Loss of copy numbers of retrotransposons (HERVK) on chromosome 7p11.2 impacts EGFR (Epidermal Growth Factor Receptor)-induced phenotypes for platinum sensitivity and long-term survival in ovarian cancer-A study from the OVCAD consortium.

We analyzed variations in the epidermal growth factor receptor (EGFR) gene and 5'-upstream region to identify potential molecular predictors of treatment response in primary epithelial ovarian cancer. Tumor tissues collected during debulking surgery from the prospective multicenter OVCAD study were investigated. Copy number variations in the human endogenous retrovirus sequence human endogenous retrovirus K9 (HERVK9) and EGFR Exons 7 and 9, as well as repeat length and loss of heterozygosity of polymorphic CA-SSR I and relative EGFR mRNA expression were determined quantitatively. At least one EGFR variation was observed in 94% of the patients. Among the 30 combinations of variations discovered, enhanced platinum sensitivity (n = 151) was found dominantly with HERVK9 haploidy and Exon 7 tetraploidy, overrepresented among patients with survival ≥120 months (24/29, p = .0212). EGFR overexpression (≥80 percentile) was significantly less likely in the responders (17% vs. 32%, p = .044). Multivariate Cox regression analysis, including age, FIGO stage, and grade, indicated that the patients' subgroup was prognostically significant for CA-SSR I repeat length <18 CA for both alleles (HR 0.276, 95% confidence interval 0.109-0.655, p = .001). Although EGFR variations occur in ovarian cancer, the mRNA levels remain low compared to other EGFR-mutated cancers. Notably, the inherited length of the CA-SSR I repeat, HERVK9 haploidy, and Exon 7 tetraploidy conferred three times higher odds ratio to survive for more than 10 years under therapy. This may add value in guiding therapies if determined during follow-up in circulating tumor cells or circulating tumor DNA and offers HERVK9 as a potential therapeutic target.

Prognostic role of transcription factor ARID1A in patients with endometrial cancer of no specific molecular profile (NSMP) subtype.

OBJECTIVE: As more than 50% of newly diagnosed endometrial cancers remain classified as 'no specific molecular subtype' (NSMP) due to a lack of established biomarkers to further improve molecular subtyping, this study aims to evaluate the prognostic value of ARID1A in endometrial cancers of NSMP subtype. METHODS: Prospectively collected molecular profiling data of all consecutive patients with endometrial cancer who underwent primary surgery at our department between August 2017 and June 2022 and for whom both molecular profiling and clinical follow-up data were available were retrospectively evaluated. Tumor specimens were evaluated by combined mismatch repair protein immunohistochemistry and targeted next-generation hotspot sequencing. ARID1A mutational status, as defined by full-length gene sequencing, was matched with risk of recurrence, progression-free and disease-specific survival within the NSMP cohort. RESULTS: A total of 127 patients with endometrial cancer were included. Among 72 patients with tumors of NSMP subtype (56.7%), ARID1A mutations were identified in 24 cases (33.3%). ARID1A mutations were significantly associated with a higher risk of recurrence (37.5% vs 12.5%, OR 4.20, 95% CI 1.28 to 13.80, p=0.018) and impaired progression-free survival (HR 3.96, 95% CI 1.41 to 11.15, p=0.009), but not with disease-specific survival. The results for both risk of recurrence (OR 3.70, 95% CI 1.04 to 13.13, p=0.043) and progression-free survival (HR 3.19, 95% CI 1.10 to 9.25, p=0.033) were confirmed in multivariable analysis compared with advanced tumor stage International Federation of Gynecology and Obstetrics (2009) (FIGO ≥III) and impaired Eastern Clinical Oncology Group performance status (ECOG ≥1). CONCLUSION: ARID1A appears to identify patients with endometrial cancer of NSMP subtypes with a higher risk of recurrence and could be used as a future prognostic biomarker. After clinical validation, ARID1A assessment could help to further sub-classify selected endometrial cancers and improve personalized treatment strategies.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Prognostic Value of Lymph Node Ratio in Patients with Uterine Carcinosarcoma.

Uterine carcinosarcoma is a rare high-grade endometrial cancer. Controversy has surrounded a number of aspects in the diagnosis and management of this unique clinicopathological entity, including the efficacy of adjuvant therapy, which has been questioned. An unusual surgico-pathological parameter with prognostic significance in a number of tumour sites is the lymph node ratio (LNR). The availability of data in this respect has been scarce in the literature. The primary aim of this collaborative study was to evaluate the prognostic value of LNR in patients with uterine carcinosarcoma. LNR is a recognized lymph node metric used to stratify prognosis in a variety of malignancies. In this European multinational retrospective study, 93 women with uterine carcinosarcoma were included in the final analysis. We used t-tests and ANOVA for comparison between quantitative variables between the groups, and chi-square tests for qualitative variables. A multivariate analysis using Cox regression analysis was performed to determine potential prognostic factors, including the LNR. Patients were grouped with respect to LNR in terms of 0%, 20% > 0% and >20%. The analysis revealed LNR to be a significant predictor of progression-free survival (HR 1.69, CI (1.12-2.55), p = 0.012) and overall survival (HR 1.71, CI (1.07-2.7), p = 0.024). However, LNR did not remain a significant prognostic factor on multivariate analysis. Due to limitations of the retrospective study, a prospective large multinational study, which takes into effect the most recent changes to clinical practice, is warranted to elucidate the value of the pathophysiological metrics of the lymphatic system associated with prognosis.

Verification of the prognostic precision of the new 2023 FIGO staging system in endometrial cancer patients - An international pooled analysis of three ESGO accredited centres.

BACKGROUND: Recently, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer (EC) critically integrating new pathological and molecular features was published. The present study evaluated the clinical impact of the new 2023 FIGO staging system by comparing it to the previous 2009 system. METHODS: This is an international, pooled retrospective study of 519 EC patients who underwent primary treatment (and molecular characterisation) at three European Society of Gynaecological Oncology (ESGO) accredited centres in Austria/Italy. Patients were categorised according to the 2009 and the 2023 FIGO staging systems. Stage shifts were analysed and (sub)stage specific 5-year progression-free (PFS) and overall survival (OS) rates were calculated and compared. Different statistical tests were applied to evaluate the prognostic precision of the two FIGO staging systems and to compare them to each other. RESULTS: (Sub)stage shifts occurred in 143/519 (27.6%) patients: 123 upshifts (23.7%) and 20 (3.9%) downshifts. 2023 FIGO staging system identified a stage I cohort with a notably higher 5-year PFS rate compared to 2009 (93.0% versus 87.4%, respectively). For stage II disease, the 5-year PFS rate was similar in the 2023 and the 2009 FIGO staging systems (70.2% versus 71.2%, respectively). The two new molecularly defined 2023 FIGO substages IAmPOLEmut and IICmp53abn displayed distinct, particularly favourable and adverse oncologic outcomes within early stage disease, respectively. A remarkably lower 5-year PFS rate for stage III patients was revealed in the 2023 FIGO staging system compared to 2009 (44.4% versus 54.1%, respectively). All applied statistical tests confirmed a more accurate prediction of PFS and OS by the 2023 FIGO staging system compared to 2009. CONCLUSION: The new 2023 FIGO stating system led to a substantial stage shift in about one quarter of patients leading to a higher prognostic precision. In early stage disease, the new substages added further prognostic granularity and identified treatment relevant subgroups.

Krukenberg Progression of Gastric Carcinoma in Pregnancy: Is Early Diagnosis Possible? Case Report and Review of the Literature.

Krukenberg tumors are metastatic tumors of the ovaries, associated with poor outcomes. Most commonly, these tumors are of gastric origin. The diagnosis of Krukenberg tumors in pregnant patients is extremely rare and poses specific difficulties for clinicians. We report a case of a pregnant woman presenting with an unknown abdominal tumor. Through the use of magnetic resonance imaging, multiple differential diagnoses were proposed, including a malignant ovarian tumor. A cesarean section and explorative laparotomy were conducted, revealing Krukenberg metastases of a gastric tumor, discovered during intraoperative gastroscopy. Tumor resection with concomitant chemotherapy was conducted. The main aim of this paper was to evaluate whether earlier diagnosis seems possible in such cases. A thorough literature review was conducted, unfortunately revealing no reliable method for early detection. Furthermore, no consensus regarding diagnostics or therapy exists to date. Thus, more research should be conducted regarding this rare condition to offer recommendations regarding early detection, diagnostics, and therapeutic approaches.

Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial.

PURPOSE: Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) >6 months. Immunotherapy may be synergistic with bevacizumab and chemotherapy. PATIENTS AND METHODS: ATALANTE/ENGOT-ov29 (ClinicalTrials.gov identifier: NCT02891824), a placebo-controlled double-blinded randomized phase III trial, enrolled patients with recurrent epithelial OC, one to two previous chemotherapy lines, and PFI >6 months. Eligible patients were randomly assigned 2:1 to atezolizumab (1,200 mg once every 3 weeks or equivalent) or placebo for up to 24 months, combined with bevacizumab and six cycles of chemotherapy doublet, stratified by PFI, PD-L1 status, and chemotherapy regimen. Coprimary end points were investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) and PD-L1-positive populations (alpha .025 for each population). RESULTS: Between September 2016 and October 2019, 614 patients were randomly assigned: 410 to atezolizumab and 204 to placebo. Only 38% had PD-L1-positive tumors. After 3 years' median follow-up, the PFS difference between atezolizumab and placebo did not reach statistical significance in the ITT (hazard ratio [HR], 0.83; 95% CI, 0.69 to 0.99; P = .041; median 13.5 v 11.3 months, respectively) or PD-L1-positive (HR, 0.86; 95% CI, 0.63 to 1.16; P = .30; median 15.2 v 13.1 months, respectively) populations. The immature overall survival (OS) HR was 0.81 (95% CI, 0.65 to 1.01; median 35.5 v 30.6 months with atezolizumab v placebo, respectively). Global health-related quality of life did not differ between treatment arms. Grade ≥3 adverse events (AEs) occurred in 88% of atezolizumab-treated and 87% of placebo-treated patients; grade ≥3 AEs typical of immunotherapy were more common with atezolizumab (13% v 8%, respectively). CONCLUSION: ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1-positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC.

Prognostic factors in patients with uterine sarcoma: the SARCUT study.

OBJECTIVE: Uterine sarcomas are a rare and heterogeneous group of malignancies that include different histological sub-types. The aim of this study was to identify and evaluate the impact of the different prognostic factors on overall survival and disease-free survival of patients with uterine sarcoma. METHODS: This international multicenter retrospective study included 683 patients diagnosed with uterine sarcoma at 46 different institutions between January 2001 and December 2007. RESULTS: The 5-year overall survival for leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma, and adenosarcoma was 65.3%, 78.3%, 52.4%, and 89.5%, respectively, and the 5-year disease-free survival was 54.3%, 68.1%, 40.3%, and 85.3%, respectively. The 10-year overall survival for leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma and adenosarcoma was 52.6%, 64.8%, 52.4%, and 79.5%, respectively, and the 10-year disease-free survival was 44.7%, 53.3%, 40.3%, and 77.5%, respectively. The most significant factor associated with overall survival in all types of sarcoma except for adenosarcoma was the presence of residual disease after primary treatment. In adenosarcoma, disease stage at diagnosis was the most important factor (hazard ratio 17.7; 95% CI 2.86 to 109.93). CONCLUSION: Incomplete cytoreduction, tumor persistence, advanced stage, extra-uterine and tumor margin involvement, and the presence of necrosis were relevant prognostic factors significantly affecting overall survival in uterine sarcoma. The presence of lymph vascular space involvement and administration of adjuvant chemotherapy were significantly associated with a higher risk of relapse.

Gestational and Non-gestational Trophoblastic Neoplasia. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 032/049, April 2022).

Purpose The aim was to develop and update a guideline which would improve the quality of care offered to women with gestational and non-gestational trophoblastic disease, a group of diseases characterized by their rarity and biological heterogeneity. Methods In accordance with the method used to compile S2k-guidelines, the guideline authors carried out a search of the literature (MEDLINE) for the period 1/2020 to 12/2021 and evaluated the recent literature. No key questions were formulated. No structured literature search with methodical evaluation and assessment of the level of evidence was carried out. The text of the precursor version of the guideline from 2019 was updated based on the most recent literature, and new statements and recommendations were drafted. Recommendations The updated guideline contains recommendations for the diagnosis and therapy of women with hydatidiform mole (partial and complete moles), gestational trophoblastic neoplasia after pregnancy or without prior pregnancy, persistent trophoblastic disease after molar pregnancy, invasive moles, choriocarcinoma, placental site nodules, placental site trophoblastic tumor, hyperplasia at the implantation site und epithelioid trophoblastic tumor. Separate chapters cover the determination and assessment of human chorionic gonadotropin (hCG), histopathological evaluation of specimens, and the appropriate molecular pathological and immunohistochemical diagnostic procedures. Separate chapters on immunotherapy, surgical therapy, multiple pregnancies with simultaneous trophoblastic disease, and pregnancy after trophoblastic disease were formulated, and the corresponding recommendations agreed upon.

Influence of Clinical and Surgical Factors on Uterine Carcinosarcoma Survival.

BACKGROUND: The aim of this study was to assess the impact of prognostic factors on the survival of patients diagnosed with uterine carcinosarcoma. METHODS: A sub-analysis of the SARCUT study, a multicentric retrospective European study, was carried out. We selected 283 cases of diagnosed uterine carcinosarcoma for the present study. Prognosis factors influencing survival were analyzed. RESULTS: Significant prognostic factors for overall survival were: incomplete cytoreduction (HR = 4.02; 95%CI = 2.68-6.18), FIGO stages III and IV (HR = 3.21; 95%CI = 1.83-5.61), tumor persistence after any treatment (HR = 2.90; 95%CI = 1.97-4.27), presence of extrauterine disease (HR = 2.62; 95%CI = 1.75-3.92), a positive resection margin (HR = 1.56; 95%CI = 1.05-2.34), age (HR = 1.02; 95%CI = 1.00-1.05), and tumor size (HR = 1.01; 95%CI = 1.00-1.01). Significant prognostic factors for disease-free survival were: incomplete cytoreduction (HR = 3.00; 95%CI = 1.67-5.37), tumor persistence after any treatment (HR = 2.64; 95%CI = 1.81-3.86), FIGO stages III and IV (HR = 2.33; 95%CI = 1.59-3.41), presence of extrauterine disease (HR = 2.13; 95%CI = 1.44-3.17), administration of adjuvant chemotherapy (HR = 1.84; 95%CI = 1.27-2.67), a positive resection margin (HR = 1.65; 95%CI = 1.11-2.44), presence of LVSI (HR = 1.61; 95%CI = 1.02-2.55), and tumor size (HR = 1.00; 95%CI = 1.00-1.01). CONCLUSIONS: Incomplete cytoreduction, presence of tumor residual after treatment, advanced FIGO stage, extrauterine disease, and tumor size are significant prognostic factors decreasing disease-free survival and overall survival of patients with uterine carcinosarcoma.

Efficacy and safety of maintenance olaparib and bevacizumab in ovarian cancer patients aged ≥65 years from the PAOLA-1/ENGOT-ov25 trial.

BACKGROUND: The phase III PAOLA-1/ENGOT-ov25 study (NCT02477644) showed that addition of olaparib to bevacizumab maintenance improved progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer. We evaluated maintenance olaparib plus bevacizumab in older patients in PAOLA-1. METHODS: Baseline clinical and molecular data, and PFS, were compared between older (aged ≥65 years) and younger patients (<65 years). Factors associated with olaparib efficacy, and safety in age subgroups, were also assessed. RESULTS: Of 806 randomised patients, 292 (36.2%) were ≥65 years. A lower proportion of older versus younger patients had an Eastern Cooperative Oncology Group performance status of 0 (61.0% versus 76.2%) and upfront surgery (42.0% versus 55.7%). Older patients were less likely to have a BRCA1/2 mutation (17.1% versus 36.7%) or homologous recombination deficiency-positive status (34.1% versus 55.7%). After median follow-up of 22.1 months, median PFS was 21.6 months with olaparib versus 16.6 months with placebo in the older population (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.41-0.75), comparable with the younger population (median 22.9 versus 16.9 months; HR 0.61, 95% CI 0.49-0.77). PFS benefits were observed in patients with a BRCA mutation or homologous recombination deficiency-positive tumours. Incidence of olaparib-related grade ≥3 adverse events in older patients was comparable with that of younger patients (36.8% versus 31.7%) although hypertension and anaemia were more common in older patients. No treatment-related deaths occurred in older patients receiving olaparib. CONCLUSION: Older patients enrolled in PAOLA-1 achieved similar PFS benefits compared with younger patients, with a similar safety profile.

The Prognostic Value of the Fibrinogen-Albumin-Ratio Index (FARI) in Patients with Advanced Vulvar Cancer.

The present study aims to evaluate the pretherapeutic Fibrinogen-Albumin-Ratio Index (FARI), as currently reliable biomarkers to predict therapy response and prognosis of patients with advanced vulvar cancer are missing. Data of 124 consecutive patients, who underwent primary resection for vulvar cancer ≥ pT1b, were retrospectively analyzed. Associations between the FARI and disease recurrence were assessed fitting receiver operating characteristics (ROC) and binary logistic regression models; univariate and multivariable Cox regression models for disease-specific survival (DSS) and progression-free survival (PFS) were performed. A pretherapeutic low FARI cut at its median (<9.67) is significantly associated with younger age (65.5 vs. 74.0 years) and higher risk of recurrence (52.4% vs. 26.2%). The ROC analysis calculates the area under the curve (AUC) of the FARI for a PFS < 6 months of 0.700 and for a DSS < 12 months of 0.706, outperforming fibrinogen and albumin alone. The FARI remained independently predictive for PFS (HR 0.84, 95% CI [0.99−1.03], p = 0.009) and DSS (HR 0.82, 95% CI [0.70−0.99], p = 0.019), also in multivariable survival analysis. Despite the FARI's promising predictive and prognostic value, however, further elucidation of its precise mode of action is warranted before clinical application as it appears to rely only on subtle changes of fibrinogen levels.

Corrected Allele Frequency of BRCA1/2 Mutations Is an Independent Prognostic Factor for Treatment Response to PARP-Inhibitors in Ovarian Cancer Patients.

PARP inhibitors (PARPi) have increased treatment options in ovarian cancer, particularly in patients with BRCA1/2 mutations, although there are still marked differences in the duration of patients' response to this targeted therapy. BRCA testing is routinely performed in tumor tissue of ovarian cancer patients. The resulting molecular pathological findings include the genetic nomenclature of the mutation, the frequency of the mutated allele (variant allele frequency, VAF), and the tumor cell content. VAF measures the percentage of mutated alleles from the total alleles in the cells of the examined tissue. The aim of this study was to investigate the significance of VAF on the therapeutic response to PARPis in ovarian cancer patients. Epithelial ovarian cancer patients harboring BRCA1/2 tumor mutations, who underwent germline testing and received PARPi therapy at the Medical University of Vienna (n = 41) were included in the study. Corrected VAF (cVAF) was calculated based on VAF, tumor cell content, and germline mutation. Patients were divided into two groups based on their cVAF. Median PFS under PARPi in patients with low cVAF was 13.0 months (IQR [10.3-not reached]) and was not reached in the high cVAF group. High cVAF was significantly associated with longer PFS in the multivariate analysis (HR = 0.07; 95% CI [0.01-0.63]; p = 0.017). In conclusion, high cVAF was associated with a significantly better response to PARPi in this study population.

Defining Models to Classify between Benign and Malignant Adnexal Masses Using Routine Laboratory Parameters.

Discrimination between benign and malignant adnexal masses is essential for optimal treatment planning, but still remains challenging in a routine clinical setting. In this retrospective study, we aimed to compare albumin as a single parameter to calculate models by analyzing laboratory parameters of 1552 patients with an adnexal mass (epithelial ovarian cancer (EOC): n= 294; borderline tumor of the ovary (BTO): n = 66; benign adnexal mass: n = 1192) undergoing surgery. Models comprising classical laboratory parameters show better accuracies (AUCs 0.92-0.93; 95% CI 0.90-0.95) compared to the use of single markers, and could easily be implemented in clinical practice by containing only readily available markers. This has been incorporated into a nomogram.

Real-life data on treatment and outcomes in advanced ovarian cancer: An observational, multinational cohort study (RESPONSE trial).

BACKGROUND: This study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer (OC). METHODS: This observational study collected real-world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III-IV) high-grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for ≥20 months. RESULTS: Of the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician-assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first-line chemotherapy after surgery. After ≥20 months of follow-up, 32.9% of the patients were disease-free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42-0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression-free survival (HR, 0.60; 95% CI, 0.41-0.84; p < .01). CONCLUSIONS: Women with advanced high-grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real-world population. LAY SUMMARY: Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high-grade serous or endometrioid OC could potentially be eligible for first-line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first-line PARPi maintenance treatment.

Austria-based real-world data on bevacizumab in newly diagnosed epithelial ovarian cancer.

BACKGROUND: Front-line maintenance therapy with bevacizumab demonstrates high efficacy and safety in epithelial ovarian cancer, as already shown in large phase III trials; however, the corresponding study populations are often not fully representative of patients in clinical routine. In this Austria-based multicenter study, we aimed to explore the real-world outcomes of bevacizumab use in front-line treatment of ovarian cancer, including patients with comorbidities and poor performance status. PATIENTS: This study is an open label single arm multicenter noninterventional trial and included patients with newly diagnosed advanced epithelial ovarian cancer, who were treated with platinum-based chemotherapy and were candidates for receiving bevacizumab according to the product label. Data collection started in the third quarter of 2012 and ended in the third quarter of 2018. RESULTS: In this study 50 patients were included and 575 adverse events were reported for 90% of the patients. The majority of the adverse events were mild (47%) or moderate (37%). The most common adverse events were hypertension (60%), anemia (48%), leukopenia (42%), thrombocytopenia (36%), neutropenia (36%) and proteinuria (26%). A relation to bevacizumab was documented only for 10.3% of all adverse events. In almost 50% of all adverse events, no intervention was needed and bevacizumab treatment had to be interrupted only in 3.3% of all adverse events. The median progression-free survival was 1.3 years (95% CI 1.1-1.8). CONCLUSION: The routine use of front-line bevacizumab for advanced ovarian cancer is associated with high efficacy comparable with that obtained in randomized phase III clinical trials; however, hypertension and proteinuria were reported significantly more often in our Austria-based real-world population.

Topical imiquimod compared with conization to treat cervical high-grade squamous intraepithelial lesions: Multicenter, randomized controlled trial.

OBJECTIVE: In a previous phase II trial, we showed that topical imiquimod (IMQ) therapy is an efficacious treatment for high-grade squamous intraepithelial lesion (HSIL). Aim of the present study was to investigate the non-inferiority of a 16-week topical, self-applied IMQ therapy compared to large loop excision of the transformation zone (LLETZ) in patients diagnosed with HSIL. METHODS: Phase III randomized, controlled, multicenter, open trial performed by Austrian Gynecologic Oncology group. Patients with histologically proven cervical intraepithelial neoplasia (CIN)2 (30 years and older) or CIN3 (18 years and older) and satisfactory colposcopy were randomized to topical IMQ treatment or LLETZ. Successful treatment was defined as negative HPV high-risk test result 6 months after start of the treatment. Secondary endpoints were histological outcome and HPV clearance rates. RESULTS: Within 3 years 93 patients were randomized, received the allocated treatment and were available for ITT analysis. In the IMQ group negative HPV test at 6 months after treatment start was observed in 22/51 (43.1%) of patients compared to 27/42 (64.3%) in the LLETZ group on ITT analysis (rate difference 21.2%-points, 95% two-sided CI: 0.8 to 39.1). In the IMQ group histologic regression 6 months after treatment was observed in 32/51 (63%) of patients and complete histologic remission was observed in 19/51 (37%) of patients. Complete surgical resection was observed in 84% after LLETZ. CONCLUSION: In women with HSIL, IMQ treatment results in lower HPV clearance rates when compared to LLETZ. LLETZ remains the standard for women with HSIL when treatment is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01283763, EudraCT number: 2012-004518-32.

The Pretreatment Controlling Nutritional Status Score in Ovarian Cancer: Influence on Prognosis, Surgical Outcome, and Postoperative Complication Rate.

Introduction The Controlling Nutritional (CONUT) Status score is an established predictor of impaired prognosis in patients with solid tumors. The aim of this study was to investigate the prognostic value of the CONUT score for overall survival and perioperative complication rates in patients with epithelial ovarian cancer. Patients In this retrospective study we assessed the data of 337 consecutive patients with ovarian cancer. The CONUT score was associated with surgical outcome, postoperative complications and clinicopathological parameters. We used univariate log-rank test and multivariable Cox regression models to evaluate the association between pretreatment CONUT scores and survival. Results A low CONUT score (0 - 2) was associated with an early FIGO stage (p = 0.004), complete tumor resection (p < 0.001), less neoadjuvant chemotherapy (p = 0.017) and other histologies than serous cystadenocarcinoma (p = 0.006). Postoperative complications were observed in 51.4% and 60.5% of patients with a CONUT score of 0 - 2 and a score > 2, respectively (p = 0.161). A shorter overall survival was observed in patients with a CONUT score > 2 compared to patients with a low CONUT score, with 5-year overall survival rates of 31.5% and 58.7%, respectively (p < 0.001). In multivariable analysis, both advanced age (p < 0.001) and FIGO stage (p < 0.001), residual disease (p < 0.001) and a high CONUT score (p = 0.048) were independently associated with unfavorable overall survival. Conclusion Pretreatment CONUT score is an independent prognostic marker for overall survival and associated with successful surgery. Patients with a high CONUT score might benefit from pretreatment nutritional intervention.

Association of a Combined Cancer Exhaustion Score with Circulating Tumor Cells and Outcome in Ovarian Cancer-A Study of the OVCAD Consortium.

We investigated the prognostic role of systemic characteristics for cancer exhaustion and the presence of circulating tumor cells (CTCs) in primary epithelial ovarian cancer (EOC) patients. We included 185 patients in this multicenter study with a median follow-up time of 10.25 years. Albumin, c-reactive protein (CRP) and the kynurenine to tryptophan ratio (Kyn/Trp) as well as the CTC-related marker cyclophilin C (PPIC) were obtained before primary therapy and were correlated to the respective clinical and outcome data. The information provided by albumin and Kyn/Trp was integrated in a combined score for cancer exhaustion (CCES). A high CCES characterized by hypoalbuminemia and a high Kyn/Trp was associated with both decreased overall and progression-free survival, independent from other known prognostic factors in a multivariable analysis. The presence of PPIC-positive CTCs was significantly associated with a high CCES, highlighting that the interplay between the systemic microenvironment and CTCs should be considered in "liquid biopsy" biomarker assessment.

Overweight as a Favorable Clinical Biomarker for Checkpoint Inhibitor Therapy Response in Recurrent Gynecologic Cancer Patients.

Despite increasing clinical interest in adapting checkpoint inhibitor (CPI) therapies for patients with gynecologic malignancies, no accurate clinical biomarkers to predict therapy response and prognosis are currently available. Therefore, we aimed to assess the predictive and prognostic value of pretherapeutic body mass index (BMI) for recurrent gynecologic cancer patients as previously validated for other solid tumors. We evaluated patients with programmed cell death ligand 1 (PD-L1) positive and, in endometrial cancer, also mismatch repair deficient (MMR) gynecologic malignancies, who received the PD-1 inhibitor pembrolizumab as monotherapy (200 mg fixed-dose q3 w) from 2017 to 2020 (n = 48). Thirty-six patients receiving at least four courses were included in the final analysis. Associations between a BMI increase per 5 kg/m2 and overall response rate (ORR; complete + partial response), disease control rate (DCR; ORR + stable disease), progression-free (PFS), and overall survival (OS) were assessed. An elevated BMI was univariately associated with ORR (OR 10.93 [CI 2.39-49.82], p = 0.002), DCR (OR 2.19 [CI 0.99-4.83], p = 0.048), prolonged PFS (HR 1.54 [CI 1.03-2.34], p = 0.038), and OS (HR 1.87 [CI 1.07-3.29], p = 0.028). All results could be confirmed in the multivariate analyses. Pretherapeutic BMI therefore appears to be a promising readily available biomarker to identify patients with PD-L1-positive and/or MMR-deficient gynecologic malignancies who could particularly benefit from CPI treatment.