SLCT (N = 405) in the NCDB from 2004 – 2020 were determined via histology (ICD-O-3 code = 8631). A retrospective cohort analysis using demographic factors such as race, age, sex, insurance status, urban/rural, facility type, and Charleson-Deyo score were analyzed by descriptive statistics and incidence trends were interpreted in regression analysis. Results: A total of 405 patients with a diagnosis of PD-SLCT were identified in the database with a steady incidence of patients diagnosed per year (mean = 23.8 per year, R2 = 0.1). The average age of diagnosis was 41.7 years (SD = 20.1, range = 8 – 90 years). The majority of patients were non-Hispanic (82.5%) and White (69.4 %). More patients were in the top quartile of income earners (30.8.%) and were privately insured (56.8%) relative to those who were uninsured or insured by Medicare/Medicaid (43.2%). A greater percentage of patients with PD-SLCT were treated at a non-academic program (54.0%) compared to an academic/research program (46.0%). More patients lived in metropolitan counties with a population greater than 1 million (59.8%) versus less populated metropolitan communities or urban communities (40.2%). Most individuals (84.2%) had Charlson-Deyo comorbidity scores of 0. Conclusions: This novel study of the NCDB addresses a significant knowledge gap on patients with PD-SLCT, as it provides demographic insight into this rare type of tumor and the patients who are diagnosed with it. Most PD-SLCT patients tend to be in the premenopausal age, as previously described in literature. Most patients are White and non-Hispanic. This is the first time the socioeconomic factors of PD-SLCT patients have been described in the literature: patients are more likely to be in the top income quartile, live in densely populated metropolitan areas, and be treated in a non-academic program. Further research is needed to better understand the impact of these factors on the diagnosis of, treatments utilized, and overall survival of patients with PD-SLCT to ensure that all patients receive the best possible care, regardless of their background.
Prognostic risk stratification of low-grade serous ovarian cancer: Model development and validation based on machine learning algorithm.
Authors: Chen Zhongshao , Zhang Kai , Chu Ran , Song Kun
Published: June 2023

e17569

Background: Low-grade serous ovarian cancer (LGSOC) is a rare ovarian tumor that lacks a prognostic prediction model. We attempted to construct a clinical nomogram to predict the recurrence and survival of patients with LGSOC. Methods: A multicenter clinical cohort of 199 patients with pathologically confirmed LGSOC was constructed. The predictive model factors were recurrence and survival related clinical factors, which were determined by univariate and multivariate COX regression analysis. The area under receiver operating characteristic curve (AUC), and calibration curve were used to assess the accuracy and discrimination of the nomogram. The concordance index(C-index), net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to evaluate the efficacy of nomogram and FIGO staging in predicting recurrence and survival. Results: A total of 155 patients were included, and four independent prognostic factors were identified to construct the prediction model. The AUC ( > 0.8) showed satisfactory discriminative ability of the nomogram, and the calibration curve showed good agreement between the predicted outcome and the actual outcome. The C-index (PFS: 0.791 vs 0.693; OS: 0.808 vs 0.674), NRI values (0.181 for 3-year and 0.278 for 5-year OS prediction) and IDI values(0.141 for 3-year and 0.147 for 5-year OS prediction, 0.089 for 3-year and 0.079 for 5-year PFS prediction) results showed that nomogram performed better than FIGO staging in predicting prognosis(p < 0.01). Conclusions: We constructed and validated clinical nomogram to individually predict recurrence and survival outcomes in patients with LGSOC, which can help evaluate the prognosis of patients.
The impact of lymphadenectomy on survival outcomes of ovarian clear cell carcinoma: A systematic review and meta-analysis.
Authors: Liu Yan , Song Kun , Huang Changzhen , Chu Ran
Published: June 2023

e17572

Background: The treatment strategies for ovarian clear cell carcinoma (OCCC) are the same as those for epithelial ovarian cancer. Due to the rarity of OCCC, no prospective studies of its surgery have been reported. Therefore, the therapeutic significance of lymphadenectomy for OCCC needs to be further clarified. Methods: The Web of Science, Scopus, PubMed, and other sources (e.g. Google Scholar) were searched from each database’s earliest inception to June 2021. English-language publications of observational studies that investigated the role of lymphadenectomy in patients with OCCC were included.The pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated. Results: The analysis demonstrated that lymphadenectomy is associated with significantly improved disease-specific survival (DSS) (HR = 0.76; 95%CI = 0.60-0.95; P = 0.02; I2= 0.0%) and disease-free survival (DFS) (HR = 0.58; 95%CI = 0.33-1.00; P = 0.05; I2= 61%), but not for overall survival (OS) (HR = 0.80; 95%CI = 0.60-1.06; P = 0.12; I2= 19%) and progression-free survival (PFS) (HR = 0.95; 95%CI = 0.64-1.42; P = 0.79; I2= 0.0%). But it is worth noting that several single studies indicated a tendency of improved OS, PFS, DFS, DSS with lymphadenectomy. The discrepancy of different results from similar studies should be viewed with caution. Conclusions: Lymphadenectomy could not significantly improve OS and PFS for OCCC, but is associated with improved DFS and DSS. Gynecologic oncologists should tailor treatment to patients to achieve optimal outcomes. Lymph node metastasis should be detected as accurately as possible before and during surgery to identify patients who can benefit from lymphadenectomy. The establishment of an international OCCC database and the development of multicenter clinical studies with international cooperation will help improve the treatment strategy.
Effect of testing for BRCA1/2 on outcomes in patients with ovarian cancer treated with PARPi in 1st line maintenance (1LM).
Authors: Gordan Lucio N. , Vasudevan Anupama , English Sandy , Roos Alison , Fares Marielle , Aton Lindsay , Wang Brandon , Blanc Simon
Published: June 2023

e17576

Background: The treatment of ovarian cancer (OC) has expanded with the approval of PARPi in 1LM. Guidelines recommend that all women with OC get tested for BRCA1/2 and HRD status, given the therapeutic implication. Methods: This retrospective observational study used de-identified records from the Integra Connect PrecisionQ database enriched with information obtained by curation. Adult patients (>18 yrs) with OC who had initiated treatment between 01/01/2019 and 12/31/2021 were included. Categorical variables were reported as proportions and continuous variables as median (interquartile range, IQR), as appropriate. Results: In the 1,093 patients studied, the median age was 69 yrs and 75% had high grade carcinomas. Patients were predominantly White (74%); 9% were African American. 65% were ECOG 0-1 and 8% were ECOG 2. The first line (1L) treatment included platinum (Pl) chemotherapy alone in 60% (678) and Pl + bevacizumab (bev) in 37% (401), with 86% of patients being Pl-sensitive (929/1079). Most patients (84%, 782/929) received a BRCA test, of which 415 were tested for BRCA only and 367 were BRCA/HRD. The median turnaround time was 11 days (IQR=9) for BRCA tests and 15 days (IQR=35) for HRD tests. Of 929 patients who were Pl-sensitive, 503 (54%) received 1LM and 426 (46%) did not receive 1LM. Of 503 patients who received 1LM, 86% (435) had BRCA test results and 41% (208) had HRD results before maintenance initiation. In 48 patients who received 1LM, BRCA/HRD test results were not reported before initiation of maintenance. Patients who received Pl-only induction received bev (24), niraparib (94), olaparib (O) (78), rucaparib (5), O+bev (2), or nira+bev (6) in 1LM. Patients who had Pl+bev induction received bev (134), niraparib (28), O (29), and O+bev (57), or nira+bev (18) in 1LM. The median time to discontinuation (TTD) in all patient groups regardless of BRCA/HRD testing and results, was 24 mo. (13.8-NR) with O+bev and 22 mo. (17-NR) with O alone, compared to 7.8 mo. (6.9-10.1) with bev, and 8.2 mo. with niraparib (6.7-9.9). The probability of remaining on treatment at 3 mo. for O, niraparib, or O+bev was >90% compared to 80% with bev alone and remained high at 6 mo. (>80% for O or O+bev). The benefit was sustained for O and O+bev-treated groups, with an 18-mo. prob. of remaining on treatment of 57% (45-67) for O and 52% (36-65) for O+bev compared to 16% (10-24) for bev. Ongoing analyses will evaluate the TTD in patient subgroups by BRCA/HRD mutation status. Conclusions: Patients who had a test result and started a PARPi in 1LM had a longer TTD compared to bev-only treated groups, underscoring the importance of genetic testing for the initiation of 1LM and outcome improvement. [Table: see text]
Prognostic value of insulin-like growth factor receptor 1 (IGF1R) expression in high-grade serous ovarian cancer (HGSOC) treated with first line platinum derivative based chemotherapy.
Authors: Szymanowski Bartosz , Bieńkowski Michał , Pęksa Rafał , Cierniak Szczepan , Duchnowska Renata
Published: June 2023

e17577

Background: Insulin-like growth factor receptor 1 (IGF1R) expression is frequently observed in ovarian cancer patients. Based on data from the literature, the IGF1(IGF2)/IGF1R pathway may be associated with resistance to platinum derivative based chemotherapy. Methods: The study group included 64 Caucasian women with serous high-grade ovarian cancer (HSOC) stage III-IV TNM/FIGO classification, treated 1st line platinum derivative based chemotherapy between 2004-2014. The analysis of clinical data was carried out based on data from medical records. IGF1R expression was assessed by immunohistochemistry using the monoclonal antibody Roche Rabbit Monoclonal (G11) in tissues from paraffin-embedded blocks. Progression free survival (PFS) was analyzed as the time from the start of chemotherapy to progression. Overall survival (OS) was defined as the time from diagnosis to the patient's death, regardless of cause, or to the last contact with the patient. In all analyses, the significance level was p = 0.05. Statistical analysis was performed using the 3.4.3 version of R statistical environment. Results: The median follow-up was 1023 days (range 157 to 3420 days). The median PFS was 14.0 (95%CI: 11.9-18.0) months. Median OS was not reached. The average patients age was 62 years (range 37-83). Platinum-sensitivity, partial platinum-sensitivity, platinum resistance and platinum-insensitivity were found in 23 (37.1%), 17 (27.4%), 21 (33.9%) and 1 (1.6%) patients, respectively. Any IGF1R expression was noted in 57 patients with the median H-score of 220 (range: 0-300; IQR: 100-207). Median PFS for IGF1R H-score 220 and IGF1R > 220 was 15.4 (95% CI: 13.1-23.3) and 10.8 (95% CI: 9.6-NA) months, respectively. In multivariate analysis PFS was associated with the extent of surgery: cytoreduction secondary vs. primary (WR = 1.94; p = 0.03), suboptimal vs. optimal (WR = 2.16; p = 0.01), body mass index (WR = 0.44; p = 0.05) and IGF1R expression ( > 220) (WR = 2.84; p = 0.04). Conclusions: High expression of IGF1R (H-score > 220) in stage III/IV HGSOC patients treated in 1st line platinum derivative-based chemotherapy is a negative prognostic factor.
Targeting regeneration capacity of stem cells to improve surgical wound healing outcomes in ovarian cancer patients.
Authors: Kelly Rebeca , Buchbinder Michelle , Aviles Diego , Hunter Krystal , Ostrovsky Olga
Published: June 2023

e17578

Background: Despite advancements in care and treatment, ovarian cancer continues to be a challenging and deadly disease. Currently, standard treatment comprises a combination of cytoreductive surgery, often followed by platinum-based chemotherapy, known to negatively affect wound healing recovery. Therefore, achieving optimal post-surgical wound healing is critical in preventing delays in treatment, which can greatly impact patient outcomes and overall survival. Adipose-derived stem cells (ASC) have been shown to be crucial in regeneration of tissue and wound closure, as well as in regulating inflammatory differentiation and proliferation processes. Thus, improving the regeneration capacity of ASCs in wounds may speed post-surgical recovery and subsequent treatments. While a number of compounds have been shown to potentiate the regeneration ability of ASCs, we hypothesize that naturally derived epigenetic compounds with anti-cancer properties (I3C and EGCG), as well as anti-inflammatory compounds (non-psychoactive cannabidiol, CBD), may have a role in increasing regeneration capacity of stem cells. Therefore, ASCs were primed with these compounds and expression of major inflammatory, anti-inflammatory, proliferation and regeneration markers was evaluated. Methods: ASCs were primed with either I3C 50uM, EGCG 10 uM, or CBD 100nM. Conditioned medium from these treatments was collected and underwent a protein array assay for detection of levels of 40 human inflammatory markers and cytokines according to the manufacturer instructions. A one-way ANOVA test and Tukey post-hoc testing analyzed intensities for each marker between the control group and each of the primed groups. Results: Our results indicate that ASCs primed with our epigenetic treatments significantly decrease expression of a multitude of inflammatory markers and cytokines. I3C primed ASCs showed significantly decreased expression of the following factors: I-309, IL-11, IL-12 p40, IL-12p70, IL-1α, IL-6sR, M-CSF, MIG, MIP-1α, MIP-1β, MIP-1δ, IL-6, MCP-1, TIMP-2. EGCG primed ASCs significantly decreased expression of IL-12p70, IL-13, IL-6sR, MIP-1α, MIP-1δ, RANTES, IL-6, IL-8, MCP-1, TIMP-2. CBD primed ASCs significantly decreased expression of IL-6. A p< .05 was used. Conclusions: Priming ASCs with EGCG, I3C and CBD significantly down-regulate expression of a number of pro-inflammatory markers known to delay and interfere with the kinetics of wound healing processes, including wound inflammation, closure and scar formation. Therefore, these results suggest that naturally derived epigenetic compounds and CBD successfully potentiated ASCs’ ability to attenuate inflammation and wound healing processes. Consequently, our findings can lead to new diet and surgical ASC protocols which could optimize cancer post-operative wound healing closure time while decreasing inflammation.
Clinical assessment of HRD scoring in relation to PARPi response in terms of statistical guidance on reporting results for CDx tests evaluation.
Authors: Bisgin Atil , Boga Ibrahim , Eskut Kaan Ihsan , Rencuzogullari Cagla , Sonmezler Ozge , Kose Fatih , Besen Ali Ayberk , Olmez Omer Fatih , Disel Umut , Kocer Nazım Emrah , Bolat Filiz , Jinga Dan-Corneliu , Lazar Ioana , Pathak Surajit
Published: June 2023

e17597

Background: Homologous recombination deficiency (HRD) is a tumor characteristic that can be assessed via different biomarkers such as individual mutations in BRCA1 and BRCA2 genes, and/or other HRR genes and genomic instability. We assessed a combined HRD score in three measures; BRCAs mutations, HRR mutation (HRRm) status, and genomic instability scoring via a specific bioinformatic algorithm of the testing panel to establish clinical validation. Methods: We tested 157 ovarian cancer patients’ FFPE samples to define HRD score, BRCA1/2 mutation and other HRRm status, to camper the responses to PARP inhibitors. For the HRD scoring, all the samples that were previously tested with alternative HRD tests and the cases had an indication of PARPi also tested via HRDInfo (CE-IVD) Panel for clinical diagnostics in this study. The PPA, NPA and OPA have been measured according to the FDA regulations of overall agreement for a follow-on CDx to show clinical evidence. Results: Depending on the three levels of testing strategy, BRCA1-2 mutation status in relation to the clinical response for PARPi has the lowest positive percent agreement (PPA) with 63.41% while HRD score has the highest with 97.62% that is higher than the any alternative HRD tests. All the PPA, NPA and OPA measures showed in the Figure for BRCA1-2 status and Genomic Instability stand alone and all BRCA1-2 plus other HRR genes plus Genomic Instability Status (GIS) to define HRD scoring. Conclusions: Even though the testing rate of HRD tests are still low all around the world and limited to specific cancers, there is an increasing requirement for different types of cancers. However, most alternative HRD tests have high overall concordance but fail to reach FDA CDx test requirements. Thus, this study showing the clinical evidence in the treatment of PARPi response data together with high PPA, NPA and OPA measures of HRDInfo panel and its bioinformatics algorithm. [Table: see text]
Real-world outcomes of first-line maintenance with niraparib or bevacizumab in advanced ovarian cancer.
Authors: Vasudevan Anupama , English Sandy , Gart Mike , Oladipo Taofikat , Hartman John , Iadeluca Laura L. , Kudrik Fred J.
Published: June 2023

e17598

Background: Niraparib and bevacizumab are the only FDA-approved first-line maintenance (1LM) therapies for advanced ovarian cancer (AOC) without a biomarker requirement. However, little information exists regarding the effectiveness of these treatments in the real world. Methods: We identified 89 AOC patients from the US-based deidentified Integra PrecisionQ database who received 1LM bevacizumab (n=31) or niraparib (n=58) following induction chemotherapy (CT) ± bevacizumab initiated between July 1, 2019, and March 31, 2021, and followed them until the data cut-off of March 31, 2022. Using the start of maintenance therapy as the index date, we examined patient characteristics, time to next treatment or death (TTNT; often used as a real-world proxy for progression-free survival), and overall survival (OS) for these treatment groups. Results: For patients who received 1LM bevacizumab, the median age was 69 years, 65% had Stage III cancer at index date, 84% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and 87% received CT + bevacizumab as first-line therapy. For patients who received 1LM niraparib, the median age was 68.5 years, 66% had Stage III cancer at index date, 88% had an ECOG performance status of 0–1, and 79% received chemotherapy alone as first-line therapy. Only 1 bevacizumab (BRCAm) and 11 niraparib (4 BRCAm, 7 BRCAwt HRd) patients had known homologous recombination deficiency (HRd)-positive tumors. Patients treated with bevacizumab had a median TTNT of 4.5 months (mo) and a 12-month OS mark of 83.6%; for patients treated with niraparib, the corresponding values were 9.9 mo and 96.3%. Conclusions: Our study provides real-world outcomes data for newly diagnosed AOC patients receiving maintenance niraparib or bevacizumab following CT +/- bevacizumab. HRd testing results were only available for 19% of bevacizumab- and 40% of niraparib-treated patients, highlighting a need for greater testing in the real world. Future studies should examine which patient characteristics are associated with long-term survival for these and other treatment options to aid in the decision-making process. Funding: GSK215281. [Table: see text]
PARPi monotherapy as first-line maintenance following chemotherapy + bevacizumab in advanced ovarian cancer.
Authors: Kudrik Fred J. , Vasudevan Anupama , English Sandy , Gart Mike , Oladipo Taofikat , Hartman John , Iadeluca Laura L.
Published: June 2023

e17601

Background: Chemotherapy (CT) + bevacizumab is a standard-of-care option for first-line (1L) treatment for patients with advanced ovarian cancer (AOC). Real-world approaches to 1L maintenance (1LM) treatment include, among others, bevacizumab monotherapy or switching to poly(ADP-ribose) polymerase inhibitor (PARPi) monotherapy after completing 6–9 cycles of induction CT + bevacizumab. Methods: We identified 61 patients with AOC from the US-based, deidentified Integra PrecisionQ database who received 1LM bevacizumab monotherapy (n=27) or PARPi monotherapy (n=34) after 1L CT + bevacizumab initiated between July 1, 2019, and March 31, 2021, and followed them until the data cut-off of March 31, 2022. Using the start of 1LM therapy as the index date, we examined patient characteristics, time to next treatment or death (TTNT; often used as a real-world proxy for progression-free survival), and overall survival (OS) for these two treatment groups. Results: For patients who received 1LM bevacizumab, the median age was 69 years, 89% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1, 63% had Stage III disease at index, and only 1 (4%) had a recorded/documented homologous recombination deficiency (HRd)-positive tumor. Of the 34 patients who switched to 1LM PARPi monotherapy, 21 (62%) received olaparib, 12 (35%) niraparib, and 1 (3%) rucaparib. The median age of these patients was 63.5 years, 94% had ECOG performance status 0–1, 62% had Stage III disease at index date, and 47% had HRD+ tumors. For patients who switched to 1LM PARPi monotherapy, the median TTNT was 10.8 months (mo) and 97% were still alive at the 12-month mark. For patients who continued with 1LM bevacizumab, the median TTNT was 4.9 mo and 81% remained alive at the 12-month mark. Conclusions: This study suggests that switching to maintenance with PARPi monotherapy following induction CT + bevacizumab is a viable option for the treatment of AOC. A higher prevalence of HRd patients switching to PARPi monotherapy may indicate clinician preference for PARPi monotherapy in biomarker-selected subgroups, and further analysis is needed to examine which patients are most likely to benefit from switch maintenance. Funding: GSK215281. [Table: see text]
OncoTherad immunotherapy plus platelet rich plasma as potential therapeutic strategy for ovarian cancer: The role of toll-like receptors 2 and 4 signaling pathways.
Authors: Oliveira Gabriela , Ribeiro de Souza Bianca , Lima Baggio de Paula Juliane , Henrique da Silva Santos Daniel , Camargo Gabriela Cardoso de Arruda , Fávaro Wagner José , Duran Nelson
Published: June 2023

e17602

Background: Ovarian cancer (OC) has the most devastating death rate of gynecological cancers with only 44% of women surviving 5 years after diagnosis. Toll-like receptors (TLRs) signaling can play an important role in the OC treatment. TLR activation in immune cells can help activate an effective antitumor response. In this scenario, a new perspective is represented by combined OncoTherad (MRB-CFI-1) immunotherapy and Platelet Rich Plasma (PRP). OncoTherad (MRB-CFI-1) leads to the distinct stimulation of the innate immune system mediated by TLR2 and TLR4, resulting in an increased activation of the IFN signaling pathway. Also, PRP acts on immune activation and exerts antitumor effects. This study characterized the histopathological and molecular effects of the OncoTherad associated with PRP in the treatment of OC chemically induced in rats and described the possible mechanisms of action of this association involving the TLRs 2 and 4 signaling pathways. Methods: Fischer 344 female rats were divided into 5 groups (n = 7 animals per group): Control (Sham surgery) group; Cancer (7,12 dimethylbenzoanthracene – DMBA injection in the ovarian bursa, 1.25 mg/kg) group; OncoTherad (20mg/kg) group; PRP (328.103 – 549.103 platelets/mm3) group and; OncoTherad+PRP (same doses of the isolated treatments) group. Intraperitoneal doses were administered twice a week for 4 weeks. Immunohistochemistry was analyzed as total immunoreactivity and intensity of immunoreaction. Results: Our results showed serous type ovarian carcinoma, follicular atresia, absence of corpora lutea and hyperplasia of the germinal epithelium and tunica albuginea in the Cancer group. The histopathological changes in the PRP group were similar as Cancer group. In contrast, the animals treated with OncoTherad singly or in combination with PRP showed decrease of ovarian neoplastic lesions and histopathological recovery. TLR4 and IL-6 immunoreactivities were significantly lower (p < 0.05) in the Cancer group. PRP treatment reduced (p < 0.05) TLR2. In the Oncotherad+PRP group, the immunoreactivities of TLR4, MyD88, IRF-3 and TNF-α were lower. OncoTherad treatment alone led to stimulation of the innate immune system mediated by TLR2 and TLR4, resulting in an increased activation of the MyD88 signaling pathway (intensified IL-6 and TNF-α immunoreactivities). Conclusions: OncoTherad immunotherapy was able to reduce ovarian lesions and stimulated the TLR2 and 4 signaling pathways in the OC microenvironment, leading to antitumor effects by activating the production of inflammatory cytokines. Thus, OncoTherad immunotherapy could be considered an important therapeutic strategy for OC.
Serial monitoring of ovarian cancer risk in women with adnexal mass.
Authors: Pappas Todd C. , Ghosh Srinka , Reilly Gerard P. , Phan Ryan
Published: June 2023

e17608

Background: Monitoring of ovarian malignancy risk in indeterminate masses is typically done using TVUS and other clinical factors. No biomarkers are available to assist physicians in clinical management of benign or indeterminate adnexal mass either on initial visit or in follow-up. We recently characterized the clinical performance of a deep neural network-derived multivariate index assay (MIA3G) [1] to assess ovarian malignancy risk in retrospective and prospectively collected multi-site clinical studies. Here we present data on MIA3G serial follow-up to monitor ovarian cancer risk in women presented with adnexal mass from the prospective studies. Methods: Data are presented from ongoing multisite clinical studies in which total 924 patients presented with adnexal masses were enrolled. Follow-up visits, scheduled at clinician’s discretion, may have included imaging and blood collection. Specimens were processed for serum and run on a clinical analyzer. MIA3G score from 0-10 was calculated using seven serum biomarkers coupling with patient age and menopausal status based on previously published neural network-based algorithm. MIA3G with NPV of 99.7% (CI:99.2–99.9) was used to risk stratify the patient with an adnexal mass into low probability of malignancy or indeterminate with a validated cut off at 5.0. For this analysis, MIA3G scores were binned into the following Zones: I (0-2.49), II (2.50 -4.99) and II (5.00-10.00). Results: Of 924 enrolled patients, 538 patients had completed clinical and biomarker data on initial study draw. Of these, 145 had at least one follow-up test and 31 had at least two follow-up test. Median duration to first follow-up test was 108 d (~3.6 mon), and median duration to second follow-up test was 272 d (~9.1 mon). Follow-up in 3 MIA3G score zones at the 0 -3.6 and 3.6 - 9.1 mon interval consistently showed 88% patients within zone I remained unchanged, whereas 12% of patients moved to zones II and III. In the 0 - 3.6 mon interval, the median change in MIA3G score from I to II was 2.25 (n = 9, range 0.54 - 3.52) and from I to III was 5.92 (n = 8, range 5.08-7.62 ). In the 3.6 - 9.1 mon testing interval, the median change in MIA3G score from zone I to II was 3.11 (n = 2, range 2.75 to 3.46) and the single patient change from I to III was 6.89. Across both testing intervals, 17%-50% of patients in zone II remain unchanged while approximately 25% patients had score increase to zone III. Importantly, 50% of patients in zone III remained unchanged in the absence of clinical intervention whereas 50% had MIA3G score reduction in association with clinical management. Conclusions: These results indicate that i) the serial follow-up with MIA3G is recommended to monitor the clinical status of the adnexal mass every 3 months, ii) MIA3G score changes of > 2.25 suggest clinical follow-up, and finally iii) the MIA3G is a suitable tool for the effectiveness of clinical management of adnexal mass. [1]: DOI 10.3389/fmed.2023.1102437.
Real-world characteristics and treatment pattern of patients with newly diagnosed endometrial cancer in China.
Authors: Yin Aijun , Wang Dong , Luo Yanlin , An Ruifang , Yao Shuzhong , Shen Yufei , Sun Li , Lei Cuirong , Tian Yan , Wang Li , Zhong Dan , Xu Manman , Jiang Yuanyuan , Zhang Min , Zhang Binqi , Mao Huirong , Dong Fengshi , Zhang Yu , Kong Beihua
Published: June 2023

e17613

Background: Endometrial cancer (EC) is the second most common gynecologic cancer in China with an increasing incidence. Currently, there is no comprehensive profile of EC patients in China. This real-world multicenter retrospective study aimed to depict the characteristics and treatment patterns in newly diagnosed EC patients in China. Methods: Medical records of newly diagnosed EC at 8 hospitals between January 1, 2015 and December 31, 2019 were retrospectively reviewed. The demographic and clinical characteristics at diagnosis as well as the treatment received within 6 months after diagnosis were collected. Results: A total of 1397 patients were enrolled in the study. The average age was 53.5 years. The number of patients (n=1256) classified as stage I, II, III, and IV was 885 (70.5%), 141 (11.2%), 207 (16.5%) and 23 (1.8%), respectively. The number of patients (n=1340) presented with low-grade (G1-2) and high-grade (G3) tumors was 924 (74.0%) and 324 (26.0%), respectively. Invasion of lymphovascular space was detected in 237 (17.0%) out of 1397 patients. Among 1389 patients with pathological data, pure endometrioid carcinoma (90.3%) and serous carcinoma (5.1%) accounted for the majority of pathological types. Estrogen receptor (ER) expression was positive in 91.0% (977/1074) of patients and progesterone-receptor (PR) expression was positive in 85.2% (904/1061) of patients. Mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) was identified in 26.6% (107/402) of patients. Among 1393 patients with treatment information, surgery was performed in 99.6% of patients and 66.9% received adjuvant treatment following surgery according to clinicopathological risk factors. The percentage of patients receiving adjuvant chemotherapy, adjuvant radiotherapy, and adjuvant chemoradiotherapy was 36.7%, 7.3%, and 22.0%, respectively. Among 306 patients who received chemoradiotherapy, 47.1% underwent concurrent chemoradiotherapy, 31.0% underwent sandwich chemoradiotherapy, and 21.9% underwent sequential chemoradiotherapy. Conclusions: To date, this is the first real-world study with largest sample size of EC patients in China. EC is frequently diagnosed at early 50s in Chinese patients, which is at a younger age compared with European and American population. Newly diagnosed EC patients in China are primarily treated with surgery. Chemotherapy and radiotherapy remain the main adjuvant treatment after surgery. MSI-H/dMMR patients accounted for about 1/4 of newly diagnosed patients, for whom immunotherapy may open up better prognosis in the future.
Immunohistochemical expression of ER and p53 as predictive biomarkers of immunotherapy in endometrial cancer.
Authors: Liontos Michael , Papanota Aristea-Maria , Svarna Anna , Pergialiotis Vasileios , Fiste Oraianthi , Markellos Christos , Kunadis Elena , Potiri Eirini , Andrikopoulou Angeliki , Papatheodoridi Alkistis , Koutsoukos Konstantinos , Kaparelou Maria , Goula Kalliroi , Pavlakis Kitty , Thomakos Nikolaos , Haidopoulos Dimitrios , Rodolakis Alexandros , Zagouri Flora , Dimopoulos Meletios A.
Published: June 2023

e17626

Background: Immune Checkpoint Inhibitors (ICIs), either as monotherapy or in combination with tyrosine kinase inhibitors (TKIs), were recently incorporated into the therapeutic guidelines for recurrent/metastatic endometrial cancer (EC). Microsatellite Instability (MSI) is the only biomarker to guide treatment. We evaluated the predictive significance of Estrogen Receptor (ER) and p53 expression. Methods: Medical charts of EC patients that received ICIs in our institution for advanced/metastatic disease were retrospectively reviewed. TP53 and ER expression were determined by immunohistochemistry. Survival analysis was performed using IBM SPSS statistics v.25. Results: Thirty-two patients were included in our analysis. The median age was 63.1 years (25th-75th percentile: 57.6 – 69.6). 62.5% of the patients had endometrioid histology, 21.9% serous histology and 15.6% of them displayed other histology. 46.9% of the patients had grade 1-2 tumors and 53.1% grade 3 tumors. 21.9% of them were diagnosed with stage 1-2 disease, while 78.1% presented with stage 3 disease. 62.5% received 0-1 prior lines of treatment and 37.5% of them received more than 2 prior lines. Molecular characteristics are presented in the table. All MSI-High patients received anti-PD1 monotherapy with a median PFS of 11.9 months (95% CI:2.3-21.5). Microsatellite Stable (MSS) patients received pembrolizumab-lenvatinib combination with median PFS 7.54 months (95% CI:2.6-11.5). ER positivity was associated with significant PFS benefit in both the ICI monotherapy group (11.9 vs. 0.63 months, p=0.061) and the group that received ICI/TKI combination (11.3 vs. 1.75 months, p=0.001). Analogous benefit was noted in the Overall Survival post start of IO or IO/TKI treatment (9.8 vs 0.6 months in MSI-high patients and 20.6 vs 5.9 months in MSS patients). ER-positivity remained an independent predictive factor favoring PFS in the Multivariate Cox regression analysis when adjusting for immunotherapy type, histology, and previous lines of therapy (HR=0.216, p=0.013). Conclusions: ER expression proved to be an independent prognostic factor regarding PFS in our cohort of patients. Further studies are needed to investigate the role of ER as a predictive biomarker for immunotherapy in EC. [Table: see text]
The utilization of lenvatinib with pembrolizumab for the treatment of recurrent endometrial cancer.
Authors: Barbi Mali , Lee Chung-Shien , Rahman Husneara , Cheng Kit , Jean Lee , John Veena S.
Published: June 2023

e17627

Background: The landscape for the treatment of microsatellite-stable-recurrent endometrial cancer has changed with the published results of the KEYNOTE-775, demonstrating an overall response rate of 37.2% with Pembrolizumab and Lenvatinib 20 mg. However, recent retrospective studies have suggested that a lower dose of Lenvatinib may be safer and equally efficacious. We aimed to retrospectively review our institutional data to compare the efficacy and toxicity of Lenvatinib at a low (≤10 mg) vs. high (>10 mg) dose. Methods: Retrospective review of patients with recurrent endometrial cancer who received ≥ 3 cycles of Pembrolizumab with Lenvatinib. A Univariate analysis was used to estimate the 1-year progression-free survival (PFS) and overall survival (OS), and a Multivariate Cox PH regression model was used to estimate the hazard ratio (HR) with a 95% confidence interval (CI) and p<0.05. Results: 77 patients were included in this analysis, the median age and BMI were 70 years and 28.5 kg/m2, respectively (Table 1). Most tumors were PDL-1<1% (67.2%) and were microsatellite stable (95%). 4 patients had MSI-H. Most patients started at a lower dose (66%, median of 10 mg), and 34% of patients started at a higher dose (n=26, median of 14 mg). The most common dose was 10 mg (41%, n=32) and 13% of patients received 20 mg (n=10). In the lower dose group, 71% had ECOG 0-1 vs. 77% in the higher dose, and were more likely to have > 2 lines of treatment (45% vs. 22%). The median time to interruption was 41 vs. 51 days respectively. The PFS and OS were not statically different (Table 1). Multivariate analysis showed a significantly higher HR in the lower dose group (2.5 [CI 1.12-5.56], p=0.025). Conclusions: TheFDA-recommended dose of Lenvatinib of 20 mg is perceived to be difficult to tolerate and patients are often started on a lower dose. In this study, we observed that the time to interruption was longer in the higher dose than in the lower dose group. Though we failed to detect a significant differences in PFS/OS, when adjusted for age, we observed a significantly higher HR of progression or death in the lower dose group. Possible explanations for our observations are that patients who received a lower dose were older and frailer. Our findings call to question the common practice of starting Lenvatinib at a low dose. Further analysis is warranted to delineate the required dose that is both efficacious and safe. [Table: see text]