European Journal of Cancer

Population-adjusted indirect treatment comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 trials evaluating maintenance olaparib or bevacizumab or the combination of both in newly diagnosed, advanced BRCA-mutated ovarian cancer

In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm). An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses. Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95). Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm.

Survival associated with the use of sentinel lymph node in addition to lymphadenectomy in early-stage cervical cancer treated with surgery alone: A sub-analysis of the Surveillance in Cervical CANcer (SCCAN) collaborative study

The aim of this study was to assess whether the use of sentinel lymph node (SLN) in addition to lymphadenectomy was associated with survival benefit in patients with early-stage cervical cancer. International, multicenter, retrospective study. cervical cancer treated between 01/2007 and 12/2016 by surgery only; squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, FIGO 2009 stage IB1-IIA2, negative surgical margins, and laparotomy approach. Patients undergoing neo-adjuvant and/or adjuvant treatment and/or with positive para-aortic lymph nodes, were excluded. Women with positive pelvic nodes who refused adjuvant treatment, were included. Lymph node assessment was performed by SLN (with ultrastaging protocol) plus pelvic lymphadenectomy ('SLN' group) or pelvic lymphadenectomy alone ('non-SLN' group). 1083 patients were included: 300 (27.7 %) in SLN and 783 (72.3 %) in non-SLN group. 77 (7.1 %) patients had recurrence (N = 11, 3.7 % SLN versus N = 66, 8.4 % non-SLN, p = 0.005) and 34 (3.1 %) (N = 4, 1.3 % SLN versus N = 30, 3.8 % non-SLN, p = 0.033) died. SLN group had better 5-year disease-free survival (DFS) (96.0 %,95 %CI:93.5-98.5 versus 92.0 %,95 %CI:90.0-94.0; p = 0.024). No 5-year overall survival (OS) difference was shown (98.4 %,95 %CI:96.8-99.9 versus 96.8 %,95 %CI:95.4-98.2; p = 0.160). SLN biopsy and lower stage were independent factors associated with improved DFS (HR:0.505,95 %CI:0.266-0.959, p = 0.037 and HR:2.703,95 %CI:1.389-5.261, p = 0.003, respectively). Incidence of pelvic central recurrences was higher in the non-SLN group (1.7 % versus 4.5 %, p = 0.039). Adding SLN biopsy to pelvic lymphadenectomy was associated with lower recurrence and death rate and improved 5-year DFS. This might be explained by the lower rate of missed nodal metastasis thanks to the use of SLN ultrastaging. SLN biopsy should be recommended in patients with early-stage cervical cancer.

Antibody drug conjugate targets are highly differentially expressed across the major types of ovarian cancer

Antibody-drug conjugates (ADCs) are emerging anti-cancer agents. The folate receptor alpha (FOLRα)-directed ADC mirvetuximab soravtansine recently demonstrated clinical activity in platinum-resistant ovarian cancer, with other ADCs currently in development. The relative expression of FOLRα and other ADC targets is largely unknown across ovarian cancer histotypes. Expression levels of the ADC targets FOLRα, TROP2 and B7-H4 were assessed by immunohistochemistry in patient cohorts using tumour tissue microarrays of the major ovarian cancer histotypes: high grade serous (HGSOC, n = 331); endometrioid (EnOC, n = 101) and clear cell ovarian carcinoma (CCOC, n = 60). Degree of expression was quantified by membrane histoscore. We observed differences in ADC target expression patterns across ovarian cancer histotypes. FOLRα expression was highest in HGSOC, with few EnOC or CCOC demonstrating positivity (HGSOC: 70.9 % FOLRα histoscore ≥50 vs 21.1 % and 29.3 % in EnOC and CCOC). B7-H4 was expressed in HGSOC, EnOC and CCOC (99.7 %, 89.8 % and 80.7 % with histoscore ≥50). CCOC were mostly TROP2 negative (89.3 % with histoscore <50); a subset of HGSOC and EnOC expressed TROP2 (54.8 % and 57.7 % with histoscore ≥50, respectively). There was no significant association between ADC target expression and molecular subtypes of HGSOC (BRCA1/2-mutant, CCNE1-gained, other) or EnOC (TP53-mutant, CTNNB1-mutant, POLE-mutant, MMR deficient, no specific molecular profile). In CCOC, ARID1A/B mutation was associated with lower B7-H4 expression (P-adj=0.024). EnOC and CCOC are usually FOLRα negative, while HGSOC, EnOC and CCOC frequently express B7-H4. TROP2 positivity is limited to HGSOC and EnOC. Careful consideration of histotype and ADC target expression levels is warranted when designing and analysing clinical studies of ADCs.

Impact of different adjuvant treatment approaches on survival in stage III endometrial cancer: A population-based study

Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage III endometrial cancer (EC) have a substantial risk of adverse outcomes. After surgery, adjuvant therapy is recommended with external beam radiotherapy (EBRT), chemotherapy (CT) or both EBRT and CT. Recent trials suggest that EBRT + CT is superior to EBRT or CT alone but also results in more toxicity. We have compared the outcome of different adjuvant treatments in a population-based cohort to identify subgroups that benefit most from EBRT + CT. All patients diagnosed with FIGO stage III EC and treated with surgery in 2005-2016 were identified from the Netherlands Cancer Registry. The primary outcome was overall survival (OS); associations with adjuvant treatment were analysed using Cox regression analysis. Among 1241 eligible patients, EBRT + CT was associated with a better OS than CT (hazard ratio [HR] = 1.84, 95% confidence interval [CI] = 1.34-2.52) and EBRT alone (HR = 1.37, 95% CI = 1.05-1.79). In stage IIIC, there was a significant benefit of EBRT + CT compared with CT or EBRT alone. In stage IIIA-B, there was no difference between EBRT + CT or EBRT alone. In endometrioid EC (EEC) and carcinosarcomas, EBRT + CT was associated with a better OS than CT or EBRT alone. For uterine serous cancers, there was no survival benefit of EBRT + CT over CT. In all analysis by stage and histology, any adjuvant treatment was superior to no adjuvant therapy. In this population-based study, adjuvant EBRT + CT was associated with improved OS compared with CT or EBRT alone in FIGO stage IIIC EC, EEC and carcinosarcoma. This suggests that application of EBRT + CT in stage III should be further stratified according to these subgroups.

Feasibility and efficacy of gonadotropin-releasing hormone agonists for the prevention of chemotherapy-induced ovarian insufficiency in patients with malignant ovarian germ cell tumours (KGOG 3048R)

This study assessed the effects of gonadotropin-releasing hormone agonists (GnRHa) on the prevention of chemotherapy-induced ovarian insufficiency among young patients with malignant ovarian germ cell tumour (MOGCT) receiving chemotherapy. This multicentre, retrospective study was conducted at 15 sites affiliated with the Korean Gynecologic Oncology Group and enrolled 354 patients between January 1995 and September 2018. Among them, 227 patients were included in this study and divided into two groups according to the use of GnRHa during chemotherapy (GnRHa versus no GnRHa groups). The primary objective was to compare the rates of menstrual resumption between the two groups. We also assessed the clinical determinants affecting menstrual resumption among the study groups. There were no significant differences between the GnRHa (n = 63) and no GnRHa (n = 164) groups regarding age at diagnosis, parity, ethnicity, age at menarche, body mass index, International Federation of Gynecology and Obstetrics stage, mode of surgery and surgery type. The rate of menstrual resumption after chemotherapy was 100% (63 of 63) in the GnRHa group and 90.9% (149 of 164) in the no GnRHa group (p = 0.013). The mean periods from last chemotherapy to menstrual resumption were 7.4 and 7.3 months in the GnRHa and no GnRHa groups, respectively. GnRHa co-administration during chemotherapy reduced the likelihood of amenorrhoea after chemotherapy, although statistical significance was not confirmed in the univariate analysis (odds ratio: 0.276; 95% confidence interval, 0.004-1.317; p = 0.077). Temporary ovarian suppression with GnRHa during chemotherapy does not significantly increase the chances of menstrual resumption in young patients with MOGCT.

Risk factors for lymph node metastasis in women with FIGO 2018 IA cervical cancer with a horizontal spread of &gt; 7 mm

In the FIGO 2018 classification, women with cervical cancer and a depth of invasion ≤ 5 mm and a horizontal spread of > 7 mm in excisional biopsy with tumour-free margins, are now classified as stage IA instead of IB. This stage shift may reduce the likelihood of surgical lymph node staging. It is therefore crucial to estimate the risk and risk factors of lymph node metastasis (pN+) in this group. Women diagnosed with cervical cancer between 2005 and 2022 were identified from nationwide population-based registries from the Netherlands, Denmark, and Sweden. Inclusion criteria were squamous cell carcinoma or adenocarcinoma, FIGO 2009 stage IB1, a depth of invasion ≤ 5 mm and horizontal spread of > 7-≤ 40 mm. All cases underwent radical hysterectomy or radical trachelectomy, and surgical lymph node staging. Logistic regression was used to identify risk factors of pN+. We included 992 women (pN+ 4.1 %; n = 41). Lymphovascular space invasion (LVSI) was a significant risk factor of pN+ (odds ratio 4.26, 95 % confidence interval 2.24-8.32). Accordingly, the risk of pN+ was ≥ 7.3 % in LVSI-positive tumours. The risk was lowest in LVSI-negative tumours with a size of > 7-≤ 20 mm (2.2 %), although this varied by depth of invasion and histological subtype (pN+ range 0.6-5.1 %). Women with LVSI-positive FIGO 2018 IA cervical cancer and a horizontal spread > 7 mm, should undergo surgical lymph node staging. In LVSI-negative tumours, lymph node staging should not be routinely performed; tumour size, depth of invasion and histology should be considered.

External validation and clinical utility assessment of PREDICT breast cancer prognostic model in young, systemic treatment-naïve women with node-negative breast cancer

PARP inhibitor predictive value of the Leuven HRD test compared with Myriad MyChoice CDx PLUS HRD on 468 ovarian cancer patients from the PAOLA-1/ENGOT-ov25 trial

The PAOLA-1/ENGOT-ov25 trial showed improved progression-free (PFS) and overall survival (OS) in homologous recombination deficient (HRD) positive patients treated with olaparib, but not when HRD negative (HRD tested with MyChoice CDx PLUS [Myriad test]). The academic Leuven HRD test consists of capture-based targeted sequencing of genome-wide single-nucleotide polymorphisms and coding exons of eight HR genes including BRCA1, BRCA2, and TP53. We compared the predictive value of the Leuven HRD versus Myriad HRD test for PFS and OS in the randomised PAOLA-1 trial. 468 patients had left-over DNA after Myriad testing for Leuven HRD testing. Positive/negative/overall percent agreement for the Leuven versus Myriad HRD status was 95%/86%/91%, respectively. Tumours were HRD+ in 55% and 52%, respectively. In Leuven HRD+ patients, 5years PFS (5yPFS) was 48.6% versus 20.3% (HR 0.431; 95% confidence intervals (CI) 0.312-0.595) for olaparib versus placebo, respectively (Myriad test 0.409; 95% CI 0.292-0.572). In Leuven HRD+/BRCAwt patients 5yPFS was 41.3% versus 12.6% (HR 0.497; 95% CI 0.316-0.783), and 43.6% versus 13.3% (HR 0.435; 95% CI 0.261-0.727) for the Myriad test. 5yOS was prolonged in the HRD+ subgroup with both tests 67.2% versus 54.4% (HR 0.663; 95% CI 0.442-0.995) for the Leuven test, and 68.0% versus 51.8% (HR 0.596 95% CI 0.393-0.904) for the Myriad test. HRD status was undetermined in 10.7% and 9.4% of the samples, respectively. A robust correlation between the Leuven HRD and Myriad test was observed. For HRD+ tumours, the academic Leuven HRD showed a similar difference in PFS and OS as the Myriad test.

Re: A federated approach to identify women with early-stage cervical cancer at low risk of lymph node metastases

Are all mismatch repair deficient endometrial cancers created equal? A large, retrospective, tertiary center experience

One third of endometrial carcinomas (ECs) presents with mismatch repair deficiency (MMRd). Of these, 70 % are caused by somatic hypermethylation of MLH1 promoter; the remaining cases are determined by Lynch syndrome or double somatic inactivation of MMR genes. Although associated with good-intermediate prognosis, heterogeneity in treatment response and survival has been reported among MMRd ECs. We aim to investigate differences in pathologic aggressiveness and event-free survival (EFS) among three MMRd EC subtypes, classified by immunohistochemistry (IHC) and MLH1 methylation analysis. Subjects undergone surgical staging for EC were retrospectively included. IHC analysis was performed in all patients to assess MMR and p53 status. Methylation analysis was performed in MMRd patients with IHC-negative MLH1. The MMRd population was classified into: 1)MLH1-hypermethylated (MLH1-HyMet); 2)MLH1-unmethylated (MLH1-UnMet); 3)IHC-negative MSH2 and/or MSH6 or PMS2 alone (non-MLH1). Of 1171 patients undergoing surgical staging and IHC assessment, 362 (30.9 %) were classified as MMRd and included in the analysis. Among these, 59.7 % (n = 216) were MLH1-HyMet, 11 % (n = 40) MLH1-UnMet, and 29.3 % (n = 106) non-MLH1. Compared to MLH1-UnMet and non-MLH1, MLH1-HyMet was associated with older age, higher BMI, larger tumor size, deeper myometrial invasion, substantial lymphovascular space invasion, lower frequency of early-stage and low-risk disease. EFS was similar when comparing the MMRd subtypes, even after adjusting for stage and tumor histology. However, a trend of MLH1-HyMet toward poorer prognosis can be observed, particularly in the advanced/metastatic setting. MLH1-hypermethylated MMRd ECs display more aggressive clinicopathologic features compared to the other MMRd subgroups. However, although a suggestive trend toward poorer EFS was observed in the hypermethylated subset, particularly in the advanced setting, no significant differences in prognosis were detected among the MMRd subtypes.

Efficacy of cancer vaccines in selected gynaecological breast and ovarian cancers: A 20-year systematic review and meta-analysis

Therapeutic cancer vaccination is an area of interest, even though promising efficacy has not been demonstrated so far. A systematic review and meta-analysis was conducted to evaluate vaccines' efficacy on breast cancer (BC) and ovarian cancer (OC) patients. Our search was based on the PubMed electronic database, from 1st January 2000 to 4th February 2020. response rate (ORR) was the primary end-point of interest, while progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Analysis was performed separately for BC and OC patients. Pooled ORRs were estimated by fixed or random effects models, depending on the detected degree of heterogeneity, for all studies with more than five patients. Subgroup analyses by vaccine type and treatment schema as well as sensitivity analyses, were implemented. Among 315 articles initially identified, 67 were eligible for our meta-analysis (BC: 46, 1698 patients; OC: 32, 426 patients; where both BC/OC in 11). Dendritic-cell and peptide vaccines were found in more studies, 6/10 BC and 10/13 OC studies, respectively. In our primary BC analysis (21 studies; 428 patients), the pooled ORR estimate was 9% (95%CI[5%,13%]). The primary OC analysis (12 studies; 182 patients), yielded pooled ORR estimate of 4% (95%CI[1%,7%]). Similar were the results derived in sensitivity analyses. No statistically significant differences were detected by vaccine type or treatment schema. Median PFS was 2.6 months (95% confidence interval (CI)[1.9,2.9]) and 13.0 months (95%CI[8.5,16.3]) for BC and OC respectively, while corresponding median OS was 24.8 months (95%CI[15.0,46.0]) and 39.0 months (95%CI[31.0,49.0]). In almost all cases, the observed toxicity was only moderate. Despite their modest results in terms of ORR, therapeutic vaccines in the last 20 years display relatively long survival rates and low toxicity. Since a plethora of different approaches have been tested, a better understanding of the underlying mechanisms is needed in order to further improve vaccine efficacy.

Randomised controlled trial confirms benefit of enhanced recovery after surgery on length of stay in ovarian cancer: How low can we go?

Response to: A multicentre retrospective cohort study of ovarian germ cell tumours: Evidence for chemotherapy de-escalation and alignment of paediatric and adult practice

Re: A multicentre retrospective cohort study of ovarian germ cell tumours: Evidence for chemotherapy de-escalation and alignment of paediatric and adult practice

Tumour infiltrating lymphocytes and correlation with response to intensified platinum-based chemotherapy in BRCA-like tumours

JQ1 inhibits tumour growth in combination with cisplatin and suppresses JAK/STAT signalling pathway in ovarian cancer

Overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET (Bromodomain and extraterminal domain family) bromodomain (BRDs) inhibitor, has been found to suppress tumour progression in several cancer cell types. Using a panel of ovarian cancer cell lines and primary cell cultures from human ovarian cancer ascites, we demonstrated that JQ1 significantly suppressed cell proliferation and induced apoptosis in an ovarian cancer cell by targeting BRD4 and c-Μyc. In addition, JQ1 sensitized ovarian cancer cells to cisplatin, the most commonly used chemotherapeutic agent in ovarian cancer. Importantly, this effect was observed in ovarian cells, which exhibited resistance to cisplatin alone. Finally, we show that JQ1 interacts with the JAK-STAT signalling pathway, a pathway important in supporting ovarian cancer cell survival by suppressing or inducing genes involved in cell survival and apoptosis, respectively. Our data, taken together, suggest that JQ1 is an attractive antitumour candidate for further investigation in the treatment of ovarian cancer, as it associates with cell proliferation, apoptosis, and alterations in the JAK-STAT signalling pathway, especially in patients with a platinum-resistant profile or in patients with relapsed disease.

Challenging the believed proportion of ovarian cancer attributable to BRCA2 versus BRCA1 pathogenic variants

BRCA1 and BRCA2 pathogenic variant carriers and endometrial cancer risk: A cohort study

An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative. Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants. Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74-3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested. Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure.

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.

Performance evaluation of machine learning models in cervical cancer diagnosis: Systematic review and meta-analysis

Cervical cancer is one of the most frequent malignancies worldwide and one of the leading causes of death in women. Recently, artificial intelligence-based tools have been developed for the early diagnosis of malignancies, including cervical cancer, based on data generated in the healthcare area. This systematic review aimed to evaluate the diagnostic performance of machine learning models based on sociodemographic, epidemiologic, and clinical data for the detection of cervical cancer. A systematic literature search was performed in PubMed, Scopus, and Embase, with no time limit until July 31, 2025. The screening process was performed by two independent authors using the Rayyan® platform, as well as the risk of bias assessment process using the QUADAS-2 tool. A third author resolved cases of dispute. Meta-analysis and sensitivity analysis were performed in Stata17®. A total of 7 studies were included, in which the machine learning models selected several demographic and clinical variables for the classification of patients. Pooled diagnostic measures of these models were 0.97 (95 % CI 0.90-0.99) for sensitivity, and 0.96 (95 % CI 0.93-0.97) for specificity (I Machine learning models are presented as a new tool with high diagnostic performance, making their introduction into cervical cancer screening programs feasible. However, this systematic review discusses some issues that should be addressed to validate and incorporate these models into clinical practice.

Specific targeting of the pseudogene RPSAP52 reduces ovarian tumor growth in patient-derived orthoxenograft models

The RPSAP52 pseudogene is transcribed in the opposite direction to the oncofetal gene HMGA2 and is reexpressed in various human cancers. Here, we investigate the impact of RPSAP52 in ovarian cancer (OC) and explore the potential therapeutic application of GapmeR antisense oligonucleotides against RPSAP52 in preclinical models. RPSAP52 and HMGA2 expression were investigated in TCGA for OC and further explored in a panel of orthotopic PDXs and commercial cell lines by RT-qPCR. The Kaplan-Meier method was used to estimate survival associated with RPSAP52 expression in a dataset within the OC TCGA cohort. The effect of specific silencing of RPSAP52 on tumor growth in vitro and in vivo was evaluated by lentiviral-mediated depletion and antisense LNA GapmeRs against RPSAP52. The pseudogene RPSAP52 was overexpressed in epithelial OC in both patient samples and OC preclinical models coinciding with the overexpression of HMGA2. Elevated expression levels of RPSAP52 in the early stages of OC were associated with poorer clinical outcomes and could stratify patients in stages I and II. The specific depletion of RPSAP52 led to a reduction in OC tumor growth in vitro and in vivo. Furthermore, the treatment with antisense LNA GapmeRs against RPSAP52 showed significant antitumoral effect in OC cell lines and in a PDOX model (without evident toxicity). Our findings demonstrate that RPSAP52 displays pro-growth features in OC, underscoring the significance of pseudogenes in cancer pathophysiology. This pseudogene has potential utility as therapeutic target in OC and as valuable prognostic biomarker for the early stages of this disease.

Predictive value of BRCA1/RAD51C methylation in HGSOC – An ancillary study of the PAOLA-1/ENGOT-ov25 phase 3 trial

In high-grade serous ovarian cancer (HGSOC) bevacizumab (bev)/olaparib (ola) maintenance was approved for patients with homologous recombination DNA repair deficiency (HRD+) tumors. Although different methods exist to score genomic instability, DNA quality, tumor cell content, and costs may impair our ability to identify patients that will benefit from treatment. We analyzed BRCA1 and RAD51C methylation as an HRD determination tool in patients newly diagnosed of HGSOC (n = 519) based on data from the PAOLA-1/ENGOT-ov25 trial phase III prospective trial. Methylation was analyzed using quantitative methylation specific PCR, correlated to HRD scores, PFS and OS. 67 (12.9 %) were BRCA1 and 25 (4.8 %) were RAD51C methylated. Of the 81 samples with a failed HRD score, 13 were methylated. Methylated samples were HRD+ (mean score [95 % CI]; 65.9 [62.7-69.1] and 53.3 [48.0-58.6]) and almost mutually exclusive of BRCA1&2 mutations. A significant PFS1 benefit independently of methylation ratios was observed in patients with methylated tumors with bev-ola maintenance compared to bev alone (HR=0.49, 95 % CI 0.29-0.83, P = 0.008). An OS benefit was shown for patients defined as "all-HRD" (including methylation) (HR=0.59, 95 % CI 0.41-0.86, P = 0.007). This study confirms the feasibility and clinical value of BRCA1/RAD51C methylation for predicting response to ola-bev maintenance in newly diagnosed HGSOC. Assessment of methylation in parallel to mutation testing allowed the identification of nearly 85 % of HRD+ samples at low costs. This study suggests that methylation testing could be easily implemented to optimize the selection of patients that benefit from olaparib+bevacizumab maintenance.

Homologous recombination deficiency in ovarian cancer: Global expert consensus on testing and a comparison of companion diagnostics

Poly (ADP ribose) polymerase inhibitors (PARPis) are a treatment option for patients with advanced high-grade serous or endometrioid ovarian carcinoma (OC). Recent guidelines have clarified how homologous recombination deficiency (HRD) may influence treatment decision-making in this setting. As a result, numerous companion diagnostic assays (CDx) have been developed to identify HRD. However, the optimal HRD testing strategy is an area of debate. Moreover, recently published clinical and translational data may impact how HRD status may be used to identify patients likely to benefit from PARPi use. We aimed to extensively compare available HRD CDx and establish a worldwide expert consensus on HRD testing in primary and recurrent OC. A group of 99 global experts from 31 different countries was formed. Using a modified Delphi process, the experts aimed to establish consensus statements based on a systematic literature search and CDx information sought from investigators, companies and/or publications. Technical information, including analytical and clinical validation, were obtained from 14 of 15 available HRD CDx (7 academic; 7 commercial). Consensus was reached on 36 statements encompassing the following topics: 1) the predictive impact of HRD status on PARPi use in primary and recurrent OC; 2) analytical and clinical validation requirements of HRD CDx; 3) resource-stratified HRD testing; and 4) how future CDx may include additional approaches to help address unmet testing needs. This manuscript provides detailed information on currently available HRD CDx and up-to-date guidance from global experts on HRD testing in patients with primary and recurrent OC.

Harmonization of homologous recombination deficiency testing in ovarian cancer: Results from the MITO16A/MaNGO-OV2 trial

Homologous Recombination Deficiency (HRD) status predicts response to treatment with poly(ADP-ribose) polymerase inhibitors in Ovarian Cancer (OC) patients. The Myriad myChoiceCDx Assay is approved by Food and Drug Agency for the HRD assessment. Here we compared the HRD status obtained by three commercial panels with the results from Myriad reference test. The HRD analysis was performed on DNA from formalin-fixed and paraffin-embedded tumor samples of 100 untreated OC patients for which Myriad assay results were available, using TruSight Oncology 500 HRD assay (Illumina), Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific) and SOPHiA DDM HRD solution panel (SOPHiA Genetics). A good overall concordance with the reference method was demonstrated at three different levels: BRCA mutational status (from 94.4 % to 97.7 %), the genomic instability value (from 88.2 % to 95.3 %) and for the HRD status (from 90.4 % to 97.6 %). Moreover, a trend in favour of HRD positive patients for response rate, progression-free survival and overall survival similar to Myriad was observed for all three tests. Our data suggest the feasibility of commercial testing for assessing HRD status, with a good concordance with the reference method and association with clinical outcome.

Differentiation of survival outcomes by anatomic involvement and histology with the revised 2023 International Federation of Gynecology and Obstetrics staging system for endometrial cancer

The International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer underwent revision in 2023, incorporating histology, lymphovascular space invasion, and molecular classification. Herein, we compare overall survival (OS) outcomes by anatomic and histologic involvement for patients staged by the 2009 system versus 2023 system. The National Cancer Database (NCDB) was queried for patients with newly-diagnosed uterine adenocarcinoma from 2004 to 2015, with follow-up data extending through 2020. Stage was determined by both the 2009 and 2023 FIGO staging systems. Kaplan-Meier estimators and Cox proportional hazards models were used for survival analysis. A total of 134,677 patients were analyzed. Per 2023 classification, patients with stage I disease decreased from 96,161 to 70,101 (-27.1%, p < 0.01), while stage II disease increased from 9295 to 36,294 (+390.5%, p < 0.01). Greatest OS change was observed for 2023 stage IA3 patients (low-risk, synchronous endometrial and ovarian tumors with a clonal relationship), whose 10-year OS was 73.4%, compared to 52.6% for 2009 stage IIIA disease. Ten-year OS for 2023 stage IIIB2 (pelvic peritoneal involvement), previously 2009 stage IVB, was 49.4%, compared to 18.7% for 2009 stage IVB patients. Akaike information criterion, Bayesian information criterion, and Harrel's concordance index were used to evaluate OS prognostication of each staging system across all stages, with likelihood ratio favoring the 2023 system (p = 0.020). With FIGO's 2023 endometrial cancer anatomic and histologic staging system, stage migration is greatest in early-stage disease. New staging groups may offer more precise prognostication. These changes may affect future management.

Prediction of prognosis and treatment response in ovarian cancer patients from histopathology images using graph deep learning: a multicenter retrospective study

Ovarian cancer (OV) is a prevalent and deadly disease with high mortality rates. The development of accurate prognostic tools and personalized therapeutic strategies is crucial for improving patient outcomes. A graph-based deep learning model, the Ovarian Cancer Digital Pathology Index (OCDPI), was introduced to predict prognosis and response to adjuvant therapy using hematoxylin and eosin (H&E)-stained whole-slide images (WSIs). The OCDPI was developed using formalin-fixed, paraffin-embedded (FFPE) WSIs from the TCGA-OV cohort, and was externally validated in two independent cohorts from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and Harbin Medical University Cancer Hospital (HMUCH). The OCDPI showed prognostic ability for overall survival prediction in the PLCO (HR, 1.916; 95% CI, 1.380-2.660; log-rank test, P < 0.001) and HMUCH (HR, 2.796; 95% CI, 1.404-5.568; log-rank test, P = 0.0022) cohorts. Patients with low OCDPI experienced better survival benefits and lower recurrence rates following adjuvant therapy compared to those with high OCDPI. Multivariable analyses, adjusting for clinicopathological factors, consistently identified OCDPI as an independent prognostic factor across all cohorts (all P < 0.05). Furthermore, OCDPI performed well in patients with low-grade tumors or fresh-frozen slides, and could differentiate between HRD-deficient or HRD-intact patients with and without sensitivity to adjuvant therapy. The results from this multicenter cohort study indicate that the OCDPI may serve as a valuable and labor-saving tool to improve prognostic and predictive clinical decision-making in patients with OV.

Association between hospital volume and outcomes in invasive ovarian cancer in Belgium: A population-based study

To study the association between hospital volume and outcomes in patients with invasive epithelial ovarian cancer (EOC). This study included 3988 patients diagnosed with invasive EOC between 2014 and 2018, selected from the population-based database of the Belgian Cancer Registry (BCR), and coupled with health insurance and vital status data. The associations between hospital volume and observed survival since diagnosis were assessed with Cox proportional hazard models, while volume associations with 30-day post-operative mortality and complicated recovery were evaluated using logistic regression models. Treatment for EOC was very dispersed with half of the 100 centres treating fewer than six patients per year. The median survival of patients treated in centres with the highest-volume quartile was 2.5 years longer than in those with the lowest-volume quartile (4.2 years versus 1.7 years). When taking the case-mix of hospitals into account, patients treated in the lowest volume centres had a 47% higher hazard to die than patients treated in the highest volume centres (HR: 1.47, 95% CI: 1.11-1.93, p = 0.006) over the first five years after incidence. A similar association was found when focussing on the surgical volume of the hospitals and considering only operated patients with invasive EOC. Lastly, the 30-day post-operative mortality decreased significantly with increasing surgical volume. The large dispersion of care and expertise within Belgium and the volume-outcome associations observed in this study support the implementation of the concentration of care for patients with invasive EOC in reference centres.

Validation of MiROvaR, a microRNA-based predictor of early relapse in early stage epithelial ovarian cancer as a new strategy to optimise patients' prognostic assessment

Early-stage epithelial ovarian cancer (eEOC) patients have a generally favorable prognosis but unpredictable recurrence. Accurate prediction of risk of relapse is still a major concern, essentially to avoid overtreatment. Our robust tissue-based miRNA signature named MiROvaR, predicting early EOC recurrence in mostly advanced-stage EOC patients, is here challenged in an independent cohort to extend its classifying ability in the early-stage EOC setting. We retrospectively selected patients who underwent comprehensive surgical staging at our institution including stages from IA to IIB. miRNA expression profile was analysed in 89 cases and MiROvaR algorithm was applied using the previously validated cut-off for patients' classification. The primary endpoint was progression-free survival (PFS) at 5 years. Complete follow-up time (median = 112 months) was also considered as secondary analysis. MiROvaR was assessable on 87 cases (19 events of disease progression) and classified 68 (78%) low-risk and 19 (22%) high-risk patients. Recurrence rate at primary end-point was 39% for high-risk patients as compared to 9.5% for low-risk ones. Accordingly, their Kaplan-Meier PFS curves were significantly different at both primary and secondary analysis (p = 0.0006 and p = 0.03, respectively). While none of the prominent clinical variables had prognostic relevance, MiROvaR significantly predicted disease recurrence at the 5-year assessment (primary endpoint analysis; HR:5.43, 95%CI:1.82-16.1, p = 0.0024; AUC = 0.78, 95%CI:0.53-0.82) and at complete follow-up time (HR:2.67, 95%CI:1.04-6.8, p = 0.041; AUC:0.68, 95%CI:0.52-0.82). We validated MiROvaR performance in identifying at diagnosis eEOC patients' at higher risk of early relapse thus enabling selection of the most effective therapeutic approach.

Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy

The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3-11.3), 5.4 (4.8-5.8) and 2.9 (2.8-4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1-22.4) and 8.3 (7.1-10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.

Response to letter entitled: Re: Can we replace adjuvant chemotherapy with surveillance for stage IA-C immature ovarian teratomas of any grade? An international multicenter analysis

Re: ‘Can we replace adjuvant chemotherapy with surveillance for stage IA-C immature ovarian teratomas of any grade? An international multicenter analysis’

Reporting the trajectories of adverse events over the entire treatment course in patients with recurrent platinum-sensitive ovarian cancer treated with platinum-based combination chemotherapy regimens: A graphical approach to trial adverse event reporting

Clinical trials report adverse events (AEs) in a dense table focusing on the frequency of 'worst grade' AEs experienced over the duration of treatment. There is usually no granular information provided on the timing and trajectory of AEs or whether they are likely to worsen, improve, or remain constant over time. Non-hematologic (NH) AE data was extracted from the CALYPSO trial comparing carboplatin with pegylated liposomal doxorubicin (CD) to carboplatin with paclitaxel (CP) in recurrent ovarian cancer (ROC). Generalised estimating equations (GEE) were used to assess the risk and trajectory of combined Grade 2 or higher (G2+) AE and of each specific AE. The risk of G2+AE was also compared between treatment arms. The study included 976 patients and AE were reported for the duration of treatment. Most patients experienced at least one G2+NHAE (CP:CD, 96.0%:80.6%). Risk of combined G2+AE increased with CP (4.1% per-cycle) but decreased with CD (0.8%, P <0.01). When alopecia and sensory neuropathy were excluded, risk of G2+ AE decreased by 2.7% per-cycle, with no significant difference between treatment arms. G2+ nausea improved (15.2% per-cycle, P <0.01). G2+ sensory neuropathy worsened (29.3% per-cycle, P <0.01). Fatigue was stable (17% per-cycle, P =0.06) whilst G2+ pain decreased over time (13.4% per-cycle, P <0.01), with no difference between treatment arms. Existing trial data can be used to provide AE trajectories as illustrated here for ROC. These trajectories have utility in guiding treatment choice and potentially optimising AE management with novel therapies and treatment combinations.

tRNA-derived small RNA 3′U-tRFValCAC promotes tumour migration and early progression in ovarian cancer

Despite recent advances in epithelial ovarian cancer (EOC) management, the highly heterogenous histological/molecular tumour background and patients' treatment response obstructs personalised prognosis and therapeutics. Herein, we have studied the role and clinical utility of the novel subclass of tRNA-derived small RNA fragments emerging via 3'-trailer processing of pre-tRNAs (3'U-tRFs) in EOC. SK-OV-3 and OVCAR-3 cells were used for in vitro study. Following transfection, cell growth and migration were assessed by CCK8 and wound healing assays, respectively. 3'U-tRFs levels were assessed by reverse transcription quantitative PCR (RT-qPCR), following 3'-end RNA polyadenylation. A screening (OVCAD, n = 100) and institutionally independent validation (TU Munich, n = 103) cohorts were employed for survival analysis using disease progression and patients' death as clinical end-points. Bootstrap analysis was performed for internal validation, and decision curve analysis was used to evaluate clinical benefit on disease prognosis. Following primary clinical assessment, target prediction and gene ontology analyses, the 3'U-tRF 3'U-tRF

Effect of delay in surgical therapy for early-stage cervical cancer: An implication in the coronavirus pandemic

Addressing the diagnostic and therapeutic dilemmas of ovarian immature teratoma: Report from a clinicopathologic consensus conference

Ovarian immature teratoma is a rare subtype of germ cell tumour that can be pure or associated with non-teratomatous germ cell tumour elements and is graded based on extent of the immature neuroectodermal component. Immature teratoma (IT) can also be associated with somatic differentiation in the form of sarcoma, carcinoma, or extensive immature neuroectodermal elements and may produce low levels of serum alpha-fetoprotein. Variable interpretation of these issues underlies diagnostic and management dilemmas, resulting in substantial practice differences between paediatric and adult women with IT. The Malignant Germ Cell International Consortium (MaGIC) convened oncologists, surgeons, and pathologists to address the following crucial clinicopathologic issues related to IT: (1) grading of IT, (2) definition and significance of 'microscopic' yolk sac tumour, (3) transformation to a somatic malignancy, and (4) interpretation of serum tumour biomarkers. This review highlights the discussion, conclusions, and suggested next steps from this clinicopathologic conference.

Adverse events in the placebo arm of maintenance therapy trials in advanced ovarian cancer: A systematic review and meta-analysis

Maintenance treatment is standard of care for front-line (FL) and platinum-sensitive recurrent ovarian cancer (PSROC) following response to chemotherapy. Adverse events (AEs) on maintenance therapies are common and usually attributable to investigational treatments but could also be unrelated. Randomised controlled trial (RCT) with blinded placebo design is the gold standard for determining the relative differences in efficacy and AEs between treatment arms. We performed a meta-analysis to quantify AE rates in placebo arms of RCTs to determine AEs not due to investigational agents. We performed an electronic search to identify eligible RCTs in FL and PSROC settings. Data from placebo arms were extracted and pooled using the inverse variance method to determine the risk of any AE, overall and specific grade 3 or higher (G ≥ 3) AEs, and AE-related treatment delay, reduction and discontinuation. We identified 13 eligible RCTs (FL, N = 8; PSROC, N = 5) with 2224 patients who received placebo (FL, N = 1541; PSROC, N = 683). The majority experienced an AE of any grade (FL, 93.0%; PSROC, 95.2%). Substantial proportions experienced G ≥ 3 AEs (FL, 14.6%; PSROC, 18.2%). In the FL setting, AEs led to treatment delay in 14.4%, dose reduction in 4.1% and discontinuation in 2.6%. Findings were similar for PSROC: 8.4%, 5.5% and 2.1%, respectively. AEs not due to investigational agents are common in ovarian cancer patients in maintenance therapy RCTs. Potential explanations include the nocebo effect, residual toxicities from previous treatment or underlying disease. Further research is required to identify better approaches to assessing AEs in this population.

Wait-time for adjuvant radiotherapy and oncologic outcome in early-stage cervical cancer: A treatment implication during the coronavirus pandemic

Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer

The PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, the decentralized SeqOne assay, which relies on shallow Whole Genome Sequencing (sWGS) to capture genomic instability and targeted sequencing to determine BRCA status. The study comprised 368 patients from the PAOLA-1 trial. The SeqOne assay was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS). We found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI); 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 91%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with SeqOne assay and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.99 (95% CI; 0.68-1.42) and 1.05 (95% CI; 0.70-1.57) with SeqOne and Myriad assays. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with the SeqOne and Myriad assay. The SeqOne assay offers a clinically validated approach to detect HRD.

Progression-free survival and safety at 3.5 years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer

To report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported. In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40-0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56-0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49-0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature. Niraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified.

Associations between changes in MASLD status and cancer development in young adults: A nationwide cohort study

Artificial intelligence to predict cancer risk, are we there yet? A comprehensive review across cancer types

Hysteroscopic versus cervical injection for sentinel node detection in endometrial cancer: A multicenter prospective randomised controlled trial from the Multicenter Italian Trials in Ovarian cancer (MITO) study group

During the last years, the role of sentinel lymph node mapping (SLNM) for endometrial cancer (EC) surgical treatment has increased in popularity. However, several controversies remain about different technical steps of SLNM. Thus, a randomised control trial was designed to compare cervical (CI) and hysteroscopic (HI) indocyanine green (ICG) injection for SLNM of newly diagnosed EC undergoing surgical staging. The primary end-point of the study was to compare these two techniques in terms of para-aortic detection rate. Patients with apparent stage I or II histologically confirmed EC undergoing surgery were included in the study. This randomised trial distinguished patients in two study groups according to two different techniques of ICG SLNM: CI versus HI injection. Patients who met the inclusion criteria were randomly assigned to CI or HI injection in a 1:1 ratio. The central randomisation system allocated patient randomisation numbers sequentially in the order in which the patients were enrolled. This randomised trial was not blinded for either patients or the surgeons. From March 2017 until April 2019, a total of 165 patients were randomised in this study: 85 (51.5%) in the CI group and 80 (48.5%) in the HI group. After randomisation, 14 (8.5%) patients were excluded from the study. Finally, 151 patients were included in the analysis: 82 (54.3%) in the CI group and 69 (45.7%) in the HI group. Hysteroscopy injection shows an ability to detect Sentinel nodes (SNLs) in the para-aortic area of about 10% greater compared with CI injection, although this difference did not reach statistical significance. The HI technique was superior in detecting isolated para-aortic SLNs (5.8% Versus 0%). The CI injection was correlated with higher SLN detection rates at the pelvic level compared with HI injection. Pelvic and overall detection was higher in the CI group. The present study supports the adoption of CI instead of HI injection because the former allows better identification of sentinel nodes (especially in the pelvic area). Detection of SLN in the para-aortic area was slightly higher in patients receiving a HI injection, but the difference with the CI route was not statistically significant.

Differences in immunogenicity of TP53-mutated cancers with low tumor mutational burden (TMB) A study on TP53mut endometrial-, ovarian- and triple-negative breast cancer

To explore why in large phase III randomized clinical trials TP53-mutated (TP53mut) endometrial cancer (EC) was the only tumor showing survival benefit to immune checkpoint inhibitors (ICIs) added to chemotherapy when compared with other low TMB TP53mut cancers, such as high-grade serous ovarian (HGSOC) and triple-negative breast cancer (TNBC). From 606 patients with one of the three mentioned cancers, "The Cancer Genome Atlas" data on clinical outcome, TMB and detailed composition of the tumor immune-microenvironment (TIME) (immune infiltrating cells, cytokines, and other immune-modulators) were compared using the Kruskal-Wallis test, followed by Pearson correlation. Prognostic value of studied variables was assessed by Kaplan-Meier and Cox-regression analyses. TMB was very low in all three TP53mut entities, being lowest in EC (median: 1.27 Mut/Mb; p < 0.001). Interestingly, high TMB was significantly associated with improved clinical outcome in every entity, whereby best discrimination for PFS was found in EC (HR: 0.52). Compared to EC, immune-suppressing regulatory T-cells were higher in HGSOC and TNBC (p < 0.001) and M2-like macrophages higher in HGSOC (p < 0.001). In contrast, immune-activating mDCs were more prominent in EC than in HGSOC (p < 0.001). Differential modulator expression analyses revealed highest discrimination for the immune-inhibiting FOXP3, C1QA and XBP1, which all exhibited lower levels in EC compared with HGSOC and TNBC (p < 0.001). Characteristics of TIME differ substantially among the assessed entities in terms that EC exhibits fewer immunosuppressive traits, expecting a higher likelihood for responding to ICIs, despite a very low TMB, whereas HGSOC and TNBC exhibit an immune hostile TIME.

European trends in ovarian cancer mortality, 1990–2020 and predictions to 2025

Over the last decades, ovarian cancer mortality in Europe has been decreasing, but disparities in trends were observed. In this paper, we analysed ovarian cancer mortality trends in Europe over the period 1990-2020 and predicted the number of deaths and rates by 2025. We extracted population and death certification data from ovarian cancer in women for 31 European countries, between 1990 and 2020 from the World Health Organization database. We computed age-standardised mortality rates (ASMR) per 100,000 women-years, based on the world standard population. We also obtained predictions for 2025 using a joinpoint regression model and calculated the number of avoided deaths over the period 1994-2025. Over the observed period, mortality from ovarian cancer showed a favourable pattern in most countries. In the EU-27, rates declined by 5.9% from 2010-2014 to 2015-2019, reaching an ASMR of 4.66/100,000. During the same period, the decline in ovarian cancer mortality was more pronounced in the EU-14 countries (-7.0%) compared to Transitional countries (-2.1%). Declines were also observed in the United Kingdom, to reach an ASMR of 5.29. Decreases in mortality from ovarian cancer are predicted until 2025, to 4.17/100,000 for the EU-27. Favourable trends in ovarian cancer mortality are expected to persist in Europe and can be mainly attributed to the increased use of oral contraceptives in subsequent generations of European women. Decreased use of menopausal Hormone Replacement Therapy and improved diagnosis and management may also have played a role.

Informative censoring in maintenance therapy trials for advanced ovarian cancer: An empirical assessment of its impact on treatment benefit

A considerable proportion of patients in ovarian cancer maintenance trials may be censored in progression-free survival (PFS) analyses, the primary study endpoint. Such censoring is often informative, reflecting discontinuation due to toxicity, preference, or early switch to alternative therapies, potentially biasing results toward overestimating PFS benefit. We aimed to quantify the impact of informative censoring on PFS in these trials. Double-blind, placebo-controlled maintenance therapy trials were selected, and individual patient data reconstructed from published survival curves. A sensitivity analysis reclassified varying proportions of all censored events as progressions to model scenarios from 0 % to 100 % informative censoring. Hazard ratios (HRs) were re-estimated and compared with the originally reported values. Duration of therapy was compared with PFS. Twenty-two trial units (N = 8256) were included. Nineteen reported statistically significant results, falling to 14 (74 %) at the upper limit of analysis. HRs diminished progressively, with a 6 % reduction at 10 % censoring and 29 % at 100 %. In nine PARP inhibitor trials, treatment duration was shorter than PFS (mean of medians = 12.5 vs 17.6 months). Results were consistent when limited to PARP inhibitor studies. No correlation was observed between adverse events and censoring. Informative censoring can substantially distort PFS benefit estimates in ovarian cancer maintenance trials. Transparent reporting of censoring rates and their causes is essential for meaningful clinical interpretation and should be standard in all randomised maintenance therapy trials.

ENDOESTRO score: Where is the dark side? Evaluation of estrogen receptor expression cutoff in endometrial cancer molecular classification, an ambispective study

Estrogen receptor (ER) expression has prognostic value in endometrial cancer (EC), also in the context of molecular classification. However, a standardized cutoff to define ER positivity is lacking. To identify the ER expression cutoff that best correlates with survival outcomes overall and within each molecular subgroup. We conducted an ambispective study comprising a retrospective phase (Feb 2017-Feb 2022) and a prospective phase (Mar 2022-Jan 2024), including patients with EC who underwent surgery at our institution. In the retrospective cohort, molecular subgroups were defined by immunohistochemistry (IHC): 1) MMRp Among 2084 patients, ER < 10 % was the strongest cutoff for prognosis based on disease-free survival (DFS). Patients with ER < 10 % and < 1 % shared similar unfavorable clinicopathological and molecular features, while ER ≥ 10 % was associated with more favorable profiles. ER < 10 % was an independent adverse prognostic factor in uni- and multivariate analyses for DFS and overall survival, particularly in MMRp ER < 10 % expression is a robust prognostic indicator, associated with worse outcomes and may serve as a clinically meaningful cutoff in endometrial cancer risk stratification. Further prospective validation is warranted.

Exploring isolated tumor cells entity in endometrial cancer

Endometrial cancer (EC) management includes nodal staging and molecular classification. Despite molecular advancements, the biological significance of isolated tumor cells (ITC) in EC remains unclear. This study aimed to characterize ITC in the context of pathological and molecular features MATERIALS AND METHODS: A multicenter, retrospective analysis included EC patients diagnosed between June 2018 and May 2024 who underwent surgical staging via sentinel lymph node (SLN) biopsy and molecular profiling. ITC cases detected through SLN ultrastaging or One Step Nucleic Acid Amplification (OSNA) were compared with N0 and N + (micro-/macrometastasis) groups. Among the 1821 patients included, nodal status was N0 in 84.5 %, ITC in 5.1 %, micrometastases in 5.3 %, and macrometastases in 4.5 %. ITC patients exhibited deep myometrial invasion in 67.7 % of cases vs. 28.7 % in N0 (p < 0.001). Diffuse lymphovascular space invasion (LVSI) was significantly higher in ITC (52.1 %) than N0 (12.2 %, p < 0.001). MMR deficiency was more frequent in ITC (33.3 %) vs. N0 (25.0 %, p = 0.07). POLE mutations were more common in N0 (4.2 %) and ITC (3.1 %) vs. N + (1.1 %), though not statistically significant. p53-abnormal tumors were significantly associated with N + status (19.4 %) compared to ITC (7.3 %, OR 0.33, p = 0.008). No relapses occurred among ITC patients with low-risk features. These findings suggest that ITC may represent an early form of nodal involvement, biologically distinct from micro- and macrometastases. The association with MMR deficiency and the absence of aggressive markers such as p53 abnormalities support a less aggressive profile. Integrating molecular and pathological features may refine risk stratification and inform management strategies for EC patients with ITC.

MRI in advanced ovarian cancer: multicentre MISSION trial.

For patients with advanced ovarian cancer, complete cytoreductive surgery (CRS) offers the best chance for long-term survival and cure. Currently, staging relies on CT and, in selected cases, diagnostic laparoscopy, both of which have important limitations. This study assessed the diagnostic performance of MRI for predicting complete interval CRS. This prospective multicentre cohort study included FIGO stage III-IV ovarian cancer patients scheduled for interval CRS. Radiologists, blinded to surgical findings, independently scored the MRI-derived Peritoneal Cancer Index (mriPCI). Gynaecologic oncologists recorded the surgical PCI (sPCI) before and after intraoperative disclosure of MRI findings (revised-sPCI). The primary endpoint was the ability of mriPCI to predict complete interval CRS (no macroscopic residual disease). Secondary endpoints included concordance between mriPCI and sPCI, diagnostic yield from MRI disclosure, and inter-reader agreement. Sample size calculations indicated that 189 patients undergoing interval CRS should be included. Between 2018 and 2023, 270 patients were recruited, of whom 194 were eligible for analysis. Complete interval CRS was achieved in 149/194 patients (77%). The diagnostic performance of mriPCI showed an AUC of 0.76 for predicting a complete CRS. The revised-SPCI, after intraoperative disclosure of MRI led to an AUC of 0.88. MRI findings led to a change in sPCI in 19% of patients. Interobserver reliability for mriPCI was substantial (Interclass correlation coefficient 0.81, 95% CI 0.67-0.88). MRI enables accurate, non-invasive prediction of complete interval CRS feasibility in advanced ovarian cancer. Integration of MRI into surgical planning enhances intraoperative detection of lesions and can facilitate decision-making, supporting its role as a non-invasive staging tool. NCT03399344.

The prognostic and clinical significance of substantial lymphovascular space invasion in early-stage endometrial carcinoma

Substantial lymphovascular space invasion (LVSI) has been incorporated into the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial carcinoma. This study aims to evaluate whether classifying LVSI into substantial LVSI (≥5 involved vessels) and no/focal LVSI (≤4 involved vessels) provides meaningful prognostic differentiation in early-stage endometrial carcinoma. We retrospectively enrolled patients with FIGO 2009 stage I-II endometrial carcinoma who underwent surgical staging between January 2013 and August 2020. LVSI was graded as no LVSI, focal LVSI (1-4 involved vessels), or substantial LVSI (≥5 involved vessels), following the World Health Organization 2020 definition. Among 1796 patients, 112 (6.2 %) had substantial LVSI, 170 (9.5 %) had focal LVSI, and 1514 (84.3 %) had no LVSI. The 5-year progression-free survival (PFS) rates were 81.7 % for substantial LVSI, 89.9 % for focal LVSI, and 95.0 % for no LVSI (P < 0.001). Multivariate analysis found that substantial LVSI was an independent predictor of worse PFS (substantial vs. no LVSI: HR 2.49, P < 0.001; substantial vs. focal LVSI: HR 1.90, P = 0.047). No statistically significant difference in PFS was observed between patients with focal LVSI and those with no LVSI (HR 1.31, P = 0.321). The overall survival (OS) analysis showed consistent results. Substantial LVSI is an independent prognostic factor for PFS and OS in early-stage endometrial carcinoma, while focal LVSI shows similar outcomes to no LVSI. Our findings support the use of substantial LVSI (≥5 involved vessels) as a key determinant for risk stratification and staging, aligning with the FIGO 2023 staging system recommendations.

Sentinel-node biopsy in apparent early stage ovarian cancer: final results of a prospective multicentre study (SELLY)

To evaluate the sensitivity and specificity of sentinel-lymph-node mapping compared with the gold standard of systematic lymphadenectomy in detecting lymph node metastasis in apparent early stage ovarian cancer. Multicenter, prospective, phase II trial, conducted in seven centers from March 2018 to July 2022. Patients with presumed stage I-II epithelial ovarian cancer planned for surgical staging were eligible. Patients received injection of indocyanine green in the infundibulo-pelvic and, when feasible, utero-ovarian ligaments and sentinel lymph node biopsy followed by pelvic and para-aortic lymphadenectomy was performed. Histopathological examination of all nodes was performed including ultra-staging protocol for the sentinel lymph node. 174 patients were enrolled and 169 (97.1 %) received study interventions. 99 (58.6 %) patients had successful mapping of at least one sentinel lymph node and 15 (15.1 %) of them had positive nodes. Of these, 11 of 15 (73.3 %) had a correct identification of the disease in the sentinel lymph node; 7 of 11 (63.6 %) required ultra-staging protocol to detect nodal metastasis. Four (26.7 %) patients with node-positive disease had a negative sentinel-lymph-node (sensitivity 73.3 % and specificity 100.0 %). In a multicenter setting, identifying sentinel-lymph nodes in apparent early stage epithelial ovarian cancer did not reach the expected sensitivity: 1 of 4 patients might have metastatic lymphatic disease unrecognized by sentinel-lymph-node biopsy. Nevertheless, 35.0 % of node positive patients was identified only thanks to ultra-staging protocol on sentinel-lymph-nodes.

Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma

Half of high grade serous tubo-ovarian carcinomas (HGSOC) demonstrate homologous recombination repair (HRR) deficiency, most commonly through germline or somatic pathogenic variants in BRCA1/2 (gBRCA1/2 or sBRCA1/2). gBRCA1/2 is associated with favourable survival, greater response rate to platinum-based chemotherapy, and marked sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. sBRCA1/2 has been assumed to confer a similar clinical phenotype; however, few studies have specifically investigated sBRCA1/2 versus gBRCA1/2 to demonstrate their equivalence. We investigated the association of gBRCA1/2, sBRCA1/2 and non-BRCA HRR gene mutations with HGSOC patient survival using two patient cohorts (cohort 1, n = 174 matched FFPE tumour and normal with panel-based sequencing; cohort 2, n = 279 matched fresh tumour and normal with whole genome sequencing). TCGA-OV samples (n = 316) were used for external validation. Patients with HRR-mutant tumours (BRCA1, BRCA2, non-BRCA HRR-mutant) demonstrated prolonged survival across both cohorts (cohort 1: multivariable hazard ratio [multiHR] 0.53 [0.32-0.87]; cohort 2: multiHR 0.36 [0.25-0.51]). gBRCA1/2 and sBRCA1/2 were associated with a similar survival benefit compared to the HRR-wildtype group in the combined cohort (cohort 1 +2) (gBRCA1/2: multiHR 0.50 [0.34-0.71]; sBRCA1/2: multiHR 0.41 [0.25-0.68]). These findings were recapitulated using the TCGA-OV dataset (gBRCA1/2: multiHR 0.56 [0.34-0.91]; sBRCA1/2: multiHR 0.48 [0.25-0.92]). Non-BRCA HRR mutations were associated with marked survival advantage (multiHR vs HRR-wildtype 0.22 [0.11-0.45]). The survival advantage in BRCA1-mutant cases (germline or somatic) was less marked (multiHR for non-BRCA HRR-mutant vs BRCA1-mutant 0.41 [0.19-0.90]). gBRCA1/2, sBRCA1/2 and non-BRCA HRR mutations were all associated with high HRDetect scores measuring HRR deficiency (median 1.00 versus 0.56 in HRR-wildtype, P < 0.01). gBRCA1/2 and sBRCA1/2 are equivalent in their association with prolonged survival. Non-BRCA HRR gene mutations may be associated with markedly favourable survival in HGSOC.

Back to the future: The impact of oestrogen receptor profile in the era of molecular endometrial cancer classification

The aim of this study is to evaluate the impact of the oestrogen receptor (ER) profile on oncologic outcomes in the new endometrial cancer (EC) risk classification. Immunohistochemistry (IHC) analyses were performed in a retrospectively reviewed large series of ECs to assess the presence/absence of oestrogen receptors (ER0\1+ or ER2+\3+) and other molecular factors (i.e. p53 mutation, p53mut; and mismatch repair mutational status, MMRd (mismatch repair deficient) versus MMRp (mismatch repair proficient)), histopathologic and clinical outcomes. ER status was correlated with molecular, histologic, clinical and prognostic data. 891 EC patients were included in the study (211 ER0\1+ and 680 ER2+\3+). The ER0\1+ phenotype was associated with an unfavourable clinicopathological profile (i.e. grading, histotype, lymphovascular space invasion (LVSI), stages, etc.). Simple regression showed that risk class, p53mut, and ER0/1+ impacted on both disease-free survival (DFS) and overall survival (OS) (p  0.05). In multiple regression, age, high and advanced/metastatic risk classes influenced survival outcomes (p  0.05). ER-positivity retained a remarkable prognostic impact even after stratification of the population according to the European Society of Gynaecological Oncology, the European Society for Radiotherapy and Oncology, and the European Society of Pathology (ESGO/ESTRO/ESP) 2021 risk classes and molecular classification. ER0/1+ intermediate, high-intermediate, high and advanced risk versus ER2+/3+ intermediate, high-intermediate, high and advanced risk classes showed statistically different OS and DFS (p< 0.001). ER0/1+ status was associated with a worse prognosis when associated with MMRp, MMRd and p53mut compared to the same molecular classes associated with ER2+/3 (p < 0.001). We demonstrated that ER status has a significant impact on oncologic outcomes, regardless of risk class and p53/MMR status. Based on our results, we recommend the inclusion of ER assessment in featured EC risk classification system.

Semiquantitative evaluation of lymph-vascular space invasion in patients affected by endometrial cancer: Prognostic and clinical implications

The interpretation of lymph-vascular space invasion (LVSI) is usually qualitative, as presence or absence. The aim of this study is to investigate the prognostic role of LVSI in patients affected by endometrial cancer, when evaluated with a semiquantitative analysis. This retrospective multicentre study enrolled patients who received a histologically confirmed diagnosis of endometrial cancer. The assessment of LVSI was semiquantitative in accordance with the three-tiered scoring system (absent, focal and diffuse). Among 1258 patients with surgical-stage endometrial cancer, LVSI has been found in 32.8% of cases (n = 412), whose 12.7% (n = 160) were focal, and 20% (n = 252) diffuse. The rate of lymph node metastasis increased from the 5% in patients with no LVSI to 15% in patients with focal LVSI and 33% in those with diffuse LVSI (p < 0.001). Distant recurrences were more frequent in patients with diffuse LVSI than in focal or no LVSI (24.9% versus 14.7% and 6.6%, respectively, p < 0.001). Diffuse LVSI was found to significantly increase the risk of distant metastasis (adjusted odds ratio (A OR) 2.57, p < 0.001). Adjuvant radiation were associated with improved overall survival (OS) and disease-free survival (DFS) in patients with diffuse LVSI. The presence of diffuse LVSI is an independent risk factor for both lymph node metastasis and distant recurrence in endometrial cancer patients, and it is associated with a significantly decreased OS and DFS. Adjuvant radiation improved survival regardless of grading, histotype and lymph nodal metastasis in women with diffuse LVSI.

Malignant peritoneal cytology in endometrial cancer: Areas of unmet need for evidence

Malignant peritoneal cytology and decreased survival of women with stage I endometrioid endometrial cancer

To examine the association between malignant peritoneal cytology and survival in women with early-stage endometrioid endometrial cancer. This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results Program from 2010 to 2016. Women with stage I endometrioid endometrial cancer who had peritoneal cytology testing at hysterectomy were examined (N = 24,800). Characteristics and survival related to malignant peritoneal cytology were assessed. The propensity score inverse probability of treatment weighting was used to balance the measured covariates. Malignant peritoneal cytology was reported in 1081 (4.4%) women. In multivariable analysis, stage IB disease and moderately/poorly differentiated tumours were associated with an increased likelihood of malignant peritoneal cytology (both P < 0.05). In a weighted model, malignant peritoneal cytology was associated with decreased cause-specific survival (5-year rates, 92.1% versus 96.8%, hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.56-2.52) and overall survival (89.4% versus 93.1%, HR 1.41, 95% CI 1.16-1.72). In sensitivity analyses, malignant peritoneal cytology was associated with decreased overall survival in the high-intermediate-risk group (5-year rates, 77.8% versus 83.6%, HR 1.57, 95% CI 1.20-2.06) and decreased cause-specific survival in the low-risk group (95.4% versus 98.0%, HR 1.64, 95% CI 1.01-2.68). In the high-intermediate-risk group with malignant peritoneal cytology, postoperative chemotherapy was associated with improved overall survival compared to whole pelvic radiotherapy (5-year rates, 82.7% versus 64.6%, HR 0.36, 95% CI 0.14-0.96). This association was not observed in negative cytology cases (81.5% versus 79.7%, HR 0.78, 95% CI 0.53-1.14). Malignant peritoneal cytology may be associated with decreased survival in stage I endometrioid endometrial cancer.

Comparison of survival between primary debulking surgery and neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomised trial

Regarding the comparison between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NACT) for stage III/IV ovarian, tubal and peritoneal cancers, EORTC55971 and CHORUS studies demonstrated noninferiority of NACT. Previously, we reported reduced invasiveness of NACT in JCOG0602. This is a final analysis including the primary endpoint of overall survival (OS). Patients were randomised to PDS (PDS followed by 8x paclitaxel and carboplatin, i.e. TC regimen) or NACT (4x TC, interval debulking surgery [IDS], 4x TC). The primary endpoint was OS. The noninferiority hazard ratio (HR) margin for NACT compared with PDS was 1·161. The planned sample size was 300. Between 2006 and 2011, 301 patients were randomised, 149 to PDS and 152 to NACT. The median OS was 49·0 and 44·3 months in the PDS and NACT. HR for NACT was 1·052 [90·8% confidence interval (CI) 0·835-1·326], and one-sided noninferiority p-value was 0·24. Median progression-free survival was 15·1 and 16·4 months in the PDS and NACT (HR: 0·96 [95%CI 0·75-1·23]). In the PDS arm, 147/149 underwent PDS and 49/147 underwent IDS. In the NACT arm 130/152 underwent IDS. Complete resection was achieved in 12% (17/147) of PDS and 31% (45/147) of PDS ± IDS in the PDS arm and in 64% (83/130) of IDS in the NACT arm. Optimal surgery (residual tumour  2000 an institution with low study activity was advantageous, whereas clear/mucinous histology was disadvantageous for OS. The noninferiority of NACT was not confirmed. NACT may not always be a substitute for PDS. However, as our study had smaller numbers, the noninferiority of the previous studies cannot be denied. Ministry of Health, Labour and Welfare, Japan and the National Cancer Center, Japan. UMIN000000523.

Concordance between CA-125 and RECIST progression in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer treated in the SOLO2 trial with olaparib as maintenance therapy after response to chemotherapy

Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo. We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV). Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST. Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.

Tegafur-uracil maintenance chemotherapy post-chemoradiotherapy for cervical cancer: Randomized trial

Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer (LACC), but recurrence rates remain high. This multicenter phase-3 randomized trial (GOTIC-002) evaluated the efficacy of low-dose oral tegafur-uracil (UFT) as maintenance chemotherapy following curative CCRT for LACC. Between 2010 and 2018, 351 patients with stage Ib2-IVa cervical cancer were enrolled. After achieving complete or partial remission post-CCRT, patients were randomized 1:1 into observation (arm O) or UFT maintenance therapy (arm UFT). UFT doses were 300-400 mg/day based on body surface area for 2 years, disease progression or adverse effects occurred. The primary endpoint was progression-free survival (PFS), with overall survival (OS) and safety as secondary endpoints. Patient characteristics were similar between the groups (n = 178 in arm O, n = 173 in arm UFT). During a median follow-up of 3 years, median PFS was not reached in either group. 5-year PFS rates were similar between them (arm O: 61.3 %, arm UFT: 62.0 %, hazard ratio: 0.92, P = .634). 5-year OS rates were also comparable (77.6 % vs 76.1 %, hazard ratio: 1.04, P = .869). Compliance with UFT ranged from 87.8 % to 98.8 %. Although adverse events were more frequent in arm UFT (93.5 % vs 73.9 %, odds ratio: 5.05), most were mild or moderate. Despite its tolerability, UFT did not improve PFS or OS. These findings suggest the need to reconsider maintenance therapy strategies after CCRT for potentially shifting away from cytotoxic chemotherapy towards alternative methods to enhance survival outcomes in patients with LACC.

Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial

Cemiplimab has demonstrated significantly longer survival than physician's choice of chemotherapy in patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. We report the final survival analysis from the phase III randomized study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9). Cemiplimab (n = 304) or chemotherapy (n = 304) were administered every 3 weeks. The primary endpoint was overall survival (OS). Patients were included regardless of programmed cell death-ligand 1 (PD-L1) status. At a median follow-up of 47.3 months (data cut-off: April 20, 2023), median OS was 11.7 versus 8.5 months for patients treated with cemiplimab and chemotherapy, respectively (hazard ratio 0.67, 95 % confidence interval 0.56-0.80, p < .00001). OS benefit was seen in PD-L1 positive and negative populations, even though more patients with PD-L1 < 1 % (n = 92), had poor performance status in the cemiplimab arm than the chemotherapy arm (61.4 % vs 47.9 %). This final analysis confirms that cemiplimab maintains survival benefit compared with chemotherapy in recurrent cervical cancer after progression on first-line platinum therapy, regardless of PD-L1 expression. The safety profile was consistent with published data; incidences of adverse events were similar between cemiplimab and chemotherapy groups. These results support the use of second-line cemiplimab for patients with recurrent cervical cancer.

Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first-line before poly(ADP-ribose) polymerase inhibitor era: A Gynaecologic Cancer Intergroup meta-analysis

In patients with advanced ovarian cancer, the modelled CA-125 ELIMination rate constant K (KELIM) is an early indicator of the tumour intrinsic chemosensitivity. We assessed the prognostic and surrogate values of KELIM with respect to those of surgery outcome (based on post-operative residual lesions) in the Gynaecologic Cancer Intergroup (GCIG) individual patient data meta-analysis MAOV (Meta-Analysis in OVarian cancer) built before the emergence of poly(ADP-ribose) polymerase (PARP) inhibitors. The dataset was split into learning and validation cohorts (ratio 1:2). The individual modelled KELIM values were estimated, standardised by the median value, then scored as unfavourable (<1.0) or favourable (≥1.0). Overall survival (OS) and progression-free survival (PFS) analyses were performed with a two-step meta-analytic approach and surrogacy through a two-level meta-analytic model. KELIM was assessed in 5884 patients from eight first-line trials (learning, 1962; validation, 3922). A favourable KELIM score was significantly associated with longer OS (validation set, median, 78.8 versus 28.4 months, hazard-ratios [HR] 0.46, 95% confidence interval [CI], 0.41-0.50, C-index 0.68), and longer PFS (validation set, median 30.5 versus 9.8 months, HR 0.49, 95% CI, 0.45-0.54, C-index 0.68), as were International Federation of Gynaecology and Obstetrics (FIGO) stage and debulking surgery outcome. Three prognostic groups were identified based on the surgery outcome and KELIM score, with large differences in OS (105.1, ∼45.0, and 22.1 months) and PFS (58.1, ∼15.0, and 8.0 months). Surrogacy for OS and for PFS was not established. KELIM is an independent prognostic biomarker for survival, complementary to surgery outcome, representing a new determinant of first-line treatment success.

Platinum-based chemotherapy and PARP inhibitors for patients with a germline BRCA pathogenic variant and advanced breast cancer (LATER-BC): retrospective multicentric analysis of post-progression treatments

Patients with breast cancer (BC) harbouring a germinal BRCA pathogenic variant (gBRCA-PV) may have an enhanced sensitivity to platinum-based chemotherapy (PBC) and PARP inhibitors (PARPi). As reported in ovarian cancer, however, sensitivity and resistance to these treatments could partially overlap. In patients with a gBRCA-PV and advanced BC (aBC), it remains unclear whether prior exposure to PARPi/PBC affects tumour response to subsequent PBC/PARPi, respectively. We conducted a retrospective, multicentric study to investigate the clinical benefit of post-PBC PARPi and vice versa in patients with a gBRCA-PV and aBC. Patients included had received (neo)adjuvant PBC and then PARPi in advanced setting (group 1), PBC followed by PARPi (group 2) or PARPi followed by PBC (group 3), both in advanced setting. We reported median progression-free survival (mPFS) and disease control rate (DCR) in each group. A total of 67 patients from six centres were included. PARPi-mPFS in advanced setting was 6.1 months in patients in group 1 (N = 12), while PARPi-DCR was 67%. In group 2 (N = 36), PARPi-mPFS was 3.4 months and PARPi-DCR was 64%. Age  6 months were associated with longer PARPi-PFS; previous PBC-PFS > 6 months and PBC in first to second line were associated with longer PARPi-DCR. Patients in group 3 (N = 21) reported a PBC-mPFS of 1.8 months and a PBC-DCR of 14%. PARPi-PFS ≥ 9 months and PARPi-FI ≥ 6 months were associated with better PBC-DCR. Sensitivity and resistance to PARPi and PBC partially overlap in patients with a gBRCA-PV and aBC. Evidence of PARPi activity emerged in patients who progressed on previous PBC.

An audit of 1632 routinely collected cervical cancer screening smears from 398 women in Germany: Results from the TeQaZ Study

There is evidence in Germany that half of the cervical cancer (CC) cases had undergone screening frequently in the decade preceding their diagnosis, signaling cytology quality issues. This study investigates routine smear assessment accuracy in Germany. Within a population-based case-control study in 9 German states, we recruited cases (women with a histologically confirmed diagnosis of CC) and population controls (women with no history of CC or hysterectomy). Two independent expert cytologists audited Pap smears taken within the 10 years preceding CC diagnosis (cases)/study entry (controls). We report the prevalence of positive results, as well as routine assessment's accuracy, as sensitivity, specificity, false-positive and false-negative rates along with 95% confidence intervals (95% CI). We also examined cases' smear history, to investigate possible false-positive recurrence. We audited 1632 smears of 392 women (18.9% cases, 81.1% controls). In the routine assessment, the overall prevalence of positive results was 4.5% (29.0% among cases). According to the expert audit, the overall prevalence of positive results was 7.7% (40.8% among cases). When restricting analyses to the 3 years preceding diagnosis/study entry, this prevalence increased to 11.9% overall (61.4% among cases). The overall sensitivity of the routine assessment was 54.9% (66.8% for cases). As cytology remains an important part of CC screening, quality issues must be urgently addressed in Germany. Shifting to objective methods such as primary high-risk HPV screening followed by triaging may help CC elimination in Germany.

Tumor Treating Fields therapy in platinum-resistant ovarian cancer: Results of the ENGOT-ov50/GOG-3029/INNOVATE-3 pivotal phase 3 randomized study

Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression. The pivotal, phase 3 ENGOT-ov50/GOG-3029/INNOVATE-3 study evaluated efficacy and safety of TTFields therapy with paclitaxel (PTX) vs PTX in patients with platinum-resistant ovarian cancer (PROC). Adult patients with PROC with ≤ 5 total prior lines of therapy (LOT), including ≤ 2 prior LOT for platinum-resistant disease, and ECOG PS of 0-1 were randomized 1:1 to receive TTFields (200 kHz; ≥ 18 h/day) + PTX (80 mg/m Between March 2019 and November 2021, 558 patients (ECOG PS 0, 60.2 %; median [range] age, 62 [22-91] years) were assigned TTFields+PTX (n = 280) or PTX (n = 278). 24.4 % had 4 + prior LOT. Median OS was 12.2 months with TTFields+PTX vs 11.9 months with PTX (HR, 1.01; 95 % CI, 0.83-1.24; p = 0.89). Grade ≥ 3 adverse events (AEs) were similar between treatment groups. Grade 1/2 device-related skin AEs occurred in 83.6 % of patients receiving TTFields therapy. In exploratory post-hoc analysis in PLD-naive patients, median OS was 16 months with TTFields+PTX (n = 113) vs 11.7 months with PTX (n = 88; nominal HR, 0.67; 95 % CI, 0.49-0.94; p = 0.03). No new safety signals were identified. TTFields+PTX did not significantly improve OS compared with PTX in the intent-to-treat population. An exploratory post-hoc analysis suggests a potentially favorable benefit-risk profile for TTFields therapy in PLD-naive patients.

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

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. 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. 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. Older patients enrolled in PAOLA-1 achieved similar PFS benefits compared with younger patients, with a similar safety profile.

Maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian cancer: Main analysis of second progression-free survival in the phase III PAOLA-1/ENGOT-ov25 trial

PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64-0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64-0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab.

Long-term cervical cancer risk following negative hrHPV-based versus negative cytology-based screening: A population-based study

Randomized trials have shown that hrHPV-testing provides better protection against cervical cancer than cytology. However, long-term assessment of programme sensitivity remains essential. In the Netherlands, hrHPV-screening replaced cytology in 2017. We estimated the long-term cervical cancer risk following negative results in hrHPV- versus cytology-based screening. Screening and histology data from the nationwide Dutch pathology databank (Palga) were used to identify 469,116 women without referral in 2014 (cytology-based) and 362,128 in 2017 (hrHPV-based), representing 4,071,690 person-years. Cervical cancer risk following non-referral, including interval cancers (IC) and those detected in the next screening round were analysed. The incidence rate per 100,000 person-years was 3.3 IC following non-referral in cytology-based versus 2.7 following non-referral in hrHPV-based screening. Including next-round cancers, these numbers increase to 5.7 and 4.5. HrHPV-test negative women had a 50 % lower IC risk compared to those with normal cytology (HR 0.5; 95 % CI: 0.3-0.8), and 60 % lower when including next-round cancers (HR 0.4; 95 % CI: 0.3-0.5). HrHPV-positive women without referral had the highest cancer risk: 24 IC per 100,000 person-years, rising to 45 when including next-round cancers. Their risk was 3.4 times higher than for women with positive primary cytology without referral (HR: 3.4; 95 % CI: 1.1-8.1 for IC and HR: 3.4; 95 % CI: 1.4-8.1 including next-round cancers). A negative hrHPV test was linked to lower long-term risk of cervical cancer than normal cytology, supporting longer screening intervals for hrHPV-negative women. However, hrHPV-positivity with negative cytology was associated with increased risk, suggesting the possible need for alternative triage guidelines.

Oncological outcomes after radical hysterectomy followed by adjuvant (chemo)radiation or no further treatment in women with cervical cancer FIGO 2018 IB2-IIA2 – A multinational population-based cohort study

The role of adjuvant treatment after radical hysterectomy for early-stage cervical cancer with intermediate-risk factors remains uncertain. In this international population-based cohort study, we investigated the potential benefit of adjuvant treatment on overall survival (OS) and recurrence-free survival (RFS). Utilizing population-based registers from Sweden, Denmark, and the Netherlands, we included women with early-stage cervical cancer FIGO 2018 stages IB2-IIA2 with tumor size >20 mm and negative lymph nodes. All women underwent radical hysterectomy followed by either adjuvant radiotherapy or chemoradiotherapy (AT) or no further treatment (NFT). Survival outcomes were analyzed to assess the impact of AT. A total of 976 women with early-stage cervical cancer, treated between 2010 and 2017, were analyzed. At five years, there were no significant differences in OS (87.7 % vs. 91.9 %) or RFS (79.8 % vs. 82.6 %) between the AT (309 women, 32 %) and NFT (667 women, 68 %) groups. Selecting women with the intermediate risk factors: tumor size > =4cm or tumor size 2-3,9 cm with the presence of lymphovascular space invasion, no significant differences in OS or RFS were observed between AT and NFT. In addition, a multivariable analysis found that tumor size and lymphovascular space invasion predicted adverse survival outcomes. In this population-based cohort study, adjuvant therapy after radical hysterectomy was not associated with a survival benefit in women with FIGO 2018 IB2-IIA2 cervical cancer. These findings corroborate earlier findings on the role of adjuvant therapy for cervical cancer with intermediate-risk factors and support de-escalation to avoid radiation harm for this patient population.

Oral contraceptive and intrauterine device use and the risk of cervical intraepithelial neoplasia grade III or worse: a population-based study

Hormonal contraceptive use has been associated with the development of cervical cancer, although inconsistent results are reported on the association with intrauterine device (IUD) use. The aim of this study was to evaluate the association between the type of contraceptive use and the development of cervical intraepithelial neoplasia grade III or worse (CIN3+). A retrospective population-based cohort study including women aged 29-44 years attending the cervical cancer screening program with normal cytology between 2005 and 2009 identified from the Dutch Pathology Registry. Subgroups with at least 5 years registered use of an oral contraceptive (OC) or IUD were compared with non-users. Risk ratios of CIN3+ were estimated per contraceptive type. 702,037 women were included with a median follow-up of 9.7 years, of which 6705 (0.96%) and 559 (0.08%) women developed CIN3 and cervical cancer, respectively. IUD use was associated with an increased risk of developing CIN3+ (risk ratio (RR) 1.51, 95% confidence interval (CI) 1.32-1.74), and OC use was associated with an increased risk of developing CIN3+ (RR 2.77, 95%CI 2.65-3.00) and cervical cancer (RR 2.06, 95%CI 1.52-2.79). The risk of developing CIN3+ and cervical cancer was higher for OC users compared with IUD users (RR 1.83, 95%CI 1.60-2.09 and RR 1.70, 95%CI 1.00-2.90, respectively). Both OC use and IUD use were associated with an increased risk of developing CIN3+. However, for women with a contraceptive wish, an IUD seems safer than an OC as the risk of developing CIN3+ and cervical cancer was higher for OC users.

Prevalence and size of pelvic sentinel lymph node metastases in endometrial cancer

To assess the association of prevalence and size of pelvic sentinel node (SLN) metastases with risk factors in endometrial cancer (EC). Between June 2014 and January 2024 consecutive women with a uterine confined EC undergoing robotic surgery including detection of pelvic SLNs at a University Hospital were included. An anatomically based algorithm utilizing Indocyanine green (ICG) as tracer was adhered to. Ultrastaging and immunohistochemistry (IHC) was applied on all SLNs. The prevalence and size of SLN metastases was assessed with regards to pre- and postoperative histologic types and myometrial invasion estimates. Of 1101 included women 72.6 % (759/1045) had low-grade, 7.6 % (79/1045) high-grade endometroid cancer and 19.8 % (207/1045) non-endometroid cancer. SLN-metastases were present in 174/1045 (16.6 %) women; 9.8 % of preoperatively presumed low-grade endometroid uterine stage 1A (6.4 % of low-grade stage 1A at final histology) and in 58.3 % and 47.8 % respectively in women with high-grade endometroid and non-endometroid uterine stage 1B cancer. In low-grade EC 45/95 (47.4 %) had only isolated tumor cells (ITC) in SLNs compared with 15/78 (19.2 %) in high-grade or non-endometroid cancer (p < .0001) CONCLUSION: This large population-based study, applying a consequent SLN-algorithm over time, provides important detailed information on the risk for, and size of, SLN metastases within risk groups of EC. The 9.8 % risk for metastases in women with presumed low grade uterine stage 1A endometrioid EC motivates detection of SLNs within this subgroup. The proportion of ITCs in SLNs was significantly lower in higher risk histologies.

Whole exome sequencing reveals diverse genomic relatedness between paired concurrent endometrial and ovarian carcinomas

Concurrent non-serous endometrial and ovarian tumours are often managed clinically as two separate primary tumours, but almost all exhibit evidence of a genomic relationship. This study investigates the extent of relatedness using whole exome sequencing, which was performed on paired non-serous endometrial and ovarian carcinomas from 27 patients with concurrent tumours in a cohort with detailed clinicopathological annotation. Four whole exome sequencing-derived parameters (mutation, mutational burden, mutational signatures and mutant allele tumour heterogeneity scores) were used to develop a novel unsupervised model for the assessment of genomic similarity to infer genomic relatedness of paired tumours. This novel model demonstrated genomic relatedness across all four parameters in all tumour pairs. Mutations in PTEN, ARID1A, CTNNB1, KMT2D and PIK3CA occurred most frequently and 24 of 27 (89 %) tumour pairs shared identical mutations in at least one of these genes, with all pairs sharing mutations in a number of other genes. Ovarian endometriosis, CTNNB1 exon 3 mutation, and progression and death from disease were present across the similarity ranking. Mismatch repair deficiency was associated with less genomically similar pairs. Although there was diversity across the cohort, the presence of genomic similarity in all paired tumours supports the hypothesis that concurrent non-serous endometrial and ovarian carcinomas are genomically related and may have arisen from a common origin.

Surgical stage in the era of molecular profiling of endometrial cancer

Molecular classification has reshaped risk stratification in endometrial cancer (EC), yet the relevance of tumor spread within molecular subgroups has not been reported so far. This multicenter retrospective study included 2056 EC patients treated between 1994 and 2018 across 11 European centers. All histopathological subtypes and FIGO stages were included. Tumors were classified into four molecular subgroups: POLE-mutated (POLEmut), mismatch repair deficient (MMRd), no specific molecular profile (NSMP), and TP53/p53 abnormal (p53abn). Clinical and pathological data were extracted from existing cohort databases. Patients were diagnosed with FIGO stage I (69 %), II (9 %), III (16 %), and IV (6 %), and classified into: POLEmut (8 %), MMRd (28 %), NSMP (44 %), and p53abn (21 %). The overall 5-year cancer-specific death (CSD) and recurrence rates were 16.5 % (95 % CI, 14.9 %-18.2 %) and 23.8 % (95 % CI, 22.0 %-25.7 %), respectively. In multivariable analysis cancer-specific survival (CSS) was independently associated with molecular subtype, FIGO stage, age, histopathological type, grade, lymphovascular space invasion, adjuvant therapy, residual tumor, and lymphadenectomy. FIGO stage was significantly associated with CSD also in within each molecular subgroup (p < 0.001). Patients with tumors confined to the uterus had the most favourable prognosis. Lymph node metastases significantly decreased CSS in POLEmut, MMRd, and p53abn groups. Within FIGO stage IV, molecular subtype was not significantly related to outcome. Surgical stage remains a strong prognostic factor across molecular subtypes and should be considered alongside molecular classification when tailoring adjuvant treatment in EC.

Increased survival in non-endometrioid endometrial cancer after introducing lymphadenectomy and tailoring radiotherapy – A population-based cohort study

To investigate recurrence and survival in non-endometrioid endometrial cancer in a population-based cohort and evaluate the implementation of the first national guidelines (NGEC) recommending pelvic and paraaortic lymphadenectomy for surgical staging and tailored adjuvant therapy. A population-based cohort study that used the Swedish quality registry for gynaecological cancer for the identification of all women with early-stage non-endometrioid endometrial cancer between 2010 and 2017. Five-year overall (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. The Cox proportional hazards regression model was used to evaluate the effect of age, FIGO stage, primary treatment and lymph node dissection on DFS. There were 228 patients included in the study cohort and 67 (29%) patients had a recurrence within five years. In the recurrence cohort, the OS was 13.4% (95%CI:7.3-24.7) compared to 88.5% (95%CI:83.4-93.9) if no recurrence occurred (log-rank p < 0.001). The DFS for the complete cohort was 61.9% (95%CI:55.7-68.7). The OS before implementation of NGEC was 57.3% (95%CI:48.2-68.1) and the DFS was 52.1% (95%CI:43.0-63.1) compared to an OS of 72.0% (95%CI:64.2-80.7; log-rank p = 0.018) and a DFS of 70.1% (95%CI:62.4-78.7; log-rank p = 0.008) after implementing NGEC. Patients received adjuvant radiotherapy in 92.7% before and 42.4% after NGEC implementation (p < 0.001). In the multivariable regression analysis, age, FIGO stage and lymph node dissection were found to be significant prognostic factors, where having a lymph node dissection decreased the risk of recurrence or death with a HR of 0.58 (95%CI:0.33-1.00). In this population-based cohort of preoperative early-stage non-endometrioid EC, a significant improvement in survival was seen after NGEC implementation where lymph node staging for tailoring adjuvant therapy was introduced and less pelvic radiotherapy was given.

Induction chemotherapy followed by chemoradiation in locally advanced cervical cancer: Quality of life outcomes of the GCIG INTERLACE trial

Induction chemotherapy (IC) added to chemoradiation (CRT) in locally advanced cervical cancer (LACC) improves survival at the expense of adverse events (AEs), 99 % with IC/CRT vs 95 % CRT alone, 59 % vs 48 % G3/4 AEs. We investigated the impact of this on quality of life (QoL). 500 women with FIGO 2008 stage IB1 node positive, IB2, II, IIIB and IVA cervical carcinoma were randomised to CRT alone or IC (6 weeks carboplatin AUC2 paclitaxel 80mg/m QoL (global health status, physical and social functioning) slightly worsened during IC and symptom experience slightly improved. Emotional functioning improved during IC. Peripheral neuropathy was slightly worse with IC/CRT. Fatigue and nausea/vomiting worsened from baseline to week 4 IC whilst pain and diarrhoea improved, consistent with reported AEs. Over the whole period, mean differences for these symptoms between the treatment groups was small and not clinically significant and resolved by 12-18 months. In all cases, mean score differences during trial treatment until 2 years post CRT showed only small differences (<5 units) not meeting the threshold for clinical relevance. IC added to CRT does not adversely impact QoL compared to CRT, either during IC, during CRT or later.

Survival of European adolescents and young adults diagnosed with cancer in 2010–2014

ENDORISK-2: A personalized Bayesian network for preoperative risk stratification in endometrial cancer, integrating molecular classification and preoperative myometrial invasion assessment

ENDORISK is a Bayesian network that can assist in preoperative risk estimation of lymph node metastasis (LNM) risk in endometrial cancer (EC) with consistent performance in external validations. To reflect state of the art care, ENDORISK was optimized by integrating molecular classification and preoperative assessment of myometrial invasion (MI). Variables for POLE, MSI, and preoperative assessment of MI, either by expert transvaginal ultrasound or pelvic magnetic resonance imaging (MRI), were added to develop ENDORISK-2. The p53 biomarker, part of the molecular classification, was already included in ENDORISK. External validation of ENDORISK-2 for LNM prediction was performed in two independent cohorts from: Brno (CZ), (n = 581) and Tübingen (DE), (n = 247). ENDORISK-2 yielded AUCs of 0·85 (95 % CI 0·80-0·90) (CZ) and 0·86 (95 % CI 0·77-0·96) (DE) for predicting LNM. In patients with low-grade histology, 83 % (CZ) and 89 % (DE) were estimated having less than 10 % risk of LNM, with false negative rates (FNR) of 4·3 % (CZ) and 2·2 % (DE). The previously defined set of minimally required variables, i.e.: preoperative tumor grade, three of the four immunohistochemical (IHC) markers, and one clinical marker, could be interchanged with the new variables, with comparable validation metrics, including AUC values of 0·79-0·87 for LNM prediction. Incorporation of molecular data and preoperative MI improved the flexibility of ENDORISK with comparable diagnostic accuracy for estimating LNM as when based on low-cost immunohistochemical biomarkers. In addition, the high diagnostic accuracy in patients with low-grade EC demonstrates how ENDORISK-2 could aid clinicians in identifying patients in whom surgical lymph node assessment may safely be omitted. These results underline its power for clinical use in both high and low resource countries.

Focal lymphovascular space invasion: Friend or foe? A large retrospective analysis on stage I endometrioid endometrial carcinomas

Literature is inconsistent with respect to clinical value of lymphovascular space invasion (LVSI) semiquantitative assessment. We aim to investigate the prognostic role of LVSI extent in stage I endometrioid endometrial carcinomas (ECs) classified by immunohistochemistry (IHC) analysis. Patients with stage I endometrioid EC undergone primary surgery were retrospectively included. Following World Health Organization definition for LVSI pathologic evaluation, subjects were divided into: LVSI-negative; LVSI-focal; LVSI-substantial. An IHC-based model was utilized to classify patients into: p53-aberrant (p53abn); mismatch repair deficient (MMRd); mismatch repair proficient with positive estrogen receptors (MMRp-ERpos); and mismatch repair proficient with negative estrogen receptors (MMRp-ERneg). 2091 subjects were included and divided into: 78.0 % (n:1631) LVSI-negative, 10.6 % (n:221) LVSI-focal, and 11.4 % (n:239) LVSI-substantial. Presence of LVSI (any extent) was associated with older age, larger tumor size and deeper myometrial infiltration. Patients with LVSI-substantial presented with higher incidence of grade 3 tumors, p53abn and MMRd status. Conversely, most LVSI-negative and LVSI-focal cases were MMRp-ERpos. At multivariable regression, LVSI-substantial was independently associated with reduced 5-year disease-free survival (DFS) and overall-survival (OS). LVSI-negative and LVSI-focal groups had similar DFS (p = 0.42) and OS (p = 0.09), whereas comparison with LVSI-substantial demonstrated significantly poorer outcomes for patients with substantial invasion. These findings were confirmed in sub-analyses of cases with grade 1-2 endometrioid and myometrial infiltration, and in the MMRp-ERpos cohort. In stage I endometrioid ECs, LVSI-focal was not associated with reduced oncologic outcomes compared to LVSI-negative. In contrast, LVSI-substantial was associated with aggressive clinicopathologic and molecular features and behaved as an independent prognostic factor for reduced survival. Our results were further confirmed in two low-risk EC settings: grade 1-2 with myometrial infiltration, and the MMRp-ERpos group.

Predicting benefit from PARP inhibitors using deep learning on H&amp;E-stained ovarian cancer slides

Ovarian cancer patients with a Homologous Recombination Deficiency (HRD) often benefit from polyadenosine diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy after response to platinum-based chemotherapy. HR status is currently analyzed via complex molecular tests. Predicting benefit from PARP inhibitors directly on histological whole slide images (WSIs) could be a fast and cheap alternative. We trained a Deep Learning (DL) model on H&E stained WSIs with "shrunken centroid" (SC) based HRD ground truth using the AGO-TR1 cohort (n = 208: 108 training, 100 test) and tested its ability to predict HRD as evaluated by the Myriad classifier and the benefit from olaparib in the PAOLA-1 cohort (n = 447) in a blinded manner. In contrast to the HRD prediction AUROC of 72 % on hold-out, our model only yielded an AUROC of 57 % external. Kaplan-Meier analysis showed that progression free survival (PFS) in the PARP inhibitor treated PAOLA-1 patients was significantly improved in the HRD positive group as defined by our model, but not in the HRD negative group. PFS improvement in PARP inhibitor-treated patients was substantially longer in our HRD positive group, hinting at a biologically meaningful prediction of benefit from PARP inhibitors. Together, our results indicate that it might be possible to generate a predictor of benefit from PARP inhibitors based on the DL-mediated analysis of WSIs. However, further studies with larger cohorts and further methodological improvements will be necessary to generate a predictor with clinically useful accuracy across independent patient cohorts.

Cytoreductive surgery for advanced epithelial ovarian cancer in the poly(ADP-ribose) polymerase inhibitors era—Is it time for a new paradigm shift? A systematic review and meta-analysis

In patients with newly diagnosed advanced high-grade serous and endometrioid epithelial ovarian cancer (EOC) first-line maintenance therapy with poly(ADP-ribose) polymerase inhibitors (PARPi) tremendously improved progression-free survival (PFS). Yet, data on the effect of PARPi in proportion to postoperative residual disease status were lacking. A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items of Systematic reviews and Meta-Analysis (PRISMA) guidelines. We searched Medline/Pubmed, Embase and Cochrane databases as well as meeting abstracts until 18th March 2023. Hazard ratios (HRs) alongside their 95% confidence intervals (CIs) for PFS were extracted from the studies. A subgroup analysis was conducted to examine the effect of PARPi according to postoperative residual disease. A total of six phase III randomised controlled trials were included and comprised SOLO 1, PAOLA 1, PRIMA, PRIME, ATHENA-MONO and VELIA. Patients who received PARPi following complete gross resection showed greatest PFS benefit. Compared with placebo, maintenance with PARPi significantly improved PFS in patients with macroscopic residual disease (pooled HR 0.55; 95% CI 0.44-0.68). This magnitude was comparable to that found in patients with complete gross resection (pooled HR 0.53; 95% CI 0.41-0.67). Patients with macroscopic residual disease benefit from PARPi at the same extent as cases with complete gross resection. However, patients with complete gross resection who were treated with PARPi show the most favourable PFS rates. Hence, the pursuit of achieving complete cytoreduction remains valid in the PARPi era.

Tolerability of the niraparib individualized starting dose in the PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib first-line maintenance therapy

To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016). The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years). Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia). The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety.

Risk of secondary myelodysplastic syndromes and acute myeloid leukaemia following poly(ADP-ribose) polymerase inhibitor treatment for advanced-stage recurrent ovarian cancer: A retrospective cohort study in England

Poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance therapies are used to treat advanced ovarian cancer in first line and recurrent settings. Because of concerns about associations between PARPi therapy and secondary cancers myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), a meta-analysis of clinical trials was conducted, reporting MDS/AML incidence of 0.73 %; however, clinical trial populations are highly selective and may not reflect incidence in the wider population. This retrospective cohort study calculated incidence of MDS/AML within five years of completing first-line chemotherapy + /- PARPi maintenance for recurrent, advanced-stage ovarian cancer. Absolute and relative risks were calculated and compared to meta-analysis. Of 11,531 included patients, 1529 received PARPi and 10,002 chemotherapy only. Absolute risk of MDS/AML was 0.3 % (n = 5/1529) for chemotherapy + PARPi maintenance therapy versus 0.1 % (n = 10/10,002) for chemotherapy alone. Relative risk was 2.97 (95 % CI 1.02, 8.68, p = 0.046) in patients receiving PARPi maintenance versus chemotherapy alone. Relative risk of MDS/AML was greater in patients treated with PARPi; however, absolute risk was low in both treatment groups and lower than in the meta-analysis of trials. This analysis suggests small increased relative risk of MDS/AML associated with PARPi maintenance versus chemotherapy only, but not increased absolute risk.

Veliparib concomitant with first-line chemotherapy and as maintenance therapy in ovarian cancer: Final overall survival and disease-related symptoms results

In the VELIA trial, the addition of veliparib to standard first-line platinum-based chemotherapy and continued as maintenance resulted in significantly longer median progression-free survival (PFS) compared with carboplatin plus paclitaxel induction therapy alone (23.5 vs 17.3 months; p < 0.001) in patients with ovarian cancer. We now report final overall survival (OS) and updated safety and disease-related symptoms (DRS) from patient-reported outcomes of the trial. This randomized, placebo-controlled, double-blind, multicenter, phase 3 study enrolled adult women with an initial diagnosis of stage III/IV high-grade serous ovarian cancer undergoing primary or interval cytoreductive surgery. Patients were randomized 1:1:1 to chemotherapy plus veliparib followed by veliparib maintenance (veliparib-throughout), chemotherapy plus veliparib followed by placebo maintenance (veliparib-combination-only), or chemotherapy plus placebo followed by placebo maintenance (placebo-throughout). PFS was the primary endpoint; OS and DRS were secondary endpoints. In the intention-to-treat population (N = 1140), median OS was 59.2 months (95 % confidence interval: 52.1, 68.2) for the veliparib-throughout group, 58.0 (50.6, 64.1) months for veliparib-combination-only, and 57.8 (52.3, 63.8) months for placebo-throughout. OS outcomes were not significantly different between arms overall or in the BRCA-deficient and homologous recombination-deficient cohorts. No new safety signals were identified during the longer follow-up period and DRS analyses indicated there was no significant additional symptom-related burden overall when veliparib was added to chemotherapy or used for maintenance. No OS or DRS benefit of addition of veliparib to platinum-based chemotherapy and continued as maintenance therapy was detected in this study, despite an observed benefit over chemotherapy alone in PFS.

Lymph node staging in grade 1–2 endometrioid ovarian carcinoma apparently confined to the ovary: Is it worth?

The aim of this study was to assess the disease-free survival (DFS) and overall survival (OS) of patients with grade 1-2 endometrioid ovarian carcinoma apparently confined to the ovary, according to surgical staging. Multicenter, retrospective, observational cohort study. Patients with endometrioid ovarian carcinoma, surgical procedure performed between May 1985 and December 2019, stage pT1 N0/N1/Nx, grade 1-2 were included. Patients were stratified according to lymphadenectomy (defined as removal of any lymph node versus no lymph node assessment), and subgroup analyses according to tumor grade were performed. Kaplan-Meier curves and cox regression analyses were used to perform survival analyses. 298 patients were included. 199 (66.8 %) patients underwent lymph node assessment. Of these, 166 (83.4 %) had unilateral/bilateral pelvic and para-aortic/caval lymphadenectomy. Eleven (5.5 %) patients of those who underwent lymph node assessment showed pathologic metastatic lymph nodes (FIGO stage IIIA1). Twenty-seven patients (9.1 %) had synchronous endometrioid endometrial cancer. After a median follow up of 45 months (95 %CI:37.5-52.5), 5-year DFS and OS of the entire cohort were 89.8 % and 96.2 %, respectively. Age ≤ 51 years (HR=0.24, 95 %CI:0.06-0.91; p = 0.036) and performance of lymphadenectomy (HR=0.25, 95 %CI: 0.07-0.82; p = 0.022) represented independent protective factors toward risk of death. Patients undergoing lymphadenectomy had better 5-year DFS and OS compared to those not receiving lymphadenectomy, 92.0 % versus 85.6 % (p = 0.016) and 97.7 % versus 92.8 % (p = 0.013), respectively. This result was confirmed after exclusion of node-positive patients. When stratifying according to tumor grade (node-positive excluded), patients with grade 2 who underwent lymphadenectomy had better 5-year DFS and OS than those without lymphadenectomy (93.0 % versus 83.1 %, p = 0.040 % and 96.5 % versus 90.6 %, p = 0.037, respectively). Staging lymphadenectomy in grade 2 endometrioid ovarian carcinoma patients was associated with improved DFS and OS. Grade 1 and grade 2 might be considered as two different entities, which could benefit from different approach in terms of surgical staging. Prospective studies, including molecular profiles are needed to confirm the survival drivers in this rare setting.

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

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. 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. (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 IAm 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.

Testing for homologous recombination repair or homologous recombination deficiency for poly (ADP-ribose) polymerase inhibitors: A current perspective

Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic instability, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indication. This review aims to summarise the biological basis, clinical validation, and clinical relevance of the available diagnostic methods and assays to assess HRD.

Association between pelvic inflammatory disease and subsequent salpingectomy on the risk for ovarian cancer

Salpingectomy is associated with a lower risk for ovarian cancer, suggesting that the fallopian tubes constitute the origin of the disease. It is unclear whether the observed effect is mediated by pelvic inflammatory disease (PID); a major indication for salpingectomy and implicated in the aetiology of ovarian cancer. In this population-based cohort study, we used nationwide registry-based data on women exposed for PID with and without subsequent salpingectomy (n = 97,912) compared with the unexposed population (n = 5,429,174) between 1973 and 2010. The effect of hormone treatment was considered in a subanalysis. Of the exposed women, 9538 women underwent salpingectomy during the study period. There was a significant association between PID and ovarian cancer (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.31-1.59), whereas an inverse association was observed for exposed women with subsequent salpingectomy (HR 0.55, 95% CI 0.36-0.83). Salpingectomy performed on other indications (n = 24,895) was associated with a lower incidence of ovarian cancer (HR 0.72, 95% CI 0.56-0.93). No effect modification was observed for the use of oral contraceptives or hormonal replacement therapy. Salpingectomy is associated with a lower incidence of ovarian cancer regardless of indication.

Can we replace adjuvant chemotherapy with surveillance for stage IA-C immature ovarian teratomas of any grade? an international multicenter analysis

The role of surveillance after surgery for stage IA-C grade 2 (G2) or grade 3 (G3) immature teratomas (ITs) is controversial with many guidelines advocating adjuvant chemotherapy. Here, we investigate the safety of surveillance in stage IA-C G1-3 ITs. Clinicopathological data were analysed on postpubertal patients with stage I pure ITs in Multicenter Italian Trials in Ovarian Cancer centres and at Charing Cross Hospital, UK, between January 1985 and January 2018. Of 108 stage I patients, 66 (61.1%), 3 (2.8%) and 39 (36.1%) were International Federation of Gynecology and Obstetrics IA, IB, IC, respectively, with 31 (28.7%), 41 (38%) and 36 (33.3%) having grade 1 (G1), 2 and 3 disease, respectively. After surgery, 27 patients (25%) had adjuvant chemotherapy and 81 (75%) surveillance. There was no significant increase in the risk of malignant (G2-3 IT) relapse (9/81 vs 2/27; p = 0.72) or in disease-free survival (DFS) or overall survival in the surveillance vs chemotherapy groups. The median time to relapse was 17.8 months (range: 3-47) with no significant difference between surveillance or chemotherapy groups. The median follow-up was 64.3 months (Interquartile range (IQR) 22.2-101.7). Chemotherapy induced cures in all except for one patient who did not follow the surveillance protocol due to pregnancy and died of disease. Univariate and multivariate analyses revealed that only tumour grade (hazard ratio [HR] = 3.11; p = 0.02) and complete surgical staging (HR = 0.2; p = 0.01) were independent prognostic factors for decreased DFS. The present study suggests that in the adult setting careful surveillance appears to be an acceptable alternative to adjuvant chemotherapy for stage IA-C ITs of any grade, properly staged and with negative postoperative tumour markers.

Secondary haematologic malignancies in women with ovarian cancer receiving poly-ADP ribose polymerase inhibitor therapy

Copy number alterations in stage I epithelial ovarian cancer highlight three genomic patterns associated with prognosis

Stage I epithelial ovarian cancer (EOC) encompasses five histologically different subtypes of tumors confined to the ovaries with a generally favorable prognosis. Despite the intrinsic heterogeneity, all stage I EOCs are treated with complete resection and adjuvant therapy in most of the cases. Owing to the lack of robust prognostic markers, this often leads to overtreatment. Therefore, a better molecular characterization of stage I EOCs could improve the assessment of the risk of relapse and the refinement of optimal treatment options. 205 stage I EOCs tumor biopsies with a median follow-up of eight years were gathered from two independent Italian tumor tissue collections, and the genome distribution of somatic copy number alterations (SCNAs) was investigated by shallow whole genome sequencing (sWGS) approach. Despite the variability in SCNAs distribution both across and within the histotypes, we were able to define three common genomic instability patterns, namely stable, unstable, and highly unstable. These patterns were based on the percentage of the genome affected by SCNAs and on their length. The genomic instability pattern was strongly predictive of patients' prognosis also with multivariate models including currently used clinico-pathological variables. The results obtained in this study support the idea that novel molecular markers, in this case genomic instability patterns, can anticipate the behavior of stage I EOC regardless of tumor subtype and provide valuable prognostic information. Thus, it might be propitious to extend the study of these genomic instability patterns to improve rational management of this disease.

Pooled Safety Analysis of Single-Agent Lurbinectedin in Patients With Advanced Solid Tumours

Lurbinectedin was approved by FDA and other health regulatory agencies for treating adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Safety profile at approved dose (3.2 mg/m Data were pooled from 554 patients: 335 from all nine tumour-specific cohorts of the phase II basket trial and 219 from a randomised phase III trial (CORAIL) in platinum-resistant ovarian cancer. Events and laboratory abnormalities were graded using NCI-CTCAE v.4. Most common tumours were ovarian (n = 219, 40%), SCLC (n = 105, 19%) and endometrial (n = 73, 13%). Transient haematological laboratory abnormalities were the most frequent grade 3 or more events: neutropenia (41%), leukopenia (30%), anaemia (17%) and thrombocytopenia (10%). Most common treatment-emergent non-haematological events (any grade) were transient transaminase increases (alanine aminotransferase [66%], aspartate aminotransferase [53%]), fatigue (63%), nausea (57%), constipation (32%), vomiting (30%) and decreased appetite (25%). Dose reductions were mostly due to haematological toxicities, but most patients (79%) remained on full lurbinectedin dose. Serious events mostly consisted of haematological disorders. Eighteen treatment discontinuations (3%) and seven deaths (1%) were due to treatment-related events. This analysis confirms a manageable safety profile for lurbinectedin in patients with advanced solid tumours. Findings are consistent with those reported in patients with relapsed SCLC, Ewing sarcoma, germline BRCA1/2 metastatic breast cancer, neuroendocrine tumours and ovarian cancer.

Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer: The SENTIX trial

SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multicentre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultrastaging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. ClinicalTrials.gov (NCT02494063). We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases.

Response to the letter commenting on ʻEffect of organised cervical cancer screening on cervical cancer mortality in Europe: a systematic reviewʼ

Survival of patients with early-stage cervical cancer after abdominal or laparoscopic radical hysterectomy: a nationwide cohort study and literature review

Recently, the safety of laparoscopic radical hysterectomy (LRH) has been called into question in early-stage cervical cancer. This study aimed to evaluate overall survival (OS) and disease-free survival (DFS) in patients treated with abdominal radical hysterectomy (ARH) and LRH for early-stage cervical cancer and to provide a literature review. Patients diagnosed between 2010 and 2017 with International Federation of Gynaecology and Obstetrics (2009) stage IA2 with lymphovascular space invasion, IB1 and IIA1, were identified from the Netherlands Cancer Registry. Cox regression with propensity score, based on inverse probability treatment weighting, was applied to examine the effect of surgical approach on 5-year survival and calculate hazard ratios (HR) and 95% confidence intervals (CIs). Literature review included observational studies with (i) analysis on tumours ≤4 cm (ii) median follow-up ≥30 months (iii) ≥5 events per predictor parameter in multivariable analysis or a propensity score. Of the 1109 patients, LRH was performed in 33%. Higher mortality (9.4% vs. 4.6%) and recurrence (13.1% vs. 7.3%) were observed in ARH than LRH. However, adjusted analyses showed similar DFS (89.4% vs. 90.2%), HR 0.92 [95% CI: 0.52-1.60]) and OS (95.2% vs. 95.5%), HR 0.94 [95% CI: 0.43-2.04]). Analyses on tumour size (<2/≥2 cm) also gave similar survival rates. Review of nine studies showed no distinct advantage of ARH, especially in tumours <2 cm. After adjustment, our retrospective study showed equal oncological outcomes between ARH and LRH for early-stage cervical cancer - also in tumours <2 cm. This is in correspondence with results from our literature review.

Comment on ‘Effect of organised cervical cancer screening on cervical cancer mortality in Europe: a systematic review’

No improvement in survival of older women with cervical cancer—A nationwide study

This study aims to report trends in primary treatment and survival in cervical cancer (CC) to identify opportunities to improve clinical practice and disease outcome. Patients diagnosed with CC between 1989 and 2018 were identified from the Netherlands Cancer Registry (N = 21,644). Trends in primary treatment and 5-year relative survival were analysed with the Cochran-Armitage trend test and multivariable Poisson regression, respectively. In early CC, surgery remains the preferred treatment for ages 15-74. Overall, it was applied more often in younger than in older patients (92% in 15-44; 64% in 65-74). For 75+, surgery use was stable over time (38%-41%, p=0.368), while administration of radiotherapy decreased (57%-29%, p < 0.001). In locally advanced CC, chemoradiation use increased over time (5%-65%, p < 0.001). It was applied least often for 75+, in which radiotherapy remains most common (54% in 2014-2018). In metastatic CC, chemotherapy use increased over time (11%-28%, p < 0.001), but varied across age groups (6%-40% in 2014-2018). In patients treated with primary chemoradiation, regardless of stage, brachytherapy use increased over time (p ≤ 0.001). Full cohort 5-year survival increased from 68% to 74% (relative excess risk 0.55; 95% confidence interval [0.50-0.62]). Increases were most significant in locally advanced CC (38%-60%; 0.55 [0.47-0.65]). Survival remained stable in 75+ (38%-34%; 0.82 [0.66-1.02]). Relative survival for cervical cancer increased over the last three decades. The proportion of older patients receiving preferred treatment lags behind. Consequently, survival did not improve in the oldest patients.

Survival after a nationwide adoption of robotic minimally invasive surgery for early-stage cervical cancer – A population-based study

Lately, the safety of minimally invasive surgery (MIS) in the treatment of cervical cancer (CC) has been questioned. This study aimed to evaluate the risk of recurrence and survival after a nationwide adoption of robotic MIS for the treatment of early-stage CC in Denmark. Population-based data on all Danish women with early-stage CC, who underwent radical hysterectomy January 1st 2005-June 30th 2017 were retrieved from the Danish Gynecologic Cancer Database and enriched with follow-up data on recurrence, death and cause of death. The cohort was divided into two groups according to the year of robotic MIS introduction at each cancer centre. Chi-squared or Fischer test, the Kaplan Meier method and multivariate Cox regression were used for comparison between groups. One thousand one hundred twenty-five patients with CC were included; 530 underwent surgery before (group 1) and 595 underwent surgery after (group 2) the introduction of robotic MIS. The 5-year rate of recurrence was low: 8.2% and 6.3% (p = 0.55) in group 1 and 2, respectively. In adjusted analyses, this corresponded to a five-year disease-free survival, hazard ratio (HR) 1.23 [95% confidence interval (CI) 0.79-1.93]. No difference in site of recurrence (P = 0.19) was observed. The cumulative cancer-specific survival was 94.1% and 95.9% (P = 0.10) in group 1 and 2, respectively, corresponding to a HR 0.60 [95% CI 0.32-1.11] in adjusted analyses. In this population-based cohort study, the Danish nationwide adoption of robotic MIS for early-stage CC was not associated with increased risk of recurrence or reduction in survival outcomes.

Effect of organised cervical cancer screening on cervical cancer mortality in Europe: a systematic review

Organised cervical cancer (CC) screening programmes are delivered in many different ways across the European Union and its regions. Our aim was to systematically review the impact of these programs on CC mortality. Two independent reviewers identified all eligible studies investigating the effect of organised screening on CC mortality in Europe. Six databases including Embase, Medline and Web of Science were searched (March 2018) with predefined inclusion and exclusion criteria. Only original studies with at least five years of follow-up were considered. Validated tools were used to assess the risk of bias of the included studies. Ten observational studies were included: seven cohort and three case-control studies. No randomised controlled trials were found, and there were no eligible studies from the eastern and southern part of Europe. Among the eligible studies, seven were conducted in the twentieth century; they scored lower on the risk of bias assessment. CC mortality reduction for women attending organised screening vs. non-attenders ranged from 41% to 92% in seven studies. Reductions were similar in Western (45-92%) and Northern (41-87%) Europe and were higher in the three more recent studies (66-92%). For invited vs. non-invited women, this reduction ranged from 17% to 79% in five studies. Although data were lacking in Southern and Eastern Europe and the effect size varied between countries and studies, this systematic review provides evidence that organised CC screening reduces CC mortality in those parts of Europe where CC screening was implemented and monitored.

Cervical cancer mortality in young adult European women

The process of social, political and economic transformation, which took place in Central and Eastern Europe in the early 90's, has affected many spheres of Europeans' lives, including health-associated issues. These changes also had an impact on mortality rates due to cervical cancer (CC). Therefore, the aim of this study was to analyse CC mortality trends in Europe after 1990. Data on death due to CC, uterine cancers and unspecified uterine cancers, in women aged 20-44, were taken from the WHO Mortality Database. Trends in European countries between 1990 and 2017 were assessed using the Joinpoint Regression Program. Most of the countries experienced a decrease in CC mortality. Although the lowest rates were observed in EU15 Member States, the highest decreases were observed in Central and Eastern Europe. However, there are still differences in mortality in these countries. There are also a few countries like Belarus, Latvia and Ukraine, which experienced an increase in mortality. The range of mortality across Europe in 2017 was between 0.6 and 5.2/100,000 women. It is essential to introduce well-organised screening programmes for early detection of CC with coverage of a correspondingly high percentage of the population, particularly in East-Central Europe, as well as to introduce high-coverage HPV vaccination in all European countries.

Value of surgical lymph node assessment for patients with vulvar melanoma

Investigate the utilization and outcomes of lymphadenectomy/ sampling (LND) for patients with vulvar melanoma. Patients diagnosed between 2004-2015 with vulvar melanoma with known depth of tumor invasion and no distant metastases were identified in the National Cancer Database. Based on pathology report patients who underwent inguinal lymph node sampling/dissection were identified. Clinico-pathological characteristics and overall survival were compared between the two groups. A total of 1286 patients were identified; 62.8 % (n = 808) underwent lymphadenectomy/ sampling. Patients who underwent lymphadenectomy/ sampling were younger (median 66 vs 76 years, p < 0.001), more likely to have private insurance (42.9 % vs 27.8 %, p < 0.001), present with tumor ulceration (65.9 % vs 58.6 %, p = 0.01), have deeper tumor invasion (p < 0.001) and undergo radical vulvectomy (26.4 % vs 12.1 %, p < 0.001). Patients who underwent lymphadenectomy/ sampling had better overall survival compared to those who did not (median 49.08 vs 35.91 months respectively, p < 0.001). After controlling for patient age, race, insurance status, comorbidities, presence of tumor ulceration and Breslow depth of invasion performance of lymphadenectomy/ sampling was associated with better survival (hazard ratio: 0.78, 95 % confidence intervals: 0.67, 0.92). For patients with vulvar melanoma with at least 1 mm invasion lymphadenectomy/ sampling was associated with better overall survival likely secondary to stage migration.

Real-life efficacy and safety of cemiplimab in advanced cervical cancer from a nominal use program in Italy: The MITO 44 study

cemiplimab is an immunoglobulin G4 monoclonal antibody targeting the programmed cell death-1 receptor. A nominal use program is available in Italy in advanced cervical cancer (CC) patients treated with platinum based chemotherapy based on the results of EMPOWER-Cervical 1/GOG-3016/ENGOTcx9 trial. This real-world, retrospective cohort, multicenter study aimed at describing clinical outcomes of patients with advanced CC treated with cemiplimab in Italy. The primary objective of the study was to assess the feasibility and the replicability of the initial results in a real world setting of cemiplimab nominal use. The primary endpoint of our analysis was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and safety data. From March 2022 to December 2023, 135 patients were treated in 12 Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) Centers. Forty-two percent of patients had one or more comorbidities, hypertension being the most common (23.4%). Median PFS was 4.0 months (range 3.0-6.0) and median OS was 12.0 months (12.0- NR) with no differences according to PD-L1 status. Complete response (CR) or no evidence of disease (NED) were observed in 8.6%; partial response (PR) in 21.1%, stable disease (SD) in 14.8% and progression was recorded in 44.5% of patients. Most common drug related adverse events (AEs) were anemia (39.1%) and fatigue (27.8%). Immune related AEs occurred in 18.0%. This study confirms the feasibility and the replicability of the cemiplimab nominal use in advanced CC, in a real-world practice in Italy.

Low-grade endometrioid endometrial cancer with adnexal only metastasis: Evaluation of de-escalation of adjuvant therapy

To assess survival outcomes of stage IA3 endometrial cancer and the association of adjuvant therapy and survival. The National Cancer Database was retrospectively queried to examine 594 and 1455 patients with stage IA3 and IIIA1 endometrial cancer, respectively, from 2010-2015. Overall survival (OS) was examined based on adjuvant therapy: multimodal combination chemotherapy and external beam radiotherapy, chemotherapy alone, external beam radiotherapy alone, and none. For stage IA3 disease, 109 (18.4%) patients did not receive adjuvant therapy. The 5-year OS rates for the no adjuvant therapy group and the combination group were 86.3% and 91.4%, respectively (adjusted-hazard ratio [aHR] 1.23, 95% confidence interval [CI] 0.70-2.18). This survival association was consistent when compared to chemotherapy alone (5-year OS rates 86.3% vs 86.3%, aHR 1.11, 95%CI 0.67-1.83). The results were similar among those who underwent nodal evaluation (5-year OS rates, 92.6%, 86.6%, and 89.4% for combination therapy, chemotherapy alone, and no adjuvant therapy), including grade 1 lesions (96.2%, 89.4%, and 100%, respectively). In grade 2 lesions, 5-year OR rates was modestly lower for no adjuvant therapy than combination therapy (89.4%, 84.0%, and 82.7% for combination, chemotherapy alone, and no adjuvant therapy, P = 0.03). For stage IIIA1 disease, omission of adjuvant therapy was associated with decreased OS compared to combination therapy (43.2% vs 73.1%, aHR 1.65, 95%CI 1.30-2.11) or chemotherapy alone (43.2% vs 67.1%, aHR 1.62, 95%CI 1.32-1.99). The results of this investigation suggest that survival effects of adjuvant therapy differ for stage IA3 and IIIA1 diseases. Patients with stage IA3 disease have overall good prognosis regardless of adjuvant therapy particularly grade 1 lesions, partly supporting the FIGO committee suggestion for adjuvant therapy de-escalation in stage IA3 endometrial cancer.

A selective anatomically based lymph node sampling can replace a side specific pelvic lymphadenectomy in endometrial cancer with failed sentinel node mapping

To evaluate the locations of metastatic pelvic sentinel nodes (SLN) and the proportion of SLNs outside and within defined typical anatomical positions along the upper paracervical lymphatic pathway (UPP). Consecutive women with endometrial cancer (EC) of all risk groups underwent pelvic SLN-detection using cervically injected indocyanine green (ICG). A strict anatomically based algorithm and definitions of SLNs was adhered to. The positions of ICG-defined SLNs were intraoperatively depicted on an anatomical chart. All SLNs were examined using ultrastaging and immunohistochemistry. The proximal third of the obturator fossa and the interiliac area were defined as typical positions. The parauterine lymphovascular tissue (PULT) was separately removed. The proportions of metastatic SLNs, overall and isolated, typically, and atypically positioned were analyzed per woman. A median of two (range 1-12) SLN metastases along the UPP including the PULT were found in 162 women. 41 of 162 women (25.3 %) had isolated metastases in the obturator fossa harboring 49.1 % of all SLN metastases. Three women (1,9 %) had isolated PULT metastases. SLN metastases outside typical positions were identified in 28/162 women (17.3 %); isolated metastases were seen in seven women (4.3 %), so 95.7 % of pelvic node positive women had at least one metastatic SLN located at a typical position. A selective removal of lymph nodes at typical proximal obturator and interiliac positions and the PULT can replace a full side specific pelvic LND when SLN mapping is unsuccessful. The obturator fossa is the predominant location for metastatic disease.

Impact of molecular profile on prognosis and relapse pattern in low and intermediate risk endometrial cancer

The role of molecular classification in patients with low/intermediate risk endometrial cancer (EC) is uncertain. Higher precision in diagnostics will inform the unsettled debate on optimal adjuvant treatment. We aimed to determine the association of molecular profiling with patterns of relapse and survival. This retrospective cohort study included patients referred to The Norwegian Radium Hospital, Oslo University Hospital from 2006-2017. Patients with low/intermediate risk EC were molecularly classified as pathogenic polymerase epsilon (POLE)-mutated, mismatch repair deficient (MMRd), p53 abnormal, or no specific molecular profile (NSMP). The main outcomes were time to recurrence (TTR) and cancer-specific survival (CSS). Of 626 patients, 610 could be molecularly classified. Fifty-seven patients (9%) had POLE-mutated tumors, 202 (33%) had MMRd tumors, 34 (6%) had p53 abnormal tumors and 317 (52%) had NSMP tumors. After median follow-up time of 8.9 years, there was a statistically significant difference in TTR and CSS by molecular groups. Patients with p53 abnormal tumors had poor prognosis, with 10 of the 12 patients with relapse presenting with para-aortic/distant metastases. Patients with POLE mutations had excellent prognosis. In the NSMP group, L1CAM expression was associated with shorter CSS but not TTR. The differences in outcome by molecular groups are driven by differences in relapse frequency and -patterns and demand a higher precision in diagnostics, also in patients with low/intermediate risk EC. Tailored adjuvant treatment strategies need to consider systemic treatment for patients with p53 abnormal tumors and de-escalated treatment for patients with POLE mutated tumors.

Immunotherapy and PARP inhibitors as first-line treatment in endometrial cancer: A systematic review and network meta-analysis

Several first-line therapeutic strategies have been evaluated alongside platinum-based chemotherapy in advanced or recurrent endometrial cancer (a/rEC). However, the optimal approach remains unclear. A systematic review was conducted to identify randomized control trials (RCTs) that evaluate first-line therapeutic strategies in a/rEC involving immune checkpoint inhibitors (ICI) and PARP inhibitors (PARPi). A network meta-analysis with a frequentist framework using random-effects and an extracted individual patient data meta-analysis were performed. The primary endpoint was progression-free survival (PFS) by MMR status, p53 status within the MMRp population and PD-L1 status. A total of 3210 patients with EC were included. In the MMRp population, the combination (ICI and PARPi) showed a not statistically significant PFS benefit compared with each agent alone. In MMRp p53-abnormal patients (n = 590), combining PARPi and ICI statistically improved PFS compared to ICI alone (HR=0.47, 95 %CI 0.40-0.94) with a numerically better outcome compared to PARPi alone (HR=0.63, 95 %CI 0.26-1.57). No benefit from PARPi was observed in the p53 wild-type MMRp population. PD-L1-positivity (n = 1121) appears to predict more benefit from the addition of ICI and PARPi, with a larger benefit of combination therapy. In the MMRd population (n = 769), the best outcomes were observed with ICI alone, with no additional benefit of PARPi. Grade 3 or greater treatment-related adverse events were seen in 75.1 % patients treated with the combination. The addition of the combination of ICI and PARPi to platinum-based chemotherapy provides greatest benefit to p53-abnormal MMRp patients. PD-L1 is a potentially useful biomarker with PD-L1-positive tumors more likely to respond to ICI. Implementation of biomarkers is crucial to redefine the treatment paradigm in a/rEC.

FIGO 2023 staging for endometrial cancer, when, if it is not now?

Incorporation of pathological and (not mandatory) molecular features into the new FIGO 2023 staging system has generated some controversy. Several validations have been published recently that demonstrated the higher prognostic precision of FIGO 2023 compared to the previous FIGO 2009 scheme. In the present article, the authors want to respond to some concerns that were raised by some pathologists and clinicians.

Malignant peritoneal cytology in endometrial cancer