ESMO Open

Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies

Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM-AIRO-AISP-ANISC-AURO-Fondazione AIOM-SIAPEC/IAP-SIBioC-SICO-SIF-SIGE-SIGU-SIU-SIURO-UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.

Targeting the immune microenvironment in ovarian cancer therapy—mission impossible?

Role of surgery and hyperthermic intraperitoneal chemotherapy in ovarian cancer

Ovarian cancer is one of the deadliest gynaecological malignancies and tends to be diagnosed at an advanced stage. Similar to many malignancies, surgery plays a critical role in many aspects of ovarian cancer management. Hyperthermic intraperitoneal chemotherapy (HIPEC) involves the induction of hyperthermia and delivery of intraperitoneal chemotherapy directly into the peritoneal cavity. Combined with cytoreductive surgery, HIPEC is an emerging treatment modality for ovarian cancer. Ovarian cancer survival outcomes can be improved by treatment with surgery and HIPEC in selected patients. Thus, this study aimed to review the current role of surgery and HIPEC in epithelial ovarian cancer. Evidence from the monumental and recent literature will be introduced.

Long-term outcomes of PARP inhibitors in ovarian cancer: survival, adverse events, and post-progression insights

Poly-ADP-ribose polymerase inhibitors (PARPis) have revolutionized the management of BRCA-mutated (BRCA

Examining policy cohesion for cervical cancer worldwide: analysis of WHO country reports

Cervical cancer is controllable through appropriate interventions such as vaccination, screening, treatment, early diagnosis and palliative care. The greatest burden of cervical cancer lies in low-income countries (LIC) where most of these services are missing or developed asymmetrically. Indeed, it is important to have not just an expansion, but a symmetric and concordant development of each service. Therefore, policies of countries should be aligned to provide concordant services and achieve the best outcomes with available resources. This is called 'policy cohesion' and for the first time in literature we will analyse cervical cancer policy coherence in all the 194 WHO member states. The study is based on the 2017 WHO Non-Communicable Disease Country Capacity Surveys (NCD CCS). Although the survey covers multiple non-communicable diseases, in this report we will only discuss those results pertaining to cervical cancer, analysing the cervical cancer policy cohesion of 194 WHO member states, divided by WHO region and World Bank income group. Human papilloma virus vaccination exists in 53% of countries. 76% of countries offer cervical screening: among these countries, treatment, early diagnosis guidelines and palliative care are missing in 13%, 13% and 40%, respectively. In the African region, this discord is even more profound: 32%, 17% and 60%, respectively. Especially in those settings where resources are limited, early detection guidelines, treatment and palliative care should be implemented along with secondary prevention strategies. Symmetric development of concordant cervical cancer services maximises cervical cancer control efficacy.

Impact of health-related quality of life (HRQoL) on short-term mortality in patients with recurrent ovarian, fallopian or peritoneal carcinoma (the NOGGO-AGO QoL Prognosis-Score-Study): results of a meta-analysis in 2209 patients

Recurrent ovarian cancer is an incurable disease with variable but poor prognosis. Health-related quality of life (HRQoL) is a patient-reported outcome measure generally applied to measure effects of therapies. Our aim was the development and validation of a risk score for the prediction of short-term mortality using the combination of sociodemographic and clinical factors and HRQoL. For exploratory and validation analysis, the North-Eastern German Society of Gynecological Oncology (NOGGO) and Working Group Gynecological Oncology (AGO) study databases were screened for trials. Only trials which obtained defined HRQoL measurements were included in the final analysis. Multivariable logistic regression analyses were used to identify risk factors and their weighting for the risk score. Modulation with cubic regression analyses revealed median survival and short-term mortality defined as 1-year mortality for each value. For exploration, 974 patients from three clinical studies of the NOGGO and for validation, 1235 patients from several clinical studies of the AGO were eligible. The risk score included platinum-free interval, performance status, age, global QoL and nausea/vomiting. Receiver operating characteristic analysis showed a good predictive value with an area under the curve of 0.81 for model 1 in the exploration and 0.74 in the validation. Short-term mortality in model 1 was 8.2%, 23.5% and 58.4% in the exploration sample, and 19.7%, 38.1% and 63.4% in the validation sample for patients under low, medium and high risk, respectively. This risk score discriminates well between recurrent ovarian cancer patients under low, medium and high risk of short-term mortality. It may help to identify a risk group under high risk for short-term mortality that can be used for randomization in clinical trials and may support decision making for palliative chemotherapy.

Cediranib in addition to chemotherapy for women with relapsed platinum-sensitive ovarian cancer (ICON6): overall survival results of a phase III randomised trial

Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of 'platinum-sensitive' ovarian cancer and has been shown to improve progression-free survival (PFS). ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here. After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch-Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: -0.09 to 9.74 months). Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken.

MOVIE: a phase I, open-label, multicenter study to evaluate the safety and tolerability of metronomic vinorelbine combined with durvalumab plus tremelimumab in patients with advanced solid tumors

Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) agents have only moderate antitumor activity in some advanced solid tumors (AST), including breast cancer (BC), prostate cancer (PC), cervical cancer (CC), and head and neck cancer (HNC). Combining anti-PD-L1 with anti-cytotoxic T-lymphocyte-associated protein (CTLA) and chemotherapy may significantly improve efficacy. MOVIE is a multicohort phase I/II study examining the combination of anti-PD-L1 durvalumab (Durv; 1500 mg IV Q4W) plus anti-CTLA tremelimumab (Trem; 75 mg IV Q4W) with metronomic vinorelbine (MVino; 20-40 mg orally daily) in various AST resistant to conventional therapies. The primary objective of the phase I part was to determine the maximum tolerated dose (MTD) and recommended dose for phase II (RP2D). Among the 14 patients enrolled during phase I, including 13 women and 1 man, 9 had BC, 1 PC, 2 CC, and 2 miscellaneous cancers with high mutational loads. Median age was 53 years. A total of 12 patients were assessable for the dose-escalation part in which only one dose-limiting toxicity (DLT) was observed [one neutropenia without fever, grade (G) 4]. Two (14.3%), four (28.6%), and four (28.6%) patients had G ≥3 adverse events (AEs) related to MVino, Durv, and Trem, respectively. Treatment-related events included mostly clinical AEs with asthenia (eight G2; three G3), colitis (one G2, one G3), diarrhea (one G3), nausea (two G2), dry skin (two G2), maculopapular rash (one G3), and hyperthyroidism (three G2). No toxic death was reported. Preliminary data showed one patient (CC) who presented a complete response and four patients with stable disease (SD). MTD was not reached and dose level 2 (MVino 40 mg, Durv 1500 mg, Trem 75 mg) was selected as RP2D. The safety profile of the combination was manageable and consistent with previous reports of Trem + Durv or MVino. Phase II is currently ongoing in BC, PC, CC, HNC, and miscellaneous cohorts.

Recurrent or primary metastatic cervical cancer: current and future treatments

Despite screening programs for early detection and the approval of human papillomavirus vaccines, around 6% of women with cervical cancer (CC) are discovered with primary metastatic disease. Moreover, one-third of the patients receiving chemoradiation followed by brachytherapy for locally advanced disease will have a recurrence. At the end, the vast majority of recurrent or metastatic CC not amenable to locoregional treatments are considered incurable disease with very poor prognosis. Historically, cisplatin monotherapy, then a combination of cisplatin and paclitaxel were considered the standard of care. Ten years ago, the addition of bevacizumab to chemotherapy demonstrated favorable data in terms of response rate and overall survival. Even with this improvement, novel therapies are needed for the treatment of recurrent CC in first as well as later lines. In the last decades, a better understanding of the interactions between human papillomavirus infection and the host immune system response has focused interest on the use of immunotherapeutic drugs in CC patients. Indeed, immune checkpoint inhibitors (pembrolizumab, cemiplimab, and others) have recently emerged as novel therapeutic pillars that could provide durable responses with impact on overall survival in patients in the primary (in addition to chemotherapy) or recurrent (monotherapy) settings. Tisotumab vedotin, an antibody-drug conjugate targeting the tissue factor, is another emerging drug. Several trials in monotherapy or in combination with immunotherapy, chemotherapy, or bevacizumab showed very promising results. There is a high need for more potent biomarkers to better accurately determine which patients would receive the greatest benefit from all these aforementioned drugs, but also to identify patients with specific molecular characteristics that could benefit from other targeted therapies. The Cancer Genome Atlas Research Network identified several genes significantly mutated, potentially targetable. These molecular data have highlighted the molecular heterogeneity of CC.

Germline BRCA pathogenic variants in patients with ovarian cancer and post-poly (ADP-ribose) polymerase inhibitor myeloid neoplasms

Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline BRCA pathogenic variant (gBRCA-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to gBRCA-PV status. We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known gBRCA-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in gBRCA-PV carriers and non-carriers. A total of 166 patients were included: 95 (57%) had a gBRCA-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between gBRCA-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; P = 0.16) and, in particular, of MDSs-pCT (9% versus 1%; P = 0.04) was observed among gBRCA-PV carriers. The presence of a gBRCA-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease.

Global trends in adolescent and young adult female cancer burden, 1990-2021: insights from the Global Burden of Disease study

Homologous recombination repair status in advanced endometrial cancer: an exploratory biomarker analysis from the randomized, phase II MITOEND 3 trial

Poly (ADP-ribose) polymerase (PARP) inhibitor use in endometrial cancer (EC) requires predictive biomarkers, currently lacking in clinical practice. This study assessed the incidence of homologous recombination deficiency (HRD) using genomic loss of heterozygosity (gLOH) and a machine learning-based HRD scar signature (HRDsig). MITO END 3 was a multicenter, phase II trial of advanced EC patients randomly assigned to receive platinum-based chemotherapy ± avelumab. Of 125 patients, 102 had tumor samples available for sequencing with FoundationOne®CDx. HRD was evaluated using gLOH (cut-off ≥16%, based on ARIEL3) and HRDsig (cut-off ≥0.7, validated pan-cancer). Among 102 evaluable samples, 5 were HRDsig-positive, 90 HRDsig-negative, and 7 HRDsig unknown. gLOH was high in 10 cases, low in 53, and not assessable in 39. Most HRDsig-positive (4/5) and gLOH-high (8/10) tumors were of endometrioid histology and carried TP53 mutations. None were microsatellite instability-high. A small subgroup of advanced EC patients shows HRD positivity by gLOH or HRDsig, potentially identifying those most likely to benefit from PARP inhibitors. These tumors are typically endometrioid with TP53 mutations.

PARPi and myeloid neoplasms; the Italian MITO-MaNGO experience based on a multicentric survey

The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer has raised increasing concerns about PARPi-related myeloid neoplasms (PrMN). Therapy-related neoplasms, including myelodysplastic syndromes and acute myeloid leukemia, account for 10%-20% of cases. Expanding PARPi indications, longer survival, and aging populations may contribute to rising PrMN incidence. Randomized clinical trials and real-world analyses show a significant risk increase, but data on individual PARPi, treatment lines, and prior therapies are limited. We evaluated PrMN incidence across 17 Italian centers using a 71-item survey distributed to MITO (Multicenter Italian Trials on Ovarian cancer) and MaNGO (Mario Negri Gynecologic Oncology) centers, focusing on patients treated with PARPi outside clinical trials. Of 2320 patients (1254 BRCA-mutated), 56 (2.55%) developed MN: 35 myelodysplastic syndromes and 21 acute myeloid leukemia (2 patients had both, counted once). Among them, 31 had BRCA mutations (2.5%). Incidence by drug was: olaparib 2.5%, niraparib 2%, and rucaparib 3.4%. An unclear correlation emerged between treatment duration and PrMN risk, with a median onset of 18.9 months. Risk increased with additional therapy lines: 0.52% (first), 4.2% (second), 1.8% (third), 10.8% (fourth), and 12.2% (>fourth lines). Among PrMN cases, 4 achieved remission, 4 had partial responses, 8 progressed, and 37 died. While this survey is meant as hypotheses-generating, PrMN represent a rare but clinically relevant complication, particularly uncommon when PARPi are administered as first-line therapy. Their occurrence does not appear to be associated with the specific PARPi used or with BRCA mutation status. Early detection, monitoring, and identification of predictive factors are crucial as ovarian cancer outcomes improve and treatment exposure increases.

Early detection, clinicopathological subtyping, and prognosis prediction for endometrial cancer patients using fragmentomics liquid biopsy assay

Endometrial cancer (EC) is among the most prevalent gynecological malignancies worldwide. This study explores the use of cell-free DNA (cfDNA) fragmentomics to develop a non-invasive liquid biopsy assay, aiming to improve early detection, subtyping, and prognostication of EC, thereby enhancing therapeutic outcomes and reducing associated mortality. A cohort of 120 patients with diagnosed EC and 120 healthy volunteers was used to develop a novel non-invasive liquid biopsy assay for EC. Five distinct fragmentomic features were analyzed from preoperative plasma samples using low-pass whole-genome sequencing. Ensemble models were created by integrating base models that utilized four different machine learning algorithms for early cancer detection, clinicopathological subtyping, and prediction of recurrence-free survival. An independent test cohort of 62 EC patients and 62 healthy controls was used to assess the final ensemble model's performance. The liquid biopsy assay demonstrated high efficacy in early EC detection, achieving an area under the curve (AUC) of 0.96, with 75.8% sensitivity and 96.8% specificity in the independent test cohort. Consistent sensitivities were observed across EC stages I-IV at 74.4%, 85.7%, 75%, and 75%, respectively. The assay moderately predicted clinicopathological features including stage (AUC = 0.72), histological subtypes (AUC = 0.73), and microsatellite instability status (AUC = 0.77). The model also effectively predicted recurrence-free survival, identifying high-risk patients [hazard ratio (HR) 8.6, P < 0.001]. Additionally, similarity network fusion stratified patients into high- and low-risk clusters, with high-risk individuals exhibiting a notably increased recurrence risk (HR 6.2, P = 0.049). Patients identified as high-risk by both methods exhibited an even greater risk (HR 10.1, P < 0.0001) for recurrence. This DECIPHER-UCEC-2 study (Detecting Early Cancer by Inspecting ctDNA Features) demonstrates that by integrating cfDNA fragmentomics with machine learning, our liquid biopsy assay shows significant promise for EC's early detection, subtyping, and prognosis, potentially paving the way for enhanced patient outcomes.

Pan-Asia adapted ESMO Clinical Practice Guideline for the management of patients with newly diagnosed and relapsed epithelial ovarian cancer

The European Society for Medical Oncology (ESMO) Clinical Practice Guideline for the diagnosis, treatment and follow-up of patients with newly diagnosed and relapsed epithelial ovarian cancer (EOC), published in 2023, was adapted in July 2024, according to established standard methodology, to produce the Pan-Asian adapted ESMO consensus guideline for the management of Asian patients with EOC. The adapted guideline presented in this manuscript represents the consensus opinions reached by a panel of Asian experts in the treatment of patients with EOC representing the oncological societies of China, Indonesia, India, Japan, Korea, Malaysia, the Philippines, Singapore, Taiwan and Thailand, coordinated by ESMO and the Indian Society of Medical and Pediatric Oncology. Voting was based on scientific evidence and was independent of current treatment practices, drug access restrictions and reimbursement decisions in the represented countries. Drug access and reimbursement across Asia are discussed separately in the manuscript. The Pan-Asian consensus aims to guide the optimisation and harmonisation of management of patients with EOC in Asia, drawing on the evidence provided by both Western and Asian trials. Attention is drawn to the disparity in the drug approvals and reimbursement strategies between countries.

Tumor–stroma proportion on primary tumor as a prognostic biomarker in advanced ovarian cancer patients receiving chemo-immunotherapy as first-line therapy: analyses from the NeoPembrOV/GINECO phase II randomized trial

The efficacy of immune checkpoint inhibitors is limited in patients with high-grade serous ovarian cancer (HGSC). The predictive and prognostic value of tumor-stroma proportion (TSP) was assessed in patients with HGSC treated with platinum-based chemotherapy and pembrolizumab in the NeoPembrOV trial. TSP was quantified as the relative proportion of stromal tissue to tumor cells (low if <30% or high if ≥30%). RNA sequencing and multiplex immunofluorescence were conducted. TSP was assessed on 85 pre-treatment samples. Patients with a low TSP had a prolonged progression-free survival (PFS) compared with those with a high TSP (median PFS 23.4 versus 18.3 months, respectively, hazard ratio 0.51, 95% confidence interval 0.31-0.83, P = 0.010). The prognostic impact was higher when TSP was assessed on tubo-ovarian primary tumors (P = 0.01) and remained significant in the pembrolizumab arm (P = 0.01). Tumors with a low TSP were enriched in intratumoral CD8+PD1+ T cells and stromal proliferative CD8+Ki67+ T cells, while tumors with a high TSP exhibited an enrichment in M2 macrophages. A significant increase in intratumoral CD8+ T cells following pembrolizumab was observed only in low-TSP tumors (P = 0.02). We confirmed the prognostic value of TSP in HGSC and demonstrated its significance in patients treated with chemo-immunotherapy. TSP is associated with an immunosuppressive tumor microenvironment and influences CD8+ T-cell enrichment with immunotherapy.

HR-SC—an academic-developed machine learning framework to classify HRD-positive ovarian cancer patients and predict sensitivity to olaparib

High-grade serous ovarian cancer (OC) patients with defects in the homologous recombination repair (HRR) pathway benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. Clinically approved methods for identifying HRR status suffer from limitations, such as high failure rates and costs, leading to the clinical need for innovative approaches. To this aim, we developed Homologous Recombination Signature Classifier (HR-SC), a machine learning (ML) algorithm that integrates BRCA1/BRCA2 status and copy number signatures, leveraging the availability of OC samples recruited from two international clinical trials, namely PAOLA-1 (dataset A) and MITO16A/MaNGO-OV2 (dataset B). 569 DNA samples from datasets A and B were sequenced using a custom library design covering a backbone of structural regions and the full-length sequence of 375 genes. Data were used to train, validate (dataset A), and test (dataset B) HR-SC, using BRCA1/BRCA2 status and a compendium of previously annotated copy number signatures. Lastly, HR-SC was compared with already established approaches to evaluate its predictive and prognostic role. In dataset A, where the failure rate was 6.4%, HR-SC showed a sensitivity of 92%, a specificity of 94.73%, an accuracy of 93.18%, a positive predictive value (PPV) of 95.83%, and a negative predictive value (NPV) of 90%. In dataset B, where the failure rate was 4%, HR-SC showed a sensitivity of 90.16%, a specificity of 82.86%, an accuracy of 87.5%, a PPV of 90.16%, and an NPV of 82.86%. Univariate and multivariate survival analyses demonstrated its predictive role [progression-free survival (PFS): hazard ratio (HR) = 0.42, P < 0.0001; overall survival (OS): HR = 0.63, P = 0.036] and its prognostic role (PFS: HR = 0.56, P = 0.0095). The study demonstrates that HR-SC is a novel, clinically feasible solution with a low failure rate for predicting HRR status in OC patients and underscores the importance of leveraging ML approaches for advancing precision oncology in the era of personalized medicine.

Exposure–response relationship of niraparib in maintenance therapy for recurrent ovarian cancer: ancillary analysis of the French GINECO–NiQoLe study

Interindividual variability in pharmacokinetics may influence clinical outcomes of niraparib in patients with platinum-sensitive recurrent ovarian cancer (ROC). We aimed to investigate the pharmacokinetic-pharmacodynamic (PK-PD) relationship of niraparib in 49 patients with ROC from the multicenter phase IV NiQoLe study. Steady-state trough concentrations (C The starting dose was 200 mg/day in 39 patients (80%). Nineteen patients (39%) experienced early DLT. In multivariable analysis, the fourth quartile (Q4) of C Increased plasma exposure at D8 (C

Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study

Knowledge about the association between the BRCA1/2 mutation type and location and response to poly (ADP-ribose) polymerase inhibitors (PARPis) as single agent in ovarian cancer is limited. This study aimed to investigate the effectiveness of PARPi based on functional domains (FD) [RING, BRCT, DNA-binding (BD), RAD51-BD] and types (frameshift, missense, nonsense, splicing) of BRCA1/2 gene mutations in ovarian cancer. This multicenter real-world study retrospectively enrolled BRCA1/2-mutated ovarian cancer patients receiving olaparib maintenance between January 2010 and December 2022. Data were compared with historical series of patients who did not receive olaparib and analyzed based on the FD involved in BRCA1/2 mutations. Progression-free survival was calculated from the date of the last platinum-based treatment until recurrence or last follow-up. After a median follow-up of 46 months (range 32-60 months), 140 patients who underwent olaparib maintenance were compared with 128 who did not. PARPi showed efficacy in the overall population. The no-exon 11 patients benefitted more from olaparib than exon 11 patients [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.25-0.93]. In the BRCA1 group, patients with mutations in RING and BRCT domains had significant benefits from PARPi (HR 0.08, 95% CI 0.01-0.75; HR 0.10, 95% CI 0.02-0.38, respectively). Among BRCA2-mutated patients, RAD51-BD mutations were associated with higher response to olaparib (HR 0.23, 95% CI 0.10-0.52). According to the mutation type, the major effect of PARPi was in the missense group (HR 0.04, 95% CI 0.01-0.31). No patients with p.(Ala1708Glu) in the BRCT domain (BRCA1) receiving PARPi experienced recurring disease in the study period. BRCA1/2-mutated patients benefit from olaparib, but with variations according to the mutation type and FDs. BRCA1-mutated patients in the RING or BRCT and BRCA2-mutated in the RAD51-BD have the greatest benefit. Patients with missense mutations, especially those with p.(Ala1708Glu), have the most significant advantage from maintenance with PARPi.

BRCA functional domains associated with high risk of multiple primary tumors and domain-related sensitivity to olaparib: the Prometheus Study

Germline pathogenic variants (gPVs) in the breast cancer susceptibility gene 1/2 (BRCA1/2) genes confer high-penetrance susceptibility to breast cancer (BC) and ovarian cancer (OC). Although most female BRCA carriers develop only a single BRCA-associated tumor in their lifetime, a smaller subpopulation is diagnosed with multiple primary tumors (MPTs). The genetic factors influencing this risk remain unclear. Further, in patients with BRCA-mutated tumors, there appears to be a variability in the effectiveness of olaparib treatment. This real-world, multicenter, observational study aimed to determine whether the location of BRCA gPVs within functional domains (FDs) is associated with the development of MPTs and the magnitude of olaparib benefit. The study population comprised consecutive patients with OC who underwent hereditary cancer genetic testing between May 2015 and March 2023. MPT history was assessed based on mutated genes (BRCA1 or BRCA2) and the location of the PVs within the FDs. Clinical outcomes of olaparib first-line maintenance therapy were evaluated according to BRCA1/2 FD location. The frequency of MPT history in the overall population was 13.3% (118/882), and 20.4% in the BRCA-mutated subpopulation (68/333; P < 0.001). We observed a significant association between the DNA-binding domain (DBD) FD of BRCA2 and MPT. Specifically, 55.6% of BRCA2-mutated patients with PVs in the DBD had a history of BC as a second tumor. At a median follow-up of 48.5 months (95% confidence interval 10-70 months), the 48-month progression-free survival rates were 100.0% for patients with PVs in DBD, 91.7% for those with PVs in other FDs, and 36.4% for those with PVs in the RAD51-binding domain (RAD51-BD) of BRCA2 (P = 0.01). Results in the BRCA1 cohort were not statistically significant. The results suggest that the location of PVs within BRCA FDs may influence the onset of multiple tumors and the benefit of olaparib in patients with BRCA-mutated OC. These findings could be relevant for cancer prevention efforts, particularly given the increasing number of cancer survivors. However, further understanding is needed before these results can inform clinical decisions.

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

The recognition of homologous recombination deficiency (HRD) as a frequent feature of high-grade serous ovarian cancer (HGSOC) has transformed treatment paradigms. Poly(ADP-ribose) polymerase inhibitors (PARPis), developed based on the rationale of synthetic lethality that predicates antitumor efficacy in tumors harboring underlying HRD, now represents an important class of therapy for HGSOC. Recent data have drawn attention to the assessment of homologous recombination DNA repair (HRR) as a prognostic and predictive biomarker in HGSOC, leading to increasing debate on the optimal means of defining and evaluating HRD, both genotypically and phenotypically. At present, clinical-grade assays such as myChoice CDx and FoundationOne CDx are approved companion diagnostics which can identify patients with HRD-positive HGSOC by diagnosing a 'genomic scar' reflecting underlying genomic instability. Yet despite the rapid maturation of this field, tumoral HRD status has been recognized to be dynamic over time and with treatment pressure. In practice, this means that restoration of HRR through mechanisms of platinum and PARPi resistance are not adequately represented by genomic scar assays, and contribute toward discordance with clinical PARPi response, or lack-thereof. It is thus critical that HRD testing is optimized to address the controversies of diverse HRD testing methodology, appropriate thresholds for HRD identification, and relevant timepoints for HRD testing, in order to realize the potential for PARPis to maximally benefit patients with HGSOC. Here, we discuss the premise of HRD testing in HGSOC, current methodologies for HRD identification and their performance in the clinic, highlight upcoming strategies, and discuss the challenges faced in moving this field forward.

Unraveling the complexity of HRD assessment in ovarian cancer by combining genomic and functional approaches: translational analyses of MITO16-MaNGO-OV-2 trial

Ovarian cancer (OvC) constitutes significant management challenges primarily due to its late-stage diagnosis and the development of resistance to chemotherapy. The standard treatment regimen typically includes carboplatin and paclitaxel, with the addition of poly (ADP-ribose) polymerase inhibitors for patients with high-grade serous ovarian cancer (HGSOC) harboring BRCA1/2 mutations. However, the variability in treatment responses suggests the need to investigate factors beyond BRCA1/2 mutations, such as DNA repair mechanisms and epigenetic alterations. Notably, homologous recombination repair deficiency (HRD) is observed in an additional 20% of HGSOC cases, indicating a broader spectrum of DNA repair defects. Existing commercial HRD assays have certain limitations, prompting a global effort to develop new genomic and functional tests through academic research. This study investigates, in the 187 high-grade serous and endometrioid tumors from the MITO16/MaNGO-OV-2 trial, academic HRD genomic tests in conjunction with a RAD51 immunofluorescence assay to assess functional activation of HRD. Additionally, the study incorporates analysis of microRNA-506 (miR-506) expression as a putative epigenetic effector. The RAD51 test identified HRD in 73% of the samples and genomic HRD testing in 57%, with HRD identified in 45% of samples by both tests. The significant discrepancy between the two assays emphasizes the need to refine tumor classification for HRD. A three-group genomic classification unveiled superior progression-free survival (PFS) in high- and mild-HRD tumors compared with negative-HRD tumors. High concordance between RAD51 and genomic testing in high-HRD tumors suggests a subset of 'super-HRD' tumors exhibiting superior PFS. High expression of miR-506 may be used to further refine HRD status. The study underscores the complexities of HRD assessment and advocates for a combined genomic and functional approach to enhance predictive accuracy in OvC treatment responses.

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer was published in 2022. It was therefore decided, by both the ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO), to convene a virtual meeting in July 2022 to adapt the ESMO 2022 guidelines to take into account the variations in the management of endometrial cancer in Asia. These guidelines represent the consensus opinion of a panel of Asian experts representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). Voting was based on scientific evidence and was conducted independently of the current treatment practices and treatment access constraints in the different Asian countries, which were discussed when appropriate. The aim of this guideline manuscript is to provide guidance for the optimisation and harmonisation of the management of patients with endometrial cancer across the different regions of Asia, drawing on the evidence provided by Western and Asian trials whilst respecting the variations in clinical presentation, diagnostic practices including molecular profiling and disparities in access to therapeutic options, including drug approvals and reimbursement strategies.

Identification of molecular subtypes for endometrial carcinoma using a 46-gene next-generation sequencing panel: a retrospective study on a consecutive cohort

Traditional classification tools for endometrial carcinoma (EC), such as DNA sequencing, immunohistochemistry (IHC), or PCR, are cumbersome and time-consuming. Large next-generation sequencing (NGS) panels have simplified testing but are expensive. In this study, we propose a concise NGS panel as an effectively viable approach for classifying EC. We retrospectively enrolled a consecutive EC cohort of hysterectomy with bilateral salpingo-oophorectomy from Fudan University Shanghai Cancer Center between 2020 and 2022. A 46-gene NGS panel was utilized to identify POLE exonuclease domain mutations, microsatellite instability-high (MSI-H), TP53 mutations, and other clinically relevant targets. Tumor tissue samples from 331 EC patients were evaluated, with 284 (85.8%) cases classified as endometrioid endometrial carcinoma. The median follow-up time was 32.6 months (n = 303), during which 23 patients experienced recurrence or disease progression. Using the concise NGS panel, patients were stratified into four molecular subgroups according to the World Health Organization classification criteria: POLE mut (n = 47; 14.2%), mismatch repair deficiency (dMMR) (n = 79; 23.9%), non-specific molecular profile (n = 148; 44.7%), and abnormal p53 expression (p53 abn) (n = 57; 17.2%). POLE mut displayed the most favorable prognosis, while p53 abn had the worst prognosis (P < 0.001). The concordance between NGS and IHC was 91.8% (269/293) for detecting MMR status and 65.3% (201/308) for detecting p53 status. Patients detected solely by NGS had significantly worse prognosis than those detected solely by IHC, indicating higher accuracy of the NGS panel. With the molecular subtyping information, adjuvant treatment plans for 19.6% of patients could potentially be altered, mainly concentrated in the POLE mut and p53 abn subtypes. This panel also aids targeted therapy and poly (ADP-ribose) polymerase (PARP) inhibitor-related gene mutation detection, as well as auxiliary genetic screening. Our study demonstrates that the concise NGS panel is an effective 'one-stop' strategy for precisely classifying EC with high clinical availability.

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

We describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive. Patients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies. Forty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models. Ribociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models. ClinicalTrials.gov registry (NCT02657928).

ESMO management and treatment adapted recommendations in the COVID-19 era: gynaecological malignancies

The rapid spread of severe acute respiratory syndrome coronavirus 2 infection and its related disease (COVID-19) has required an immediate and coordinate healthcare response to face the worldwide emergency and define strategies to maintain the continuum of care for the non-COVID-19 diseases while protecting patients and healthcare providers. The dimension of the COVID-19 pandemic poses an unprecedented risk especially for the more vulnerable populations. To manage patients with cancer adequately, maintaining the highest quality of care, a definition of value-based priorities is necessary to define which interventions can be safely postponed without affecting patients' outcome. The European Society for Medical Oncology (ESMO) has endorsed a tiered approach across three different levels of priority (high, medium, low) incorporating information on the value-based prioritisation and clinical cogency of the interventions that can be applied for different disease sites. Patients with gynaecological cancer are at particular risk of COVID-19 complications because of their age and prevalence of comorbidities. The definition of priority level should be based on tumour stage and histology, cancer-related symptoms or complications, aim (curative vs palliative) and magnitude of benefit of the oncological intervention, patients' general condition and preferences. The decision-making process always needs to consider the disease-specific national and international guidelines and the local healthcare system and social resources, and a changing situation in relation to COVID-19 infection. These recommendations aim to provide guidance for the definition of deferrable and undeferrable interventions during the COVID-19 pandemic for ovarian, endometrial and cervical cancers within the context of the ESMO Clinical Practice Guidelines.

A novel BRCA mutation classification system reveals differential responses to PARP inhibition and prognostic outcomes in epithelial ovarian cancer: a multicenter study

Although poly (ADP-ribose) polymerase inhibitors (PARPis) have transformed the treatment landscape for the BReast CAncer susceptibility gene (BRCA)-mutated ovarian cancer, emerging evidence suggests significant heterogeneity in treatment efficacy. However, findings regarding the impact of mutation location and type remain debated, underscoring the necessity for more data and better subclassification. This study aimed to evaluate the association between novel BRCA mutation subgroups and PARPi response in epithelial ovarian cancer. This is a multicenter retrospective study conducted in China which enrolled BRCA1/2-mutated epithelial ovarian cancer patients between 2015 and 2024. Patients who achieved complete or partial response after surgery and platinum-based chemotherapy were included. Progression-free survival (PFS) was assessed with Kaplan-Meier curves (log-rank test) and Cox models to estimate hazard ratios with 95% confidence intervals. A total of 465 patients were included, of whom 319 (68.6%) received PARPi as maintenance therapy. We introduced a novel classification system that continuously segments the entire BRCA1 gene. Patients with mutations in the DNA-binding domain (DBD) and adjacent region [between DBD and C-terminal domain of BRCA1 (BRCT) (DB)] had poor prognosis without PARPi treatment but showed substantial benefit with PARPi (P = 0.0097 and P = 0.0016, respectively). Conversely, mutations in the Really Interesting New Gene (RING) domain and its downstream region (between RING and DBD) showed limited therapeutic benefit from PARPi and were associated with poorer overall outcomes. Patients with mutations located in the BRCT domain exhibited favorable prognosis regardless of PARPi treatment, diminishing the relative benefit of PARPi in this subgroup. According to the mutation type, patients with frameshift or nonsense mutations experienced significant improvement with PARPi (both P < 0.05). Our novel classification revealed that PARPi efficacy and prognosis varied significantly by mutation location, with the central region linked to superior outcomes compared with the N- and C-terminal regions. Comprehensive mutation profiling should guide treatment decisions to optimize outcomes in patients with BRCA-mutated ovarian cancer.

Development of a risk score based on clinical–pathological features to predict the presence of germline BRCA1/2 pathogenic variants in ovarian cancer patients

Identification of germline BRCA1/2 pathogenic variants is crucial for tailoring ovarian cancer treatment and prevention. The purpose of the study was to develop a model to predict BRCA1/2 status in ovarian cancer patients. The association between clinical-pathological features and BRCA1/2 status was analysed in a series of 1009 ovarian cancer patients, using Fisher's exact test. Logistic regression models and a decision tree classification algorithm were used to develop a risk score. Compared with noncarriers, BRCA1/2 carriers (n = 216; 21.4%) presented more frequently with serous histotype non-low-grade (92.3% versus 71.6%, P < 0.001), family history of ovarian cancer (31.6% versus 5.7%, P < 0.001), family history of breast cancer (53.7% versus 31.6%, P < 0.001), previous breast cancer (20.9% versus 8.5%, P < 0.001), advanced stage (78.8% versus 69.5%, P = 0.019) and younger age (56.9 years versus 60.8 years, P < 0.001). Multivariable logistic regression on 648 patients with complete data confirmed histotype, family history of breast/ovarian cancer, previous breast cancer and age as independently and significantly associated with BRCA1/2 status. After refining the categorization of variables according to decision tree classification algorithm results, odds ratios derived from multivariable logistic regression were used to assign weights from 1 to 3 to each feature (non-low-grade serous histotype = 3, low-grade serous/high-grade endometrioid histotype/family history of ovarian cancer = 2, age at diagnosis <50 years/family and personal history of breast cancer = 1) and to develop a score ranging from 0 to 10, associated with increasing risk of BRCA1/2 variants (from 0.6% for score 0 to 88% for score ≥7). The area under the curve of the score was 0.78 (95% confidence interval 0.74-0.82) and the optimal cut-off was ≥4 points with a sensitivity of 81% and a specificity of 62.3%. The proposed risk score may improve assessment and counselling of ovarian cancer patients.

Real-world outcomes of PARP inhibitor maintenance in advanced ovarian cancer: a focus on disease patterns and treatment modalities at recurrence

The utilization of poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) as a first-line maintenance therapy for advanced ovarian cancer has increased significantly, with ∼80% of patients potentially eligible. This expansion has led to a rise in the population experiencing platinum-sensitive recurrence, yet data on first recurrence during PARPi are limited. This real-world study from a high-volume referral center aims to elucidate recurrence rates, disease distribution, and treatment modalities at the time of progression in PARPi-treated patients. We analyzed our prospectively maintained database to identify patients receiving first-line PARPi maintenance from January 2019 to December 2022 at our institution. A total of 373 cases were identified, 51.5% of which had a BRCA mutation. With a median follow-up of 38 months, 44.8% of patients experienced recurrence, with 90.3% having a platinum-free interval exceeding 6 months. Recurrences were oligometastatic in 44.9% of cases, with BRCA mutations strongly predicting this pattern (hazard ratio 3.014, confidence interval 1.486-6.113, P = 0.002). The median progression-free survival was 39 months, significantly longer for BRCA-mutated and homologous recombination deficiency-positive patients. Over one-third of platinum-sensitive recurrent patients were candidates for local treatments, and PARPi administration was prolonged in 53.7%. Despite the notable survival improvement, a significant proportion of the population will experience a platinum-sensitive recurrence on PARPi, for which local treatments are often a viable option. Our study highlights the need for further research to determine whether the ablation of oligometastatic sites has a significant impact on post-recurrence survival and to identify if there are patient categories that would benefit from personalized follow-up due to their susceptibility to oligometastatic recurrences and local treatments.

Actionable mutations in early-stage ovarian cancer according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT): a descriptive analysis on a large prospective cohort

According to the European Society for Clinical Oncology (ESMO) guidelines, the therapeutic algorithm for early-stage epithelial ovarian carcinoma (EOC) is primarily based on grading and histotype. Adjuvant chemotherapy is usually recommended for high-grade tumors and for the International Federation of Gynecology and Obstetrics (FIGO) stage IB-IC; however, overtreatment remains a concern. Conversely, patients truly at higher risk of recurrence currently lack access to additional therapeutic strategies. This study presents a descriptive analysis of early-stage EOC patients who were prospectively sequenced and stratified into high-, intermediate-, and low-risk groups based on clinicopathological features. Oncogenic alterations were identified using OncoKB and classified according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) Tier I-III. The prevalence of molecular findings was first reported for each risk subgroup, followed by an analysis on the cohort of patients who experienced relapse. A total of 180 patients with FIGO stage I-II EOC were enrolled between January 2022 and December 2023; 126 patients (70%) had at least one ESCAT Tier I-III alteration (including 51% high risk, 35% intermediate risk, and 14% low risk); among them, approximately one-quarter (26%, 95% confidence interval 19% to 35%) had an ESCAT Tier I alteration. BRCA1 and BRCA2 alterations were observed in about one-quarter of patients, with BRCA2 often co-altered with POLE mutations (55%, P = 2.1 × 10 These findings highlight the potential for actionable alterations in most early-stage EOC patients and support the exploration of chemotherapy-free regimens for low- to intermediate-risk groups, as well as targeted maintenance therapy for high-risk individuals.

Hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of primary advanced and recurrent ovarian cancer: a systematic review and meta-analysis of randomized trials

Ovarian cancer is the most lethal gynecologic malignancy. Although treatment with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results, its role remains elusive. The aim of this study was to assess the comprehensive randomized evidence for the use versus non-use of HIPEC in primary and recurrent ovarian cancer. The Medline, Embase and Cochrane databases, as well as the European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) conference abstracts of the last 5 years, were scrutinized in January 2022 for randomized, controlled trials that studied the use of HIPEC in ovarian cancer. Overall survival (OS), disease-free survival (DFS) and progression-free survival, as well as post-operative morbidity were the outcomes of interest. This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Six randomized, controlled trials that randomized 737 patients were included in our analysis; of these, four studies (519 patients) were in primary and two (218 patients) in recurrent settings. In primary ovarian cancer, the combination of HIPEC with interval cytoreductive surgery (CRS) and neoadjuvant chemotherapy significantly improved the 5-year OS [393 patients, risk ratio (RR) = 0.77; 95% confidence interval (CI) 0.67-0.90; P value = 0.001] and DFS (hazard ratio = 0.60; 95% CI 0.41-0.87; P value = 0.008) compared with standard treatment alone. In the absence of neoadjuvant chemotherapy, the use of HIPEC + CRS was not associated with any survival advantage (126 patients, 4-year OS, RR = 0.93; 95% CI 0.57-1.53; P value = 0.781), but the sample size was smaller in this subset. Use of HIPEC in recurrent ovarian cancer did not provide any survival advantage (5-year OS: 218 patients, RR = 0.85; 95% CI 0.45-1.62; P value = 0.626). The risk for grade ≥3 adverse events was similar between HIPEC and no HIPEC (RR = 1.08; 95% CI 0.98-1.18; P value = 0.109). In primary ovarian cancer the combination of HIPEC with interval CRS and neoadjuvant chemotherapy is a safe option that significantly improved 5-year OS and DFS. Its use in other settings should continue to be considered investigational.

Maintenance therapy with a poly(ADP-ribose) polymerase inhibitor in patients with newly diagnosed advanced epithelial ovarian cancer: individual patient data and trial-level meta-analysis

We synthesize the efficacy and toxicity of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with newly diagnosed advanced ovarian cancer. We manually extracted individual patient data (IPD) for progression-free survival (PFS) from published survival curves of randomized controlled trials (RCTs) that compared PARPi versus placebo as maintenance therapy in first-line treatment, for whole study populations and subgroups, based on BRCA1/BRCA2 mutation (germline and/or somatic) and homologous recombination deficiency (HRD) status, using WebPlotDigitizer software. The respective PFS curves for each study and combined population were reconstructed from extracted IPD. The primary outcome was PFS in combined whole population and subgroups. In IPD analysis of combined population from three RCTs, with 2296 patients and 1287 events, PFS was significantly longer in PARPi versus placebo [median 20.4 (95% confidence interval (CI) 18.6-21.9) versus 14.9 (95% CI 13.9-16.5) months, respectively; hazard ratio (HR) 0.67, 95% CI 0.60-0.75; P < 0.001]. In IPD subgroup analyses from four eligible RCTs (2687 patients and 1485 events), median PFS was significantly longer in PARPi versus placebo arm, in the BRCA-mutated (45.7 versus 17.7 months, respectively; HR 0.38, 95% CI 0.32-0.46; P < 0.001), HRD-positive including BRCA-mutated (34.7 versus 17.9 months, respectively; HR 0.45, 95% CI 0.38-0.54; P < 0.001), and HRD positive excluding BRCA-mutated (22.3 versus 13.1 months, respectively; HR 0.47, 95% CI 0.34-0.65; P < 0.001) subgroups, but not in the HRD-negative (15.0 versus 11.3 months, respectively; HR 0.90, 95% CI 0.76-1.05; P = 0.75) subgroup. Results of trial-level meta-analysis were concordant with IPD analysis in whole population and subgroups. Among newly diagnosed ovarian cancer patients, PARPi maintenance therapy significantly improves PFS in those with germline and/or somatic BRCA mutation and/or HRD-positive tumor but not in those with HRD-negative tumor.

Efficacy of chemotherapy after progression during or following PARPi exposure in ovarian cancer

Poly(ADP-ribose) polymerase inhibitors (PARPis) improved advanced ovarian cancer treatment. Most patients progress during or following PARPi exposure, however, with concerns about sensitivity of subsequent chemotherapy. In this international cohort study, we evaluated the efficacy of a subsequent chemotherapy following PARPi exposure in high-grade ovarian carcinoma patients. Endpoints included progression-free survival (PFS), overall survival and a multivariable Cox model was built to identify factors influencing PFS. We included 291 patients from four international centers treated between January 2002 and December 2021. The median number of previous chemotherapy was 1 (1.0-7.0), the median duration of PARPi exposure was 6.5 months (0.2-54.3 months). PARPi was used in first line in 14.1% patients. Most progressions occurred under PARPi exposure (89.1%). A BRCA pathogenic variant was identified in 130 patients (44.7%), absent in 157 patients (54.0%), and undocumented in 4 patients (1.4%). Platinum-based CT (PBC) and non-PBC were administered as subsequent treatments in, respectively, 182 patients (62.5%) and 109 patients (37.5%). Multivariable analyses showed that platinum-free interval (PFI) >6 months [adjusted hazards ratio (HR), 0.52; 95% confidence interval (CI) 0.39-0.70] and type of initial surgery (adjusted HR, 1.41; 95% CI 1.07-1.87; interval or closing surgery versus primary surgery) were associated with PFS, independent of BRCA status or line of therapy (≥2 versus 1). In patients with a PFI >6 months, PBC was numerically associated with the best PFS (adjusted HR, 0.68; 95% CI 0.46-1.01). This is the largest real-world study assessing the efficacy of subsequent chemotherapy in patients progressing during PARPi exposure. The patients have poor outcomes. PBC is the best option in patients progressing on PARPi and eligible for PBC rechallenge (PFI >6 months).

HRD testing for all advanced high-grade ovarian carcinoma in first line?

Surgery and HIPEC in relapse for all patients with ovarian cancer?

Immune checkpoint inhibitors alone or in combination for endometrial mismatch repair-deficient/MSI-high population

The impact of single agent PD-1 or PD-L1 inhibition on advanced endometrial cancers: meta-analysis

Immune checkpoint inhibitor (ICI) therapy is an emerging option for advanced endometrial cancer (EC). Mismatch repair (MMR) status is widely regarded as a biomarker predictive of response to ICIs. The predictive value of MMR based on small, single-arm trials, however, is conflicting. In this meta-analysis, we aimed to assess the activity of single-agent ICI in advanced EC, and compared the magnitude of treatment benefit in MMR deficient (dMMR) and MMR proficient (pMMR) EC. We carried out an electronic search to identify prospective trials of single-agent ICI in advanced EC. Data on objective response rate (ORR) and progression-free survival (PFS) were extracted and pooled. ORR was estimated using the inverse variance method and subgroup difference by MMR status was examined. PFS difference according to MMR status was summarized using the Kaplan-Meier approach. From eight trials with 492 women, the pooled ORR was 19% [95% confidence interval (CI) 16% to 22%]. ORR was significantly greater in dMMR (n = 281) than pMMR EC (n = 211) (dMMR: 46%, pMMR: 8%; risk ratio 5.74, 95% CI 3.58-9.21; interaction P < 0.001). Complete response was 11% and 0.05% and median PFS was 8.3 and 2.1 months in dMMR and pMMR EC, respectively (hazard ratio PFS 0.58, 95% CI 0.38-0.89; P = 0.01). The 12-month PFS rates were 42.0% and 20.7%, respectively. Single-agent ICI is associated with a 5.74 times greater objective response and 42% reduction in risk of disease progression or death in dMMR compared with pMMR EC. MMR status should be determined prospectively and be used as a stratification factor in future trials of advanced EC. Further translational analysis is urgently required to identify the cause of dMMR and allow subclassification of EC into different dMMR molecular subtypes.

Combining PARP inhibition and immune checkpoint blockade in ovarian cancer patients: a new perspective on the horizon?

Immune checkpoint inhibitors (ICIs) have completely reshaped the treatment of many malignancies, with remarkable improvements in survival outcomes. In ovarian cancer (OC), however, this emerging class of drugs has not yet found a favorable use due to results from phase I and II studies, which have not suggested a substantial antitumoral activity of these agents when administered as monotherapy. Robust preclinical data seem to suggest that the combination ICIs with poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) may result in a synergistic activity; furthermore, data from phase II clinical studies, evaluating this combination, have shown encouraging outcomes especially for those OC patients not suitable for platinum retreatment. While waiting for ongoing phase III clinical trial results, which will clarify the role of ICIs in combination with PARPis in the newly diagnosed OC, this review aims to summarize the preclinical data and clinical evidence available to date.

Specific issues in the systemic treatment strategy for ovarian clear cell carcinoma

Venous thromboembolic event risk with PARP inhibitors in solid tumors: a systematic review and meta-analysis

First-line PARP inhibitors in ovarian cancer: summary of an ESMO Open - Cancer Horizons round-table discussion

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with

Clinical benefit of systemic therapies for recurrent ovarian cancer—ESMO-MCBS scores

Licensed systemic treatment options for platinum-sensitive recurrent ovarian cancer are platinum-based chemotherapy and maintenance treatment with bevacizumab and poly (ADP-ribose) polymerase inhibitors. For platinum-resistant disease, several non-platinum options are available. We aimed to assess the clinical benefit of these treatments according to the European Society of Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). A PubMed search was carried out including all studies evaluating systemic treatment of recurrent epithelial ovarian cancer, from 1990 onwards. Randomised trials with an adequate comparator and design showing a statistically significant benefit of the study arm were independently scored by two blinded observers using the ESMO-MCBS. A total of 1127 papers were identified, out of which 61 reported results of randomised trials of sufficient quality. Nineteen trials showed statistically significant results and the studied treatments were graded according to ESMO-MCBS. Only three treatments showed substantial benefit (score of 4 on a scale of 1-5) according to the ESMO-MCBS: platinum-based chemotherapy with paclitaxel in the platinum-sensitive setting and the addition of bevacizumab to chemotherapy in the platinum-resistant setting. The WEE1 inhibitor adavosertib (not licensed) also scores a 4, based on a recent small phase II study. Assessment of quality-of-life data and toxicity using the ESMO-MCBS showed to be complex, which should be taken into account in using this score for clinical decision making. Only a few licensed systemic therapies for recurrent ovarian cancer show substantial clinical benefit based on ESMO-MCBS scores. Trials demonstrating overall survival benefit are sparse.

Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study

Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer. In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics. Overall, 216 patients were randomized to gatipotuzumab (n  =  151) or placebo (n  =  65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P  =  0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events. Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients. ClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599.

Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study)

There is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status. Patients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with ≤4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) + intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m From 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade ≥3 treatment-related adverse events occurred in 74% of patients, with neutropenia/anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%). The PLD-olaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m

Recurrent ovarian cancer in the era of poly-ADP ribose polymerase inhibitors: time to re-assess established clinical practices

Maintenance therapy with a poly (ADP-ribose) polymerase inhibitor in patients with newly diagnosed advanced epithelial ovarian cancer: updated individual patient data and trial-level meta-analysis

A phase III randomized, controlled trial of nedaplatin versus cisplatin concurrent chemoradiotherapy in patients with cervical cancer

We evaluated the non-inferiority of nedaplatin-based and cisplatin-based concurrent chemoradiotherapy in cervical cancer patients. Patients aged 28-82 years with pathologically diagnosed cervical cancer (stage IB-IVA) were randomly chosen for the study. Patients in both the cisplatin and nedaplatin groups received radiotherapy and weekly intravenous nedaplatin 30 mg/m One hundred and sixty patients who received treatment between 10 May 2018 and 31 August 2020 were included. The 3-year overall survival in the nedaplatin group (median 30.5 months) was not significantly different from that in the cisplatin group (28.5 months; hazard ratio 0.131, 95% confidence interval 0.016-1.068; P = 0.058). No significant differences in hematological toxicity were observed between the two groups. Vomiting (40 versus 61), nausea (44 versus 67), and anorexia (52 versus 71) were more common in the cisplatin group whereas effects on liver function, including total bilirubin (7 versus 3), alanine aminotransferase (7 versus 2), and aspartate aminotransferase (6 versus 2), were more common in the nedaplatin group. Four patients in the cisplatin group had grade I creatinine elevation, whereas none in the nedaplatin group had abnormal creatinine levels. Two patients in the nedaplatin group discontinued concurrent chemotherapy because of infusion, and one patient in the cisplatin group discontinued treatment because of infusion-induced dizziness. Our findings suggest that nedaplatin has a milder gastrointestinal reaction but a more significant effect on liver function than cisplatin. In patients with cervical cancer, nedaplatin-based concurrent chemoradiotherapy could serve as an alternative treatment to cisplatin.

Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers

The programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies. This phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated. Overall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively. Atezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.

Genetic testing for BRCA1/2 variants in Northern African women with ovarian and breast cancers: a multicentre study of an under-represented ancestry

There is a lack of studies investigating the burden of BRCA1/2 pathogenic variants (PVs) in Northern African countries using next-generation sequencing (NGS)-based testing in patients with epithelial ovarian (EOC) and triple-negative breast cancer (TNBC). We established a multicentre registry for genetic testing of unselected patients referred from five centres from 2019 to 2022 across Egypt. Germline or somatic BRCA1/2 sequencing was carried out by target enrichment using the AmoyDx® BRCA1/2 Mutation Kit, and sequencing was carried out using the Illumina NextSeq500 system. Genetic testing was successfully carried out for 1349 of 1420 (95%) patients tested (EOC = 1031, TNBC = 318). The median age was 55 years (range 20-86 years). We identified 258 BRCA1/2 PVs affecting 254 (18.8%) patients. The rate of BRCA1/2 PVs in EOC and TNBC was 18.2% and 20.8%, respectively. Although the rate of PVs in our cohort was similar to the Western cancer population, there were significant differences in the enrichment at the variant level. The majority of recurrent BRCA2 PVs, but not BRCA1 PVs, were breast or ovarian lineage-unique. We developed a limited-resource conscious framework that provided a reclassification of 60% of identified variants of uncertain significance (VUS). Our findings would help to enhance cancer care and enrich the genetic epidemiology of women from such understudied ancestries.

Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge

Hereditary breast cancer (BC), ovarian cancer (OC), and pancreatic cancer (PC) are the major BRCA-associated tumours. However, some BRCA1/2-wild-type (wt) patients with a strong personal and/or family history of cancer need a further genetic testing through a multi-gene panel containing other high- and moderate-risk susceptibility genes. Our study was aimed to assess if some BC, OC, or PC patients should be offered multi-gene panel testing, based on well-defined criteria concerning their personal and/or family history of cancer, such as earliness of cancer onset, occurrence of multiple tumours, or presence of at least two or more affected first-degree relatives. For this purpose, 205 out of 915 BC, OC, or PC patients, resulted negative for BRCA1/2 and with significant personal and/or family history of cancer, were genetically tested for germline pathogenic or likely pathogenic variants (PVs/LPVs) in genes different from BRCA1/2. Our investigation revealed that 31 (15.1%) out of 205 patients harboured germline PVs/LPVs in no-BRCA genes, including PALB2, CHEK2, ATM, MUTYH, MSH2, and RAD51C. Interestingly, in the absence of an analysis conducted through multi-gene panel, a considerable percentage (15.1%) of PVs/LPVs would have been lost. Providing a multi-gene panel testing to BRCA1/2-wt BC/OC/PC patients with a strong personal and/or family history of cancer could significantly increase the detection rates of germline PVs/LPVs in other cancer predisposition genes beyond BRCA1/2. The use of a multi-gene panel testing could improve the inherited cancer risk estimation and clinical management of patients and unaffected family members.

Rationale and study design of the CHIPPI-1808 trial: a phase III randomized clinical trial evaluating hyperthermic intraperitoneal chemotherapy (HIPEC) for stage III ovarian cancer patients treated with primary or interval cytoreductive surgery

Ovarian cancer remains the most lethal gynecologic malignancy with high recurrence rates. Because recurrence involves primarily the peritoneum, intraperitoneal chemotherapy is being evaluated as a new approach to treat microscopic peritoneal disease. One trial showed that cisplatin-paclitaxel intraperitoneal chemotherapy with intravenous paclitaxel improved survival but increased morbidity. Another trial reported a significant improvement in overall survival (OS) and disease-free survival (DFS) without increasing the morbidity (P = 0.76) or mortality rates (hazard ratio 0.67, P = 0.02) after adding hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreduction. The current trial aims to evaluate the impact of adding HIPEC to primary or interval cytoreductive surgery for epithelial ovarian cancer (EOC) on the efficacy, safety, treatment feasibility, and quality of life. This is an international, multicenter, open-label, randomized (1 : 1), two-arm, phase III clinical trial that will enroll 432 patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III EOC. Patients are randomized to receive or not HIPEC with the standard of care. Inclusion criteria include patients with FIGO stage III EOC, Fallopian tube carcinoma or primary peritoneal cancer who undergo complete primary or interval cytoreduction. The primary objective is to assess DFS of the addition of HIPEC. Secondary objectives are the assessment of OS, safety, return to intended oncologic treatment, quality of life and the trade-off between efficacy and morbidity. The results might help extend the indications of HIPEC to include patients undergoing primary cytoreduction, providing a standardized protocol for HIPEC in EOC management and reliable information on the quality of life after adding HIPEC.

Aurora kinases in ovarian cancer

Aurora kinases (AURK) are key regulators of the mitotic spindle formation. AURK is frequently overexpressed in ovarian cancer and this overexpression has been frequently associated with prognosis in these tumours. Interestingly, AURK have been shown to interact with DNA repair mechanisms and other cell cycle regulators. These functions have brought light to Aurora family as a potential target for anticancer therapy. In the last years, two clinical trials with different AURK inhibitors have shown activity in epithelial and clear-cell ovarian cancer. Although there is a lack of predictive factors of AURK inhibition activity, recent trials have identified some candidates. This review will focus in the functions of the AURK family, its role as prognostic factor in epithelial ovarian cancer and potential clinical implications.

Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial

The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

Plasma Tie2 trajectories identify vascular response criteria for VEGF inhibitors across advanced biliary tract, colorectal and ovarian cancers

Vascular endothelial growth factor inhibitors (VEGFi) are compromised by a lack of validated biomarkers. Previously we showed that changes in the concentration of plasma Tie2 (pTie2) was a response biomarker for bevacizumab. Here, we investigated whether pTie2 can predict response and progression cross-tumour for generic VEGFi treatment. Patients (n = 124) with advanced biliary tract cancer (ABC) received cisplatin/gemcitabine with cediranib or placebo (ABC-03 trial). Concentrations of pTie2 were measured longitudinally from before treatment until disease progression. Data from patients with ovarian cancer (n = 92, ICON7 trial) and patients with colorectal cancer (CRC) (n = 70, Travastin trial) were also included. Cediranib-treated ABC patients were deconvoluted into distinct groups where in one group pTie2 trajectories resembled those seen in placebo-treated patients and in another pTie2 significantly reduced (t-test P = 2.7 × 10 pTie2 is the first cross-tumour, generic VEGFi, vascular response biomarker to guide optimum use of VEGFi in clinical practice.

Gene actionability according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) in No Specific Molecular Profile (NSMP) endometrial cancer

The No Specific Molecular Profile (NSMP) subtype accounts for ∼30%-40% of endometrial cancer (EC), comprising a heterogeneous group of EC. The primary outcome of this study was the prevalence of actionable genomic alterations in NSMP EC, classified according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Oncogenic and likely oncogenic alterations, pathways, and co-mutation patterns were reported. The analysis was stratified by risk group according to the European Society of Gynaecological Oncology (ESGO)-ESMO-European SocieTy for Radiotherapy and Oncology (ESTRO) guidelines. Patients with NSMP EC enrolled in the FPG500 comprehensive cancer genome profiling program (NCT06020625) were included. Two hundred and fifty-three patients with NSMP EC of any International Federation of Gynecology and Obstetrics (FIGO) stage were enrolled between 1 January 2022 and 31 December 2023. Median age was 62 years, and the most frequent histotype was endometrioid (97%). Ninety-five percent of patients were estrogen receptor positive. Two hundred and thirty-three patients (92%) had at least one ESCAT tier I-III alteration. The most frequent variants were in PTEN [88%, 95% confidence interval (CI) 84% to 92%], PIK3CA (42%, 95% CI 36% to 49%), FGFR2 (15%, 95% CI 11% to 20%), and AKT1 (6%, 95% CI 3% to 10%); 4% (95% CI 2% to 8%) of patients had an ESR1 variant, while KRAS G12C was found in 3% (95% CI 1% to 6%) of patients. The majority of PTEN variants were on the R130 hotspot. More frequent PIK3CA hotspot variants were H1047R (9%), E545D/K/Q/A (6%), and E542K (4%). In the overall population, PIK3CA with PIK3R1 (odds ratio [OR] = 0.07, P value = 4.25 × 10 Our findings highlight potentially actionable alterations in NSMP EC patients, supporting the exploration of tailored molecular-matched therapies according to risk groups.

Multimodal tumor-agnostic ctDNA analysis for minimal residual disease detection and risk stratification in ovarian cancer: results from the MITO16a/MaNGO-OV2 trial

Advanced-stage epithelial ovarian cancer (EOC) remains a therapeutic challenge due to high relapse rates and limited survival, while standard post-surgical parameters such as residual tumor (RT) incompletely capture minimal residual disease (MRD) and offer limited insight into tumor evolution. To address this gap, we investigated whether a multimodal, tumor-agnostic analysis of circulating tumor DNA (ctDNA)-integrating tumor fraction (TF) and genome-wide fragmentomic profiles (PF)-could refine early risk stratification after cytoreductive surgery and enable longitudinal monitoring during therapy. A total of 393 plasma samples from 173 patients in the phase IV MITO16a/MaNGO-OV2a trial were analyzed by shallow whole-genome sequencing at three time points: post-surgery/pre-chemotherapy (B1), post-chemotherapy (B2), and at the end of maintenance therapy or upon disease progression during maintenance (B3). Associations with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox models adjusted for clinical covariates. TF was detectable in 97% of patients at B1, including those classified as optimally debulked, and outperformed established clinical covariates in predicting survival [PFS: hazard ratio (HR) 1.02, P = 0.008; OS: HR 1.04, P = 0.005]. PF provided independent prognostic values (PFS: HR 1.06, P = 0.010; OS: HR 1.10, P = 0.005), and combined TF/PF modeling identified subgroups with distinct survival trajectories beyond clinical predictors (PFS: HR 1.76, P = 0.015; OS: HR 2.06, P = 0.029). Longitudinal copy number profiling revealed dynamic remodeling under treatment pressure, with recurrent 19q13.42 amplification emerging at B2 and B3. Together, these findings establish multimodal ctDNA profiling as a sensitive, non-invasive strategy for MRD detection and longitudinal surveillance in advanced EOC, refining prognostic assessment beyond clinical and surgical factors while paving the way for precision-guided therapeutic management.

HPV ctDNA detection of high-risk HPV types during chemoradiotherapy for locally advanced cervical cancer

Chemoradiotherapy (CRT) is the standard of care for patients diagnosed with locally advanced cervical cancer (LACC), a human papillomavirus (HPV)-related cancer that relapses in 30%-60% of patients. This study aimed to (i) design HPV droplet digital PCR (ddPCR) assays for blood detection (including rare genotypes) and (ii) monitor blood HPV circulating tumor DNA (HPV ctDNA) levels during CRT in patients with LACC. We analyzed blood and tumor samples from 55 patients with HPV-positive LACC treated by CRT in a retrospective cohort (n = 41) and a prospective cohort (n = 14). HPV-ctDNA detection was carried out by genotype-specific ddPCR. HPV ctDNA was successfully detected in 69% of patients (n = 38/55) before CRT for LACC, including nine patients with a rare genotype. HPV-ctDNA level was correlated with HPV copy number in the tumor (r = 0.41, P < 0.001). HPV-ctDNA positivity for HPV18 (20%, n = 2/10) was significantly lower than for HPV16 (77%, n = 27/35) or other types (90%, n = 9/10, P = 0.002). HPV-ctDNA detection (positive versus negative) before CRT was associated with tumor stage (P = 0.037) and lymph node status (P = 0.02). Taking into account all samples from the end of CRT and during follow-up in the prospective cohort, positive HPV-ctDNA detection was associated with lower disease-free survival (DFS) (P = 0.048) and overall survival (OS) (P = 0.0013). This is one of the largest studies to report HPV-ctDNA detection before CRT and showed clearance of HPV ctDNA at the end of treatment in most patients. Residual HPV ctDNA at the end of CRT or during follow-up could help to identify patients more likely to experience subsequent relapse.

Should all advanced BRCA-mutated patients in response to first-line platinum-based chemotherapy receive PARPi + bevacizumab as maintenance therapy?