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Simple Summary: The optimal selection of patients with advanced high-grade serous ovarian cancer (HGSOC) who are likely to benefit from upfront cytoreductive surgery remains challenging. With the results of the TRUST trial, the fifth randomized phase III trial comparing oncologic outcomes of primary versus interval cytoreductive surgery, expected to be presented soon, there is a high unmet clinical need to define novel biomarkers to optimize pretherapeutic patient assessment and allow for more personalized clinical decision making. Building on the growing evidence of the predictive and prognostic value of fibrinogen in various solid cancers, this study is the first to observe an independent association between the "Fibrinogen–Albumin-Ratio Index" (FARI) and surgical outcomes in patients with advanced HGSOC undergoing primary cytoreductive surgery. Given that the FARI seems to act as a surrogate for intra-abdominal tumor load, the further clinical validation of this cost-effective and readily available biomarker appears promising. Background/Objectives: The present study evaluates predictive implications of the pretherapeutic Fibrinogen–Albumin-Ratio Index (FARI) in high-grade serous ovarian cancer (HGSOC) patients undergoing primary cytoreductive surgery. Methods: This retrospective study included 161 patients with HGSOC International Federation of Gynecology and Obstetrics (FIGO) stage ≥ IIb, who underwent primary cytoreductive surgery followed by platinum-based chemotherapy. Associations between the FARI and complete tumor resection status were described by receiver operating characteristics, and binary logistic regression models were fitted. Results: Higher preoperative FARI values correlated with higher ascites volumes (r = 0.371, p < 0.001), and higher CA125 levels (r = 0.271, p = 0.001). A high FARI cut at its median (≥11.06) was associated with lower rates of complete tumor resection (OR 3.13, 95% CI [1.63–6.05], p = 0.001), and retrained its predictive value in a multivariable model independent of ascites volumes, CA125 levels, FIGO stage, and Charlson Comorbidity Index (CCI). Conclusions: The FARI appears to act as a surrogate for higher intra-abdominal tumor load. After clinical validation, FARI could serve as a readily available serologic biomarker to complement preoperative patient assessment, helping to identify patients who are likely to achieve complete tumor resection during primary cytoreductive surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: Low-grade serous ovarian cancer is a rare and complex subtype that usually develops slowly and predominantly affects younger women. Conventional treatment, which generally involves a combination of primary surgery and chemotherapy, often fails, leading to frequent recurrences. Due to the rarity of this cancer subtype, there are limited clinical data available to guide optimal treatment decisions. However, recent research is focusing on new, promising therapies, including targeted treatments that address specific molecular pathways and hormonal therapies. These emerging options offer hope for improved outcomes by enabling more personalized and effective management. This review aims to address the current treatment challenges and summarize the innovative therapies and their potential to enhance treatment strategies, aiming to provide better management for patients with this uncommon ovarian cancer subtype. Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer, characterized by a unique molecular background and specific clinical behavior. A growing body of molecular data underscores LGSOC as a distinct disease entity; however, clinical evidence on the optimal treatment regimens for LGSOC remains limited due to the low incidence of the disease. Consequently, treatment recommendations for LGSOC are still often derived from findings on the more common high-grade serous ovarian carcinoma (HGSOC) and typically focus on radical cytoreductive surgery and platinum-based chemotherapy. Since LGSOCs typically exhibit only limited responsiveness to platinum-based chemotherapy, the clinical management of advanced and recurrent LGSOCs remains a significant therapeutic challenge and often results in limited treatment options and suboptimal outcomes. Recent advances in molecular profiling and the identification of new, promising targets, such as the mitogen-activated protein kinase (MAPK) pathway, offer hope for improving both the prognosis and health-related quality of life in affected patients. Given the high unmet clinical need to establish new therapeutic standards beyond cytotoxic chemotherapy, this review aims to summarize the most promising molecular targets and emerging targeted agents. [ABSTRACT FROM AUTHOR]

Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum‐resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20–2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk‐reducing effect (CDH1 HR 0.66, 95% CI: 0.46–0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39–0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1‐presence and ESR1‐absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08–39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses the new 2023 FIGO staging system for endometrial cancer, which takes into account advancements in scientific knowledge and the heterogeneity of tumors. The system aims to improve prognostic precision and individualize treatment approaches by integrating biomarkers and molecular parameters. Several validation studies have demonstrated the higher prognostic value of the new staging system compared to the previous 2009 system. The article also addresses concerns about upstaging and the impact of molecular classification, as well as the need for global resource availability and cost-effective analysis. Overall, the new staging system is seen as a step forward in improving the care and treatment of women with endometrial cancer. [Extracted from the article]

Background: High-complexity and low-prevalence procedures benefit from treatment by referral centers. The volume of cases necessary to maintain high training in the treatment of gynecologic sarcoma is currently unknown. This study aimed to determine differences in survival and recurrence as a function of the volume of patients treated per center. Methods: The multicentric cross-sectional SARComa of the Uterus (SARCUT) study retrospectively collected cases of uterine sarcomas from 44 centers in Europe from January 2001 to December 2007. The survival of patients treated in high case-volume (HighCV) centers was compared with the survival of patients treated in low case-volume (LowCV) centers. Results: The study enrolled 966 patients: 753 in the LowCV group and 213 in the HighCV. Overall survival (OS) was 117 months, and cancer-specific survival (CSS) was 126 months. The difference was significant (respectively p = 0.0003 and 0.0004, log rank). After adjustment for other confounding factors, the remaining significant factors were age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03–1.05), histology (HR, 1.19; 95% CI, 1.06–1.34), extrauterine involvement (HR, 1.61; 95% CI, 1.24–2.10) and persistent disease after treatment (HR, 3.22; 95% CI, 2.49–4.18). The cytoreduction performed was significantly associated with the CSS and OS in both groups. The log rank for surgical cytoreduction was a p value lower than 0.0001 for OS, lower than 0.0001 for the LowCV centers, and 0.0032 for the HighCV centers. Conclusions: The prognosis for patients with uterine sarcoma is directly related to complete tumor cytoreduction, histologic type, and FIGO stage, with significant differences between low and high case-volume centers. Patients with uterine sarcomas should be centralized in HighCV centers to improve their oncologic outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009. Substantially more outcome and biological behavior data are now available regarding the several histological types. Molecular and genetic findings have accelerated since the publication of The Cancer Genome Atlas (TCGA) data and provide improved clarity on the diverse biological nature of this collection of endometrial cancers and their differing prognostic outcomes. The goals of the new staging system are to better define these prognostic groups and create substages that indicate more appropriate surgical, radiation, and systemic therapies. Methods: The FIGO Women's Cancer Committee appointed a Subcommittee on Endometrial Cancer Staging in October 2021, represented by the authors. Since then, the committee members have met frequently and reviewed new and established evidence on the treatment, prognosis, and survival of endometrial cancer. Based on these data, opportunities for improvements in the categorization and stratification of these factors were identified in each of the four stages. Data and analyses from the molecular and histological classifications performed and published in the recently developed ESGO/ESTRO/ESP guidelines were used as a template for adding the new subclassifications to the proposed molecular and histological staging system. Results: Based on the existing evidence, the substages were defined as follows: S tage I (IA1): non-aggressive histological type of endometrial carcinoma limited to a polyp or confined to the endometrium; (IA2) non-aggressive histological types of endometrium involving less than 50% of the myometrium with no or focal lymphovascular space invasion (LVSI) as defined by WHO criteria; (IA3) low-grade endometrioid carcinomas limited to the uterus with simultaneous low-grade endometrioid ovarian involvement; (IB) non-aggressive histological types involving 50% or more of the myometrium with no LVSI or focal LVSI; (IC) aggressive histological types, i.e. serous, high-grade endometrioid, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types without any myometrial invasion. S tage II (IIA): non-aggressive histological types that infiltrate the cervical stroma; (IIB) nonaggressive histological types that have substantial LVSI; or (IIC) aggressive histological types with any myometrial invasion. S tage III (IIIA): differentiating between adnexal versus uterine serosa infiltration; (IIIB) infiltration of vagina/parametria and pelvic peritoneal metastasis; and (IIIC) refinements for lymph node metastasis to pelvic and para-aortic lymph nodes, including micrometastasis and macrometastasis. S tage IV (IVA): locally advanced disease infiltrating the bladder or rectal mucosa; (IVB) extrapelvic peritoneal metastasis; and (IVC) distant metastasis. The performance of complete molecular classification ( POLEmut, MMRd, NSMP, p53abn) is encouraged in all endometrial cancers. If the molecular subtype is known, this is recorded in the FIGO stage by the addition of "m" for molecular classification, and a subscript indicating the specific molecular subtype. When molecular classification reveals p53abn or POLEmut status in Stages I and II, this results in upstaging or downstaging of the disease (IICmp53abn or IAmPOLEmut). Summary: The updated 2023 staging of endometrial cancer includes the various histological types, tumor patterns, and molecular classification to better reflect the improved understanding of the complex nature of the several types of endometrial carcinoma and their underlying biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence-based context for treatment recommendations and for the more refined future collection of outcome and survival data. [ABSTRACT FROM AUTHOR]

Simple Summary: The availability of multiple gene panel testing allows us to identify germline pathogenic variants of validated cancer genes. We evaluated the prevalence and clinical/prognostic impact of deleterious germline mutations in OC patients. Germline panel testing should be performed for all patients with ovarian cancer. Better prognosis was found for germline mutated ovarian cancer patients. Endometrioid and clear cell histology subtypes show more deleterious mutations in other genes. Data on deleterious variants in genes other than BRCA1/2 remain limited. A retrospective cohort study was performed, including primary OC cases with TruRisk® germline gene panel testing between 2011 and 2020. Patients with testing after relapse were excluded. The cohort was divided into three groups: (A) no mutations, (B) deleterious BRCA1/2 mutations, and (C) deleterious mutations in other genes. A total of 702 patients met the inclusion criteria. Of these 17.4% (n = 122) showed BRCA1/2 mutations and a further 6.0% (n = 42) in other genes. Three-year overall survival (OS) of the entire cohort was significantly longer in patients with germline mutations (85%/82.8% for cohort B/C vs. 70.2% for cohort A, p < 0.001) and 3-year progression-free survival (PFS) only for cohort B (58.1% vs. 36.9%/41.6% in cohort A/C, p = 0.002). In multivariate analysis for the subgroup of advanced-stages of high-grade serous OC, both cohorts B/C were found to be independent factors for significantly better outcome, cohort C for OS (HR 0.46; 95% CI 0.25–0.84), and cohort B for both OS and PFS (HR 0.40; 95% CI 0.27–0.61 and HR 0.49; 95% CI 0.37–0.66, respectively). Germline mutations were detected in a quarter of OC patients, and a quarter of those in genes other than BRCA1/2. Germline mutations demonstrate in our cohort a prognostic factor and predict better prognosis for OC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Testing for a homologous recombination deficiency (HRD) in primary high-grade ovarian cancer is crucial for recommending the appropriate therapy. Patients with a BRCA germline mutation are defined as harboring an HRD deficiency. However, there is a group of approximately 20% of patients without a BRCA mutation which harbor an HRD deficiency based on tumor genomic analyses. In the current research, we wanted to share the experience of a high-volume tertiary cancer center with implementing central HRD testing—in another institution—to reduce doubts about logistic issues and to the highlight critical aspects that hinder HRD testing. We showed that the results of HRD testing became available in a timely manner for the therapy decision. However, it was important to obtain as much tumor tissue as possible during the first diagnosis—before any other intervention—as the tumor quantity and quality were critical for HRD testing. Additional BRCA germline testing further reduced the failures of HRD testing and should additionally be routinely conducted. The chemotherapy backbone for patients with high-grade advanced epithelial ovarian cancer (HG-AOC) is carboplatin and paclitaxel followed by a maintenance therapy either with bevacizumab, with a PARP inhibitor, or with a combination of both, which is defined by the presence of a homologous recombination deficiency (HRD) and by the BRCA1/2 status. This study included patients with a primary diagnosis of HG-AOC treated between December 2019 and December 2021. The HRD status was measured using the Myriad myChoice® test on all the patients with an indication for tumor HRD testing. Germline testing was conducted on all the patients using the TruRisk® panel as recommended by the national guidelines. HRD testing was requested for 190 patients, and, for 163 patients (85.8%), an HRD test result was available. An HRD test result could not be reported in 27 patients due to an insufficient tumor yield. The median time that it took to receive the HRD test results was 37 days (range of 8–97). In total, an HRD was present in 44.7% (73/163) of the patients based on a GIS ≥ 42 in 42.9% of the patients and based on a tumor BRCA1/2 mutation in 3 cases (all with a GIS < 42). The germline testing results were available for 148 patients, and, in 18 patients (12.2%), a deleterious germline mutation was detected. Of the 27 patients without sufficient HRD testing, BRCA1/2 germline testing results were available for 19 patients (70.4%), and a deleterious germline mutation was detected in 2 patients (7.4%). The implementation of HRD testing is feasible, and the results become available for treatment decisions in a timely manner for most patients. The prerequisite for HRD testing with the Myriad myChoice® test is a sufficient amount of tumor tissue. The cotesting of HRD and BRCA1/2 germline testing should be aimed for in order to enable optimal and timely treatment decisions on maintenance therapy as well as to test patients on whom the HRD test will not be evaluable. [ABSTRACT FROM AUTHOR]