Search

Purpose: Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance. Experimental Design: This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing. Results: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P < 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum. Conclusions: Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction.

PURPOSE In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986 ), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting. METHODS This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up. RESULTS The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [ P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups. CONCLUSION Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.

DNA double-strand breaks are the most critical DNA damage to cells, and their repair is tightly regulated to maintain cellular integrity. Some cancers exhibit homologous recombination deficiency (HRD), a faithful double-strand break repair system, making them more sensitive to poly (ADP ribose) polymerase inhibitors (PARPi). PARPi have shown substantial efficacy in BRCA-mutated ovarian cancer for several years, and their indication has gradually been extended to other tumour locations such as breast, prostate and pancreas. More recently, PARPi were demonstrated to be effective in cancers with an HRD phenotype beyond BRCA mutations. Today, a major challenge is developing tests capable of detecting the HRD phenotype of cancers (HRD tests) and predicting sensitivity to PARPi to select patients likely to benefit from this therapy. This review provides a synthesis of the existing HRD tests, divided into three main approaches to detect HRD: the investigation of the HRD causes, the study of its consequences and the evaluation of the HR activity itself.

Resume L’evolution des connaissances en oncologie gynecologique conduit progressivement vers une desescalade chirurgicale dans plusieurs domaines, notamment dans celui de la chirurgie ganglionnaire. L’indication du ganglion sentinelle (GS) dans le cancer de l’endometre, initialement reserve aux risques bas et intermediaire, est maintenant elargie a tous les stades FIGO (International Federation of Gynecology and Obstetrics) I et II. Le GS a aussi une place tres importante dans la stadification ganglionnaire des cancers du col a un stade precoce. Par ailleurs, une reflexion importante est menee sur la radicalite des hysterectomies chez les patientes operees de cancer du col a un stade precoce. De meme, la stadification ganglionnaire lombo-aortique dans les cancers du col localement avances ne serait benefique qu’a une minorite de patientes. Les cancers de l’ovaire n’echappent pas a la desescalade chirurgicale avec une diminution des indications de lymphadenectomie.

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4 ) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1 , ECRTSMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1 ; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Accurate risk prediction of distant recurrence (DR) is crucial for personalized adjuvant systemic therapy of endometrial cancer (EC) stage I-III patients, as DR is associated with a 5-year overall survival of 10-20%. Risk stratification and treatment recommendation are currently based on histopathological and molecular markers, which is challenging due to high inter-observer variability and testing costs respectively. Deep Learning (DL) models can predict prognosis by identifying relevant visual features from H&E whole slide images (WSIs) at different resolutions without prior assumptions. Here, we developed and tested the first interpretable state-of-the-art DL model for WSI-based risk prediction of DR of stage I-III EC (DeREC) from the randomized PORTEC-1/-2/-3 trials and three clinical cohorts with long-term follow-up data. We used one representative H&E WSI each from 1761 EC patients, excluding those who received adjuvant chemotherapy as it lowers the risk of DR. We randomly sampled 20% as a held-out internal test set (N=353 with 62 events; 8.45 year median follow-up) and performed a 5-fold cross-validation on the training set (N=1408). WSIs were partitioned into 360 micron patches at 40x magnification. DeREC combined self-supervised representation learning of patches using a multi-resolution vision transformer and a WSI-level graph attention-based time-to-event prediction model. The model performance of correctly ranking patients by predicted risk scores and true time to DR was measured with the concordance-index and compared with a Cox’ Proportional Hazards (CPH) model fitted on histopathological variables (histotype, grade, lymphovascular space invasion, stage). Discriminative quality of the predicted risk groups was investigated with Kaplan-Meier analysis and the log-rank test. Most predictive patches by predicted risk groups were reviewed by an expert gynecopathologist for identification of prognostic morphological features. DeREC achieved a concordance-index of 0.764 [95%CI 0.754-0.773] on 5-fold cross validation and 0.757 on the test set, as compared to 0.704 [95%CI 0.662-0.746] with CPH. Predicted risk groups around quartiles 1 and 3 accurately stratified patients between low (N=89), intermediate (N=175), high (N=89) risk of DR (p Citation Format: Sarah Fremond, Sonali Andani, Jurriaan Barkey Wolf, Gitte Ørtoft, Estrid Høgdall, Jouke Dijkstra, Jan J. Jobsen, Ina M. Jürgenliemk-Schulz, Ludy CHW Lutgens, Melanie E. Powell, Naveena Singh, Linda R. Mileshkin, Helen J. Mackay, Alexandra Leary, Dionyssios Katsaros, Hans W. Nijman, Stephanie M. de Boer, Remi A. Nout, Vincent T.H.B.M Smit, Carien L. Creutzberg, Nanda Horeweg, Viktor H. Koelzer, Tjalling Bosse. Deep learning risk prediction model of distant recurrence from H&E endometrial cancer slides. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5695.

Background: Knowledge regarding the homologous recombination deficiency (HRD) status at diagnosis is essential to manage patients (pts) with advanced epithelial ovarian cancer (EOC). HRD is defined by either a BRCA1 or BRCA2 mutation, or genomic instability (GI). These genomic tests are performed on FFPE tumor samples and unfortunately non-contributive in 12-18% of cases. Advanced OC frequently presents with ascites which could provide an alternative source of Cell-free tumor DNA (cftDNA). Methods: We collected data from 53 patients undergoing primary (N=35) or interval (N=12) laparoscopy for suspected/confirmed EOC, or abdominal paracentesis at relapse (N=6). cftDNA was extracted from 20ml of ascites, or 20ml of peritoneal washings if no ascites was present. Intraperitoneal cfDNA was subjected to next generation sequencing (NGS) to confirm tumoral origin and to identify BRCA1/2 mutations, and GI was assessed by measuring large scale genomic alterations on shallow Whole Genome Sequencing (sWGS). Matching FFPE tumor samples underwent NGS and GI testing. Results: A total of 53 patient were included. Overall, intraperitoneal cfDNA was detectable in more than 90% (48/53) pts, and in 100% (35/35) of pts at diagnosis. Even among patients without visible ascites, peritoneal washings yielded cfDNA in 40% of cases (3/7). DNA quality (presence of mononucleosomal pics around 160bp and low contamination with high molecular DNA greater than 700bp) and quantity (median concentration: 3700 ng/ml; range 109 - 65 000 ng/ml) was excellent and median turn-around testing time was 21 days. Ascitic cfDNA was confirmed as tumoral in 98% of cases, largely due to detection of TP53 mutations (85,5%, 41/48), other variants in cftDNA included. Seven (15%) and 6 (12,5%) patients had BRCA1 and BRCA2 mutations, respectively. For 36 pts, NGS results on matching tumor tissue were available, and among those 97% (35/36) had concordant mutations detected in ascitic cftDNA and tumor tissue DNA. In 5 pts for whom tumor tissue-based NGS was non-contributive, NGS on cftDNA from ascites was informative and uncovered a BRCA2 mutation in one pt. We then performed GI testing on 18 cftDNA samples using sWGS and 100% of samples yielded contributive GI test results. Of these 18 pts, 42% (7/18) has failed GI testing on matching tumor sample. Conclusion: Genomic profiling on cftDNA from ascites is feasible, yields high quality and quantity tumor derived cfDNA. Importantly this approach has a fast testing turn-around time and only requires 20ml of ascites so that the majority of pts with advanced OC would be eligible to this approach. This cftDNA is suitable for HRD testing combining both BRCA mutation analysis and GI testing and should be done in every patient at primary laparoscopy Citation Format: Cyril Roussel-Simonin, Felix Blanc-Durand, Etienne Roueau, Audrey Le Formal, Laure Chardin, Elisa Yaniz, Sebastien Gouy, Amandine Maulard, Stéphanie Cherrier, Claire Sanson, Lea Mauny, Sophie Coterret, Francois Zaccarini, Roseline Tang, Alexandra Leary. Homologous recombination deficiency (HRD) testing on cell-free tumor DNA in ascites of patients with newly diagnosed advanced epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3368.

Background The disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome. Method We identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%. Results In our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival. Conclusion TIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.

Purpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

Purpose: In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical–surgical treatment. Experimental Design: The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin–paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests. Results: The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03–0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11–0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery. Conclusions: The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance. See related commentary by May and Oza, p. 4432

Background At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations. Materials and methods Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS. Results NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445). Conclusion NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.

International audience; Granulosa cell tumor (GCT) is a form of ovarian tumor characterized by its tendency to recur years after surgical ablation. Little is known about the mechanisms involved in GCT development and progression. GCTs can produce estradiol (E2), but whether this hormone could play a role in this cancer through its nuclear receptors, i.e. ER alpha and ER beta, remains unknown. Here, we addressed this issue by cell-based and molecular studies on human GCTs and GCT cell lines. Importantly, we observed that E2 significantly increased the growth of GCT cells by promoting cell survival. The use of selective agonists of each type of receptor, together with Esr1 (ER alpha) or Esr2 (ER beta)-deleted GCT cells, revealed that E2 mediated its effects through ER alpha-dependent genomic mechanisms and ER beta/ER alpha-dependent extra-nuclear mechanisms. Notably, the expression of Greb1, a prototypical ER target gene, was dose-dependently upregulated by E2 specifically through ER alpha in GCT cells. Accordingly, using GCTs from patients, we found that GREB1 mRNA abundance was positively correlated to intra-tumoral E2 concentrations. Tissue microarray analyses showed that there were various combinations of ER expression in primary and recurrent GCTs, and that ER alpha expression persisted only in combination with ER beta in similar to 40% of recurrent tumors. Altogether, this study demonstrates that E2 can promote the progression of GCTs, with a clear dependence on ER alpha. In addition to demonstrating that GCTs can be classified as a hormone-related cancer, our results also highlight that the nature of ER forms present in recurrent GCTs could underlie the variable efficiency of endocrine therapies. (C) 2022 The Pathological Society of Great Britain and Ireland.

Background Ovarian small cell carcinoma, hypercalcaemic type (SCCOHT) is a rare and lethal disease affecting young women. As histological diagnosis is challenging and urgent, there is a clear need for a robust diagnostic test. While mutations in the chromatin-remodelling gene, SMARCA4, appear to be typical, it may not be feasible routinely to be clinically relevant. Methods Previous studies have described the value of SMARCA4 IHC to differentiate SCCOHT from ovarian neoplasms (ON), with similar histologic appearances. We aimed to evaluate its clinical utility among a cohort of 44 SCCOHT and 94 rare ON frequently misdiagnosed as SCCOHT. Results Forty-three percent (16/36) of SCCOHT had been classified locally as non-SCCOHT confirming the diagnosis challenge. Sensitivity and specificity of SMARCA4 IHC were excellent at 88% and 94%, respectively. In a community setting with a much lower prevalence of the disease, estimated PPV is 40% while NPV remained high at 99%. Finally, among the 16 SCCOHT misclassified locally, SMARCA4 IHC testing would have resulted in corrected diagnosis in 88% of cases. Conclusions SMARCA4 IHC is a highly sensitive, and specific test for the diagnosis of SCCOHT and is of huge clinical utility in providing a timely and accurate diagnosis of this challenging disease.

Purpose: Regarding cancer antigen 125 (CA-125) longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecologic Cancer Intergroup (GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in patients with recurrent ovarian cancer enrolled in the CALYPSO trial. The objective was to validate the higher predictive and prognostic values of KELIM during first-line treatments. Experimental Design: Data from three large phase III trials were analyzed: AGO OVAR 9 [learning set: carboplatin-paclitaxel (CP) ± gemcitabine; n = 1,288]; AGO OVAR 7 (validation set: CP ± topotecan; n = 192); and ICON7 (validation set: CP ± bevacizumab; n = 1,388). The CA-125 profiles were fit with a nonlinear mixed-effect model during the first 100 days, and the individual KELIM were calculated. KELIM prognostic and predictive values for survival were assessed against GCIG criterion and other prognostic factors in univariate/multivariate analyses. Results: The GCIG CA-125 endpoint provided no meaningful predictive/prognostic information. C-index analyses confirmed the higher predictive value of KELIM compared with GCIG criterion for progression-free survival and overall survival (OS). KELIM provided reproducible prognostic information. Patients with favorable KELIM ≥ upper tercile (0.0711 per days) consistently experienced better OS, with HRs between 0.44 and 0.58 (e.g., median OS >65 months vs. Conclusions: Modeled KELIM provides higher predictive and prognostic information based on CA-125 longitudinal kinetics compared with GCIG response criteria during first-line chemotherapy. Integration of this endpoint in guidelines may be considered. Individual KELIM and survival simulations can be calculated at http://www.biomarker-kinetics.org/. Further assessment of the surrogate value of KELIM treatment–related variations in a GCIG meta-analysis is warranted. See related commentary by Maitland et al., p. 5182

Background/aim We evaluated patients undergoing salvage hysterectomy after brachytherapy (BT) following concomitant chemoradiation (CRT) for locally advanced cervical cancers (LACC), when residual disease was suspected. Patients and methods From 2004 to 2013, 29 patients had a radical hysterectomy at the Gustave Roussy for suspicion of clinical and/or radiological residual disease. Outcomes, morbidities and the accuracy of the evaluation of response to CRT and BT were evaluated. Results The rate of complications grade>IIIa was 24%, with no difference between the 14 patients with histological residual disease and the 15 with a complete response. Magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) revealed a sensitivity of 92% and 100%, but a poor specificity of less than 40%. Three recurrences occurred in patients with residual disease (brain, rectosigmoid colon, peritoneum and lung). Conclusion The clinical examination, MRI and PET-CT are suboptimal for diagnosing residual disease after CRT and BT. The morbidity of adjuvant hysterectomy is high and does not prevent recurrences.

BackgroundClinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood.Methods4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD geneMsh2,leading to a massive accumulation of mutations after serial passages of cells. Insertions/deletion events and mutation load were evaluated by whole exome sequencing. Mice bearing highly mutated MMRD tumor or parental tumors were treated with αPD-1 and tumor volume was monitored. Immune cell type abundance was dynamically assessed in the tumor microenvironment and the blood by flow cytometry. Neutrophils were depleted in mice using αLY6G antibody, and regulatory T (Treg) cell population was reduced with αCD25 or anti-cytotoxic T-lymphocytes-associated protein 4 (αCTLA-4) antibodies. Patients with MMRD tumors treated with immune checkpoint blockade-based therapy were retrospectively identified and neutrophil-to-lymphocyte ratio (NLR) was evaluated and examined for correlation with clinical benefit.ResultsBy recapitulating mismatch repair deficiency in different mouse tumor models, we revealed that elevated circulating tumor-induced neutrophils (TIN) in hypermutated MMRD tumors hampered response to αPD-1 monotherapy. Importantly, depletion of TIN using αLy-6G antibody reduced Treg cells and restored αPD-1 response. Conversely, targeting Treg cells by αCD25 or αCTLA-4 antibodies limited peripheral TIN accumulation and elicited response in αPD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, αPD-1+αCTLA-4 combination overcomes TIN-induced resistance to αPD-1 in mice bearing MMRD tumors. Finally, in a cohort of human (high microsatellite instability)/MMRD tumors we revealed that early on-treatment change in the NLR ratio may predict resistance to αPD-1 therapy.ConclusionsTIN countered αPD-1 efficacy in MMRD tumors. Since αCTLA-4 could restrict TIN accumulation, αPD-1+αCTLA-4 combination overcomes αPD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation.

Background The efficacy and safety of rucaparib maintenance treatment in ARIEL3 were evaluated in subgroups based on best response to most recent platinum‐based chemotherapy and baseline disease. Methods Patients were randomized 2:1 to receive either oral rucaparib at a dosage of 600 mg twice daily or placebo. Investigator‐assessed PFS was assessed in prespecified, nested cohorts: BRCA‐mutated, homologous recombination deficient (HRD; BRCA mutated or wild‐type BRCA/high loss of heterozygosity), and the intent‐to‐treat (ITT) population. Results Median PFS for patients in the ITT population with a complete response to most recent platinum‐based chemotherapy was 11.1 months in the rucaparib arm (126 patients) versus 5.6 months in the placebo arm (64 patients) (HR, 0.33 [95% CI, 0.23–0.48]), and in patients with a partial response (249 vs. 125), it was 9.0 versus 5.3 months (HR, 0.38 [0.30–0.49]). In subgroups of the ITT population based on baseline disease, median PFS was 8.2 versus 5.3 months (HR, 0.40 [0.28–0.57]) in patients with measurable disease (141 rucaparib vs. 66 placebo), 10.4 versus 4.5 months (HR, 0.31 [0.20–0.48]) in those with nonmeasurable but evaluable disease (104 vs. 56), and 14.1 versus 7.3 months (HR, 0.35 [0.24–0.51]) in those with no residual disease (130 vs. 67). Across subgroups, significantly longer median PFS was observed with rucaparib versus placebo in the BRCA‐mutated and HRD cohorts. Objective responses were reported in patients with measurable disease and in patients with nonmeasurable but evaluable baseline disease. Safety was consistent across subgroups. Conclusion Rucaparib maintenance treatment provided clinically meaningful efficacy benefits across subgroups based on response to last platinum‐based chemotherapy or baseline disease., The efficacy and safety of the PARP inhibitor rucaparib as maintenance treatment for recurrent ovarian cancer were similar regardless of whether patients had a complete or partial response to their last platinum‐based chemotherapy or according to whether they had measurable, nonmeasurable but evaluable, or no residual disease at baseline. Rucaparib also reduced the disease burden in patients who had measurable or nonmeasurable but evaluable disease at baseline.

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity., The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers

Contains fulltext : 232064.pdf (Publisher’s version ) (Open Access) PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

Background The identification of factors responsible for false negative (FN) rate at 18F- Fluorodeoxyglucose (FDG) Positron Emission Tomography /Computed Tomography (PET/CT) in para-aortic (PA) lymph nodes in the presurgical staging of patients with locally advanced cervical cancer (LACC) is challenging. The aim of this study was to evaluate the impact of PET/CT technology. Methods A total of 240 consecutive patients with LACC (International Federation of Gynecology and Obstetrics, FIGO, stage IB2-IVA) and negative Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and negative 18F-FDG PET/CT in the PA region, undergoing laparoscopic PA lymphadenectomy before chemoradiotherapy were included. The FN rate in patients studied with Time of flight (TOF) PET/CT (TOF PET) or non-Time of flight PET/CT (no-TOF PET) technology was retrospectively compared. Results Patients presented with FIGO stage IB (n = 78), stage IIA-B (n = 134), stage III (n = 18) and stage IVa (n = 10), squamous cell carcinoma (n = 191) and adenocarcinoma (n = 49). 141/240 patients were evaluated with no-TOF PET/CT and 99/240 with TOF PET/CT. Twenty-two patients (9%) had PA nodal involvement at histological analysis and considered PET/CT FN findings. The FN rate was 8.5% for no-TOF PET and 10% for TOF PET subgroup respectively (p = 0.98). Ninety patients (38%) presented with pelvic node uptakes at PET/CT. The FN rate in the PA region was 18% (16/90) and 4% (6/150) in patients with and without pelvic node involvement at PET/CT respectively (19 vs 3% for no-TOF PET and 17 vs 5% for TOF PET subgroup). Conclusions In LACC, FN rate in PA lymph nodes detection is a clinical issue even for modern PET/CT, especially in patients with pelvic uptake. Surgical lymphadenectomy should be performed in case of negative PET/CT at PA level in these patients, while it could be discussed in the absence of pelvic uptake.

Objectives: In patients with recurrent advanced endometrial carcinomas (EC), innovative treatments are needed after platinum chemotherapy. EC are characterized by frequent defective DNA repair, along with alterations of PI3K-AKT-mTor, and IGF1R pathways. In preclinical studies, the activity of PARP inhibitor is increased by the inhibition of PI3K-AKT pathway. Metformin inhibits the PI3K-AKT-mTor signaling pathway, and reduces IGF1 circulating levels. Metronomic cyclophosphamide may increase the activity of PARP inhibitors through DNA alkylating and anti-angiogenic effects. ENDOLA trial was meant to assess the safety and efficacy of the triplet olaparib (PARP 1-3 inhibitor) + metronomic cyclophosphamide + metformin in patients with advanced EC Methods: ENDOLA trial (NCT02755844) was an academic French prospective multicenter phase I/II open-label dose-escalation study meant to assess the safety, the Recommended Phase II trial Dose (RP2D), and the efficacy of olaparib combined to metronomic cyclophosphamide 50 mg PO QD and metformin 500 mg PO TID in patients with recurrent advanced EC. In the phase I part, olaparib was dose-escalated from PO 150 mg to 300 mg BID with a continual reassessment method (CRM), aiming at defining the RP2D. In the phase II part, the cohort was expanded to assess the efficacy of the triplet in terms of non-progression rate at 10 weeks (H0= 20%; H1= 50%; 1-sided α risk=0.01; power = 90%). Results: From Sept 2016 to Nov 2019, 35 patients enrolled, and 31 were assessable (median age: 69, IQR: 62-72; endometrioid: n=18 (51.4%); serous: n=11 (35.5%); carcinosarcoma: n=2 (6.5%)). In the phase I part (17 patients), 1 DLT (5.9%) was observed: grade 3 fatigue during cycle 1 at 150 mg. Dose-escalation was possible up to 300 mg BID, that was the RP2D. In the phase II part (14 patients), the overall response rate was 20.8%, and the disease-control rate was 66.6 %. The non-progression rate at 10 weeks was 61.5% (95% CI 42.8-80.2). The median PFS was 5.1 months, including 7.5 months (5.1-8.9) for endometrioid, and 4.3 months (2.7-5.8) for serous carcinomas. Treatment-related serious adverse-events (AEs) occurred in 3 patients (grade 3 fatigue; grade 4 lymphopenia; grade 4 lymphopenia & neutropenia). The most frequent grade 3-4 treatment-related AEs were lymphopenia (32.3%); anemia (16.1%); neutropenia (16.1%); and fatigue (12.9%). Conclusions: In heavily pre-treated patients with advanced EC, olaparib 300 mg BID could be safely combined to metformin 1500 mg/day and metronomic cyclophosphamide 50 mg/day. With a 61.5% non-progression rate at 10 weeks, the 1st-objective was reached. The 5.1 month median PFS (7.5 for endometrioid and 4.3 for serous) is promising compared to those observed with chemotherapy or immunotherapy-based combination in KEYNOTE-775 (Colombo et al. Proc ESMO 2021). Investigation in phase III is warranted. Citation Format: Benoit You, Alexandra Leary, Manuel Rodrigues, Philippe Follana, Cyril Abdeddaim, Florence Joly, Sylvie Bin, Laurent Villeneuve, Marine Alexandre, Florent Boutitie, Delphine Maucort-Boulch, Verane Schwiertz, Gilles Freyer. Safety and efficacy of olaparib combined to metronomic cyclophosphamide and metformin in recurrent advanced/metastatic endometrial cancer patients: ENDOLA trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT005.

High tumor mutational burden assessed in tissue biopsies (tTMB-H) or blood (bTMB-H) is associated with clinical efficacy in patients treated with immunotherapies. CheckMate 848 (NCT03668119) is a prospective phase 2 study of nivolumab (NIVO) with or without ipilimumab (IPI) in patients with advanced or metastatic solid tumors that are tTMB-H or bTMB-H (≥ 10 mutations/megabase) who were immunotherapy-naive and refractory to standard local therapies. The primary endpoint was objective response rate (ORR) in patients with tTMB-H or bTMB-H, assessed by FoundationOne® CDx-based and Clinical Trial Assays (Foundation Medicine), respectively. The study was not powered to compare NIVO + IPI vs NIVO. We present the interim and final analyses for the tTMB-H and bTMB-H cohorts, respectively (≥ 12 months follow-up, database lock June 2021). Of 1954 screened patients, 212 were randomized 2:1 to NIVO 240 mg Q2W + IPI 1 mg/kg Q6W or NIVO 480 mg Q4W for ≤ 24 months, and 201 (135 tTMB-H; 147 bTMB-H) were refractory to standard therapies. Of > 40 tumor types, colorectal (10.8%), small-cell lung (7.5%), breast (7.1%), and uterine (7.1%) were the most common. ORR and survival outcomes with NIVO + IPI were improved in patients with tTMB-H. The responses were independent of bTMB-H status in the tTMB-H cohort but improved with tTMB-H status in the bTMB-H cohort (Table). The safety profile of NIVO + IPI was manageable, and clinical outcomes with NIVO were comparable with previous studies. The impact of TMB cutoff, PD-L1 expression, and microsatellite instability were explored. In conclusion, NIVO + IPI demonstrated clinical efficacy with a manageable safety profile in patients with advanced or metastatic solid tumors that are tTMB-H or bTMB-H and refractory to standard therapies, with increased efficacy observed in patients with tTMB-H. NIVO + IPI tTMB-H cohort bTMB-H cohorta Patients, n (%)b,c 68 (32.1) 80 (37.7) Number of prior treatments, median (range) 2 (0–7) 2 (1–9) ORR, n (%)c, 95% CI 24 (35.3), 24.1–47.8 18 (22.5), 13.9–33.2 ORR in patients with bTMB-H by tTMBc: < 10 mut/Mb (n = 31), n (%), 95% CI NA 3 (9.7), 2.0–25.8 ≥ 10 mut/Mb (n = 39), n (%), 95% CI NA 13 (33.3), 19.1–50.2 ≥ 10 to < 16 mut/Mb (n = 18), n (%), 95% CI NA 3 (16.7), 3.6–41.4 ≥ 16 mut/Mb (n = 21), n (%), 95% CI NA 10 (47.6), 25.7–70.2 ORR in patients with tTMB-H by bTMBc: < 10 mut/Mb (n = 20), n (%), 95% CI 7 (35.0), 15.4–59.2 NA ≥ 10 mut/Mb (n = 43), n (%), 95% CI 16 (37.2), 23.0–53.3 NA ≥ 10 to < 16 mut/Mb (n = 12), n (%), 95% CI 3 (25.0), 5.5–57.2 NA ≥ 16 mut/Mb (n = 31), n (%), 95% CI 13 (41.9), 24.5–60.9 NA Percentage of responders (≥ 9 months) (95% CI) 91 (68–98) 88 (61–97) Median PFS, months (95% CI)c 4.1 (2.8–11.3) 2.8 (2.3–3.0) Median OS, months (95% CI)c 14.5 (7.7–NE) 8.5 (5.8–10.5) aThe bTMB cohort was randomized prior to December 20, 2019. bOut of 212 randomized patients; data presented in this table are from patients who were refractory to standard therapies. cMinimum follow-up 12 months. bTMB, blood tumor mutational burden; NA, not applicable; NE, not evaluable; PFS, progression-free survival; OS, overall survival; tTMB, tissue tumor mutational burden. Citation Format: Michael Schenker, Mauricio Burotto, Martin Richardet, Tudor Ciuleanu, Anthony Goncalves, Neeltje Steeghs, Patrick Schöffski, Paolo A. Ascierto, Michele Maio, Iwona Lugowska, Lorena Lupinacci, Alexandra Leary, Jean-Pierre Delord, Julieta Grasselli, David S. Tan, Jennifer E. Friedmann, Jacqueline Vuky, Marina Tschaika, Ruta Slepetis, Georgia D. Kollia, Misena Pacius, Ning Huang, Parul Doshi, Jonathan Baden, Massimo Di Nicola. CheckMate 848: A randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT022.

5544 Background: In ARIEL3 (NCT01968213), rucaparib maintenance treatment led to significant improvement vs placebo for the primary endpoint of investigator-assessed progression-free survival (PFS) in patients (pts) with platinum-sensitive, recurrent ovarian carcinoma responsive to the last line of platinum therapy (Coleman et al. Lancet. 2017;390:1949–61). The largest benefit was observed in pts with carcinomas with a BRCA mutation or high loss of heterozygosity (LOH), a marker of homologous recombination deficiency (HRD). However, rucaparib also improved PFS in pts with carcinomas negative by HRD test (ie, BRCA wild-type with low LOH), a subset of pts for which there is no identified molecular mechanism conferring PARP inhibitor sensitivity. Among these pts (rucaparib, n = 107; placebo, n = 54), median PFS was 6.7 vs 5.4 months, respectively (HR, 0.58 [95% CI 0.40–0.85]; P= 0.0049), and 31.8% vs 4.3% were progression-free at 1 yr. In this post hoc exploratory analysis, we further evaluated the efficacy of rucaparib maintenance vs placebo in this subset of pts. Methods: Pts were randomized 2:1 to oral rucaparib (600 mg BID) or placebo. For this analysis, investigator-assessed PFS and safety were evaluated in pts with HRD-negative carcinoma, defined as BRCA wild-type with genomic LOH < 16% using Foundation Medicine’s T5 NGS assay. Results: Visit cutoff dates for efficacy and safety were Apr 15, 2017, and Dec 31, 2019. Across subgroups based on demographic or disease characteristics, the trend of rucaparib benefit vs placebo was consistently observed in pts with HRD-negative carcinoma (Table). The safety profile of rucaparib in the HRD-negative population was consistent with that of the overall safety population reported previously. Conclusions: Rucaparib maintenance reduced risk of progression in pts with ovarian carcinomas, including those not associated with HRD, regardless of clinical prognostic factors. [Table: see text]

5554 Background: Antibodies targeting PDL1 or PD1 have been disappointing so far in the treatment of ovarian cancer (OC). A greater understanding of the complex iTME and of the impact of chemotherapy on immune features could uncover promising immune targets. We previously reported that neoadjuvant chemotherapy (NACT) increased CD4+ and CD8+ immune cells (IC) and depleted FOXP3+ suppressive T-regs in OC iTME. Here we aimed to describe the expression of PDL1 as well as other co-regulatory molecules in OC and their changes under NACT. Methods: Tumor samples and clinical data were prospectively collected from patients (pts) in the randomized CHIVA trial of NACT +/- nintedanib. Samples were evaluable for immune profiling for 116-124 pts at diagnosis and 89-107 at surgery after 3 cycles of NACT. IC stained for CD4, CD8 were scored as number of IC+/mm². Expression of immune co-regulatory molecules PDL1, TIM3, LAG3 and IDO was scored as percentage of positive cells, and tumors were classified as PDL1/TIM3/IDO/LAG3 positive if > 1% of IC and/or tumor cells (TC) were positive. Highly sensitive pts, defined as objective response to NACT and prolonged median progression-free survival (mPFS > 24months), were compared to refractory pts (progressing during or within 3mo of platinum). Results: As expected, about one third (36%) of tumors were PDL1+ at diagnosis. In contrast, the prevalence of other co-regulatory molecules was higher with 52%, 54% and 93% of tumors being positive for IDO, LAG3 and TIM3, respectively. There was no significant change in PDL1 expression with NACT. However, in paired samples NACT significantly increased IDO and LAG3 expression (p < 0.05), such that 60% and 66% of tumors post-NACT were positive for IDO and LAG3, respectively. TIM3 expression remained high post-NACT with 92% of positive tumors. Highly sensitive tumors (vs refractory tumors) had significantly higher IC expression of TIM3 after NACT (24% vs 6%, p = 0.005), and were significantly more infiltrated by CD4+ (441 vs 228 cells/mm2, p = 0.04) and CD8+ (460 vs 225 cells/mm2, p = 0.045) T cells. Conclusions: Other immune targets beyond PDL1 are highly expressed in OC. In addition NACT appears to prime the iTME by increasing effector T cell infiltration and the expression of other relevant co-regulatory molecules (LAG3, TIM3 and IDO). Future studies could be performed by priming the iTME with NACT and testing novel immune therapies based on target expression in samples obtained at interval debulking surgery.

TPS5614 Background: Besides PARP inhibitors and bevacizumab, there are no approved maintenance therapies after platinum based chemotherapy for patients with a platinum sensitive relapsed epithelial ovarian cancer (OC). Immune checkpoint inhibitors (ICI) as single agents have limited activity in OC. One attractive strategy is to turn OC from immunogenic “cold” to “hot” tumors via vaccination with tumor-associated antigens (TAAs). OSE2101 is a multiple-neoepitope vaccine restricted to HLA-A2-positive patients (45% of OC patients) targeting 5 TAAs: TP53, MAGE2, MAGE3, CEA and HER2. These neo-epitopes are modified to increase both major histocompatibility complex and the T cell receptor binding affinity. The proof of concept for this approach was recently demonstrated with OSE2101 improving overall survival in a phase III trial in lung cancer progressing after ICI (Besse et al. 2021). The combination of OSE2101 with an ICI may most effectively harness anti-tumor immunity. Methods: TEDOVA is an international randomized open-label, phase II trial evaluating the benefit of maintenance by OSE2101 alone or in combination with PD1 inhibition (pembrolizumab) after platinum based chemotherapy in relapsed OC, previously treated with bevacizumab (if eligible) and a PARP inhibitor (if eligible). Patients (N=180) with CR/PR/SD at the end of chemotherapy are randomized (1:1:2) to: Observation/BSC (Arm A), OSE2101 alone (Arm B), or OSE2101 in combination with pembrolizumab (Arm C). Experimental treatments are continued until progression, or intolerance, for up to 2 years. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response rate, safety, time to subsequent first or second treatment (TTST-1, TTST-2) and overall survival. 180 HLA-A*02 positive patients will be randomized. HLA-A*02 negative patients will be followed in a separate observational cohort. The sample size is calculated to provide 90% power to detect an improvement in PFS for Arm C vs Arm A with a HR of 0.57. Three one-sided Log-rank tests will be considered in a pre-defined sequence: H1: C (OSE2101+pembrolizumab) vs A (BSC); H2: C (OSE2101+pembrolizumab) vs B (OSE2101) and H3: B vs A. The type I error will be α=5%. The type II error will be β=10%. Tests will be one-sided. Status: The TEDOVA/GINECO-OV244b/ENGOT-ov58 trial is currently recruiting. Clinical trial information: NCT04713514.

HER2 status has not been investigated in the context of the molecular endometrial cancer (EC) classification. Here, we aimed to determine the clinicopathological features and prognostic significance of the HER2 status in the molecularly classified PORTEC-3 trial population of patients with high-risk EC (HREC). HER2 testing was performed on tumor tissues of 407 molecularly classified HREC. HER2 status was determined by HER2 immunohistochemistry (IHC, all cases) and subsequent HER2 dual in situ hybridization for cases with any (in) complete moderate to strong membranous HER2 IHC expression. The &Chi, 2 test and Spearman&rsquo, s Rho correlation coefficient were used to compare clinicopathological and molecular features. The Kaplan&ndash, Meier method, log-rank test, and Cox proportional hazards models were used for survival analysis. We identified 24 (5.9%) HER2-positive EC of various histological subtypes including serous (n = 9, 37.5%), endometrioid (n = 6, 25.0%), and clear cell (n = 5, 20.8%). HER2 positivity was highly associated with the p53-abnormal subgroup (p53abn, 23/24 cases, p &lt, 0.0001). The correlation between p53abn and the HER2 status (&rho, = 0.438, 0.0001) was significantly stronger (p &lt, 0.0001) than between serous histology and the HER2 status (&rho, = 0.154, p = 0.002). HER2 status did not have independent prognostic value for survival after correction for the molecular classification. Our study strongly suggests that molecular subclass-directed HER2 testing is superior to histotype-directed testing. This insight will be relevant for future trials targeting HER2.

Background Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort. Methods After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided. Results Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P = .12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P = .003) for “other” vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, “other,” and MLH1-hypermethylated MMRd-EC groups, respectively. Conclusions The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC.

PURPOSE The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated ( POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC ( P < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% ( P = .019); 100% versus 97% for patients with POLEmut EC ( P = .637); 68% versus 76% ( P = .428) for MMRd EC; and 80% versus 68% ( P = .243) for NSMP EC. CONCLUSION Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.

Resume Le cancer de l’endometre est frequent chez la femme âgee et souvent associe a des comorbidites. Sa prise en charge en cas de situation metastatique et/ou de rechute necessite une approche multidisciplinaire. Les progres recents dans la comprehension de l’oncogenese et la classification moleculaire permettent d’envisager de nouvelles perspectives therapeutiques. Ces premieres recommandations etablies, selon la methodologie des recommandations pour la pratique clinique (RPC) Nice-Saint-Paul, visent a integrer les avancees moleculaires dans la prise en charge diagnostique et therapeutique. En 2020, le diagnostic histologique du cancer de l’endometre est base sur la morphologie et l’immunohistochimie incluant au minimum p53, les recepteurs aux œstrogenes et a la progesterone. La recherche d’une deficience du systeme de reparation des mesappariements de l’ADN (MMR) doit etre realisee de facon systematique pour toutes les tumeurs endometriales avancees a visee oncogenetique et theranostique. Elle peut etre recherchee dans un premier temps par une analyse en immunohistochimie avec les 4 marqueurs (MLH1, MSH2, MSH6, PMS2). Le traitement medical tient compte du type histologique, de la presence de recepteurs hormonaux et du profil de la patiente pour orienter vers une chimiotherapie (carboplatine–paclitaxel) ou une hormonotherapie (par exemple de type progestatifs) ; en cas d’une deficience MMR, la meilleure option est de proposer un essai d’immunotherapie. Dans le cadre de la prise en charge globale du cancer avance de l’endometre, la place de la radiotherapie (et a un moindre niveau, de la chirurgie) doit etre discutee, notamment en cas d’evolution exclusivement locoregionale ou de maladie oligometastatique.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive malignancy that occurs in young women, is characterized by recurrent loss-of-function mutations in the SMARCA4 gene, and for which effective treatments options are lacking. The aim of this study was to broaden the knowledge on this rare malignancy by reporting a comprehensive molecular analysis of an independent cohort of SCCOHT cases. We conducted Whole Exome Sequencing in six SCCOHT, and RNA-sequencing and array comparative genomic hybridization in eight SCCOHT. Additional immunohistochemical, Sanger sequencing and functional data are also provided. SCCOHTs showed remarkable genomic stability, with diploid profiles and low mutation load (mean, 5.43 mutations/Mb), including in the three chemotherapy-exposed tumors. All but one SCCOHT cases exhibited 19p13.2-3 copy-neutral LOH. SMARCA4 deleterious mutations were recurrent and accompanied by loss of expression of the SMARCA2 paralog. Variants in a few other genes located in 19p13.2-3 (e.g., PLK5) were detected. Putative therapeutic targets, including MAGEA4, AURKB and CLDN6, were found to be overexpressed in SCCOHT by RNA-seq as compared to benign ovarian tissue. Lastly, we provide additional evidence for sensitivity of SCCOHT to HDAC, DNMT and EZH2 inhibitors. Despite their aggressive clinical course, SCCOHT show remarkable inter-tumor homogeneity and display genomic stability, low mutation burden and few somatic copy number alterations. These findings and preliminary functional data support further exploration of epigenetic therapies in this lethal disease.

Bevacizumab is approved as a maintenance treatment in first-line setting in advanced-stage III-IV ovarian cancers, because GOG-0218 and ICON-7 phase III trials demonstrated progression-free survival benefits. However, only the subgroup of patients with high-risk diseases (stage IV, and incompletely resected stage III) derived an overall survival (OS) gain in the ICON-7 trial (4.8 months). The modeled CA-125 elimination rate constant K (KELIM) parameter, based on the longitudinal CA-125 kinetics during the first 100 days of chemotherapy, is a potential indicator of the tumor primary chemo-sensitivity. In the ICON-7 trial dataset, the OS of patients within the low- and high-risk disease groups was assessed according to treatment arms and KELIM. Among the patients with high-risk diseases, those with favorable standardized KELIM of at least 1.0 (n = 214, 46.7%) had no survival benefit from bevacizumab, whereas those with unfavorable KELIM less than 1.0 (n = 244, 53.2%) derived the highest OS benefit (absolute difference = 9.1 months, 2-sided log-rank P = .10; Cox hazard ratio = 0.78, 95% confidence interval = 0.58 to 1.04, 2-sided P = .09).

Carcinoma d'ovari recurrent; Rucaparib Carcinoma de ovario recurrente; Rucaparib Recurrent Ovarian Carcinoma; Rucaparib PURPOSE To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo. PATIENTS AND METHODS Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as μTOX × TOX + TWiST, with μTOX calculated using EQ-5D-3L data. RESULTS The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib. CONCLUSION The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts. Supported by Clovis Oncology. Additional support was provided in part by the Ann Rife Cox Chair in Gynecology and the Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund (to R.L.C.) and by the National Institute of Health Research Biomedical Research Centre at University College London (to J.A.L.). C.A. is supported in part by Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748. Funding was also provided by US Department of Defense Ovarian Cancer Research Program OC120506, a V Foundation Translational Award, and a Stand Up To Cancer–Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant No. SU2C-AACR-DT16–15; all to E.M.S.). Stand Up to Cancer is a program of the Entertainment Industry Foundation; research grants are administered by the American Association for Cancer Research, a scientific partner of Stand Up To Cancer.

Background: Following disappointing results with PD-1/PD-L1 inhibitors in ovarian cancer, it is essential to explore other immune targets. The aim of this study is to describe the tumor immune microenvironment (TME) according to genomic instability in high grade serous ovarian carcinoma (HGSOC) patients receiving primary debulking surgery followed by carboplatin-paclitaxel chemotherapy +/− nintedanib. Methods: 103 HGSOC patients’ tumor samples from phase III AGO-OVAR-12 were analyzed. A comprehensive analysis of the TME was performed by immunohistochemistry on tissue microarray. Comparative genomic hybridization was carried out to evaluate genomic instability signatures through homologous recombination deficiency (HRD) score, genomic index, and somatic copy number alterations. The relationship between genomic instability and TME was explored. Results: Patients with high intratumoral CD3+ T lymphocytes had longer progression-free survival (32 vs. 19.6 months, p = 0.009) and overall survival (OS) (median not reached). High HLA-E expression on tumor cells was associated with a longer OS (median OS not reached vs. 52.9 months, p = 0.002). HRD profile was associated with high HLA-E expression on tumor cells and an improved OS. In the multivariate analysis, residual tumor, intratumoral CD3, and HLA-E on tumor cells were more predictive than other parameters. Conclusions: Our results suggest HLA-E/CD94-NKG2A/2C is a potential immune target particularly in the HRD positive ovarian carcinoma subgroup.

Background Sertoli-Leydig cell tumors (SLCTs) represent less than 0.5% of ovarian tumors. Because of the rarity of this tumor and its peak in frequency at around 25 years of age, this study aimed to describe SLCT management strategies. Objective The objective of this study was to determine the management (i.e., conservative surgery and adjuvant chemotherapy) of ovarian SLCTs. Results This retrospective analysis included 23 patients treated for ovarian SLCTs. A centralized pathologic review of the tumors was conducted. Patients were referred to or treated in our institution for an ovarian SLCT between 1994 and 2015. The median age at diagnosis was 33 years (range, 4-82 years). According to the 2014 Federation of Gynecology and Obstetrics classification, tumors were classified as stage Ia (n = 15: well differentiated, n = 1; of intermediate differentiation, n = 8; undifferentiated, n = 4; and undefined, n = 2), stage Ib (n = 1), stage Ic1 (n = 5), stage IIb (n = 1), and stage IIIc (n = 1). Surgery was conservative in 13 patients (Ia, n = 7; Ib, n = 1; Ic1, n = 5) and radical in 10 patients (Ia, n = 8; IIb, n = 1; IIIc, n = 1). Seven patients received adjuvant chemotherapy with a cisplatin-based regimen (Ia, n = 2; Ic1, n = 3; IIb, n = 1) or docetaxel + gemcitabine (IIIc, n = 1). Median follow-up was 61 months (range, 15-252 months). Eight patients experienced a relapse (Ia, n = 2; Ib, n = 1; Ic1, n = 3; IIb, n = 1; IIIc, n = 1). Of these, six had at least one peritoneal carcinomatosis, and four died (Ic1, n = 2; IIb, n = 1; and Ia, n = 1). Two patients had a local relapse (one uterus and one ovary) and survived without disease after relapse treatment. The median time between the initial treatment and relapse was 28 months (range 9-70). Conclusion Conservative surgery was safe for patients with stage Ia ovarian SLCTs. The place of conservative surgery for stage Ic1 remains to be defined. The best chemotherapy regimen remains to be defined. Implications for practice For stage Ia disease, conservative surgery (in women of reproductive age) was safe and effective for treating ovarian Seroli-Leydig cell tumors. Adjuvant chemotherapy should be proposed for stage Ia when poor prognostic factors are present (poor differentiation, retiform pattern, or heterologous elements). For stage Ic1 and more severe stages, radical surgery and adjuvant chemotherapy should be considered. The combination of bleomycin, etoposide, and cisplatin was the most frequently used regimen, but the best chemotherapy regimen remains to be defined.

BackgroundThere is a medical need in platinum resistant ovarian cancer patients. Median progression-free survival (PFS) is 3.4 months with chemotherapy and 6.7 months with chemotherapy-bevacizumab combination regimens.1 RECIST overall response rate (ORR) is 11.8% and 27.3%, respectively. The ORR is 15.9% for bevacizumab as a monotherapy with a median PFS of 4.4 months.2MethodsNCT03596281 An open-label phase 1b trial with a modified toxicity probability interval design to evaluate the combination of a flat dose of 400mg bevacizumab for 6 cycles and 200mg pembrolizumab until disease progression, unacceptable toxicity or completed 24 months of treatment in patients with platinum resistant ovarian cancer. The primary evaluation criteria is safety, the secondary endpoint is the efficacy.Results19 patients have been enrolled between January 2019 and February 2021 in 6 French centers. Patients‘ characteristics are reported (table 1). No dose limiting toxicities were observed. Grade 3 treatment related adverse events occurred in 3 patients (i.e. arterial thromboembolism, bowel perforation, proteinuria and sepsis). No grade 4/5 toxicities were induced. A median of 7 cycles (range 3–14) were administered. Median follow-up of patients was 4.1 months (1.8–23). The RECIST ORR was 26.3% (1 complete response and 4 partial responses) (table 2). The disease control rate was 78.9%. The time to progression was not yet reached in 6 patients. The ORR was equivalent whether patients have been pretreated or not with bevacizumab (27.3 and 25% respectively) (table 3). The ORR according to the combined positive score (CPS) for the evaluation of PD-L1 was 50.0% for CPS≥10% (n=4), 30.0% for a CPS≥1% (n=10) and 25.0% for CPSConclusionsA chemotherapy-free regimen combining pembrolizumab and bevacizumab was well tolerated and showed encouraging results in heavily pretreated platinum resistant ovarian cancer patients independent of their previous challenge with antiangiogenic agents.AcknowledgementsFunding for this research was provided by Fondation Cancer du Luxembourg and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationNCT03596281ReferencesPujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Onco Off J Am Soc Clin Oncol 32,1302–1308 (2014).Cannistra SA, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol Off J Am Soc Clin Oncol 33,5180–5186 (2007).Ethics ApprovalThis study was approved by CPP Sud Méditerranée V institution’s Ethics Board; approval number 18.020 (EudraCT number 2017-004197-34).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Background No series had been reported focusing on the results of fertility-sparing surgery in stage I mucinous ovarian cancers according to histotype (infiltrative vs. expansile). Investigating such outcomes was the aim of the present study. Materials and Methods The present study was a retrospective analysis of patients treated conservatively with preservation of the uterus and contralateral ovary from 1976 to 2016. The pathology of the tumors was reviewed by two expert pathologists according to the 2014 World Health Organization (WHO) classification criteria. Oncologic and fertility results were analyzed. Results Twenty-one patients fulfilled the inclusion criteria, twelve with expansile and nine with infiltrative cancer. All patients had a unilateral tumor and underwent unilateral salpingo-oophorectomy in one-step (n = 6) or two-step (n = 15) surgeries. All but one had complete peritoneal staging surgery based on cytology, omentectomy, and random peritoneal biopsies. Ten had nodal staging surgery. The International Federation of Gynecology and Obstetrics stages were IA (n = 9), IC1 (n = 6), and IC2 (n = 6); the nuclear grades were grade 1 (n = 9), grade 2 (n = 5), and grade 3 (n = 1). Two patients recurred (one expansile and one infiltrative type) 19 and 160 months after surgery, respectively. One stage IA, nuclear grade 2 expansile tumor recurred on the spared ovary; the patient remains alive. The other stage IA infiltrative tumor recurred as peritoneal spread; the patient is alive with disease. Six patients became pregnant; four with expansile tumors and two with infiltrative tumors. Conclusion The type of mucinous cancer has no impact on the oncologic outcome in this series of patients treated conservatively. Fertility-sparing surgery should be considered for early-stage infiltrative-type tumors. Implications for Practice According to the most recently updated World Health Organization classification guidelines, mucinous cancers should be classified as either expansile or infiltrative. The infiltrative type has a poorer prognosis, but there are no data about the safety of fertility-sparing surgery (FSS) in this context. A collection of 21 cases reviewed by two expert pathologists this study is the first devoted to the conservative treatment of mucinous tumors according to both subtypes. The key result was that the type of mucinous cancer has no impact on the oncologic outcome; thus, FSS may be considered in both subtypes.

Endometrial cancer is the fourth cause of cancer in women in France and is the second most common cancer of the gynecologic cancer after breast cancer with 7275 new cases in 2012. The incidence of this neoplasm tends to increase with population aging, diabetes and obesity's augmentation. In rare cases, a hereditary factor has been described: Lynch's syndrome. The therapeutic management of the patient depends on the endometrial biopsy which specifies the histological type and the histo-prognostic grade as well as the MRI which allow the tumor staging. Within the last decade, improvement in technologies such as genomic, transcriptomic and histological analyses, allowed the establishment of new and finer classifications of endometrial carcinomas. The latest classification proposed by The Cancer Genomic Atlas (TCGA), has been made routinely applicable through the international consortium TransPORTEC. It consists of 4 groups listed from good to poor prognosis: (1) ultra-mutated "POLE"; (2) hyper-mutated "MSI"; (3) low copy number "NSMP" and (4) high number of copies "TP53 mutated" (serous-like). This integrated characterization combined with mutational data opens new opportunities for therapeutic strategies.

The demonstration of frequent defects in the DNA damage response in high grade ovarian cancer has paved the way for a new therapeutic approach aimed at exploiting this unique vulnerability. The efficacy of poly (ADP) ribose polymerase inhibitors (PARPi) in patients with homologous recombination (HR) DNA repair deficient ovarian cancer (OC) resulting from a BRCA1/2 mutation has provided the proof of concept for synthetic lethality. Thus, olaparib is now approved by the EMA as maintenance therapy after response to a platinum regimen for patients with recurrent, platinum-sensitive, high-grade serous, BRCA1/2-mutated ovarian cancer. Furthermore, several recent trials in OC have demonstrated that the benefit of PARPi may not be limited to patients with BRCA mutations. These data, combined with genomic studies suggesting that a significant proportion of OC may harbor somatic and germline alterations in other HR genes open huge perspectives for exploiting DNA repair as a therapeutic strategy. The current priorities are to (i) determine whether new biomarkers of homologous recombination deficiency may identify the BRCA wild-type subset likely to derive benefit from PARPi; (ii) to determine whether the efficacy of PARPi can be improved by combinatorial strategies (with chemotherapy, radiotherapy, immunotherapy, anti-angiogenesis or DNA repair inhibitors) and (iii) to develop new approaches exploiting DNA repair deficiencies in ovarian and other gynecological tumors.

Background The morphological classification of high-risk endometrial cancer is of limited prognostic value. Recent attempts to stratify tumours according to molecular signatures have shown considerable promise. Here we attempted to further refine molecular classifications using markers of the p53 pathway. Methods We analysed the expression of p53 as well as three downstream markers of the p53 pathway, p21, mdm2 and phospho-p63 ( p p63), by immunohistochemistry in a series of 114 endometrial cancers (86 endometrioid, 28 non-endometrioid subtype) with high-risk features (such as high tumour grade and deep myometrial invasion) and correlated results with clinical outcome. The Cancer Genome Atlas (TCGA) data were used to analyse TP63 mutations and copy-number alterations using cBioPortal. TP53 was silenced in two endometrial cancer cell lines to study its effect on p21 and p63. Results About half of the tumours showed a p53 mutant phenotype and there was a strong negative correlation with p21 expression. Being marker positive for p p63 or mdm2 was associated with a significantly increased likelihood of dying, [hazard ratios 5.93 (95% CI 2.37–7.27) and 7.48 (95% CI 3.04–9.39), respectively]. These findings were seen in both p53 wildtype and p53 mutant tumours. Only 11% of TCGA endometrial cancers had a functional TP63 alteration. Upon silencing of TP53, p21 expression was decreased in one cell line, but no effects on p63 were observed. Conclusion Markers of the p53 pathway improve stratification of endometrial cancers and provide novel insights into the role of this pathway in the disease.

Resume L’arrivee des inhibiteurs de poly(ADP-ribose) polymerase (PARP) dans le cancer de l’ovaire a conduit a modifier les circuits de la consultation d’oncogenetique. Toute recherche d’une alteration constitutionnelle des genes BReast Cancer1 (BRCA1) et BRCA2 doit etre accompagnee d’une consultation d’oncogenetique. Elle est recommandee des le diagnostic pour toute femme atteinte d’un carcinome de l’ovaire, de la trompe de Fallope ou du peritoine de haut grade, quels que soient l’âge au diagnostic et son histoire familiale. En cas de rechute platine sensible ou dans la perspective de l’inclusion dans un essai therapeutique et en absence de recherche d’alteration constitutionnelle prealable, la consultation d’oncogenetique est organisee selon un circuit rapide, et une analyse du statut BRCA somatique est realisee en parallele. A ce jour, l’olaparib est indique chez des patientes atteintes d’un cancer de l’ovaire, de la trompe de Fallope ou d’une tumeur peritoneale primitive de haut grade sereux, avec mutation BRCA deletere (constitutionnelle ou somatique), et en rechute platine sensible, et en entretien apres une nouvelle reponse a une chimiotherapie a base de sels de platine. L’indication d’un traitement d’entretien par olaparib peut etre discutee pour les carcinomes de haut grade non sereux, si tous les autres criteres sont reunis, apres avis d’une reunion de concertation pluridisciplinaire (RCP). L’olaparib est prescrit en monotherapie, a debuter au plus tard 8 semaines apres le dernier cycle de chimiotherapie, sous surveillance etroite, tenant compte de ses toxicites digestives et hematologiques.

PURPOSE KEYNOTE-158 ( ClinicalTrials.gov identifier: NCT02628067) is a phase II basket study investigating the antitumor activity and safety of pembrolizumab in multiple cancer types. We present interim results from patients with previously treated advanced cervical cancer. PATIENTS AND METHODS Patients received pembrolizumab 200 mg every 3 weeks for 2 years or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR), assessed per Response Evaluation Criteria in Solid Tumors (version 1.1) by independent central radiologic review. Safety was a secondary end point. RESULTS Ninety-eight patients were treated. Median age was 46.0 years (range, 24 to 75 years), and 65.3% of patients had Eastern Cooperative Oncology Group performance status of 1. Eighty-two patients (83.7%) had programmed death-ligand 1 (PD-L1)–positive tumors (combined positive score ≥ 1), 77 having previously received one or more lines of chemotherapy for recurrent or metastatic disease. Median follow-up was 10.2 months (range, 0.6 to 22.7 months). ORR was 12.2% (95% CI, 6.5% to 20.4%), with three complete and nine partial responses. All 12 responses were in patients with PD-L1–positive tumors, for an ORR of 14.6% (95% CI, 7.8% to 24.2%); 14.3% (95% CI, 7.4% to 24.1%) of these responses were in those who had received one or more lines of chemotherapy for recurrent or metastatic disease. Median duration of response was not reached (range, ≥ 3.7 to ≥ 18.6 months). Treatment-related adverse events occurred in 65.3% of patients, and the most common were hypothyroidism (10.2%), decreased appetite (9.2%), and fatigue (9.2%). Treatment-related grade 3 to 4 adverse events occurred in 12.2% of patients. CONCLUSION Pembrolizumab monotherapy demonstrated durable antitumor activity and manageable safety in patients with advanced cervical cancer. On the basis of these results, the US Food and Drug Administration granted accelerated approval of pembrolizumab for patients with advanced PD-L1–positive cervical cancer who experienced progression during or after chemotherapy.

Faced to an undetermined ovarian mass on ultrasound, an MRI is recommended and the ROMA score (combining CA125 and HE4) can be proposed (grade A). In case of suspected early stage ovarian or fallopian tube cancer, omentectomy (at least infracolonic), appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C) and pelvic and para-aortic lymphadenectomy are recommended (grade B) for all histological types, except for the expansive mucinous subtype where lymphadenectomy may be omitted (grade C). Minimally invasive surgery is recommended for early stage ovarian cancer, if there is no risk of tumor rupture (grade B). Adjuvant chemotherapy with carboplatin and paclitaxel is recommended for all high-grade ovarian or Fallopian tube cancers, stage FIGO I-IIA (grade A). In case of ovarian, Fallopian tube or primitive peritoneal cancer of FIGO III-IV stages, thoraco-abdomino-pelvic CT scan with injection (grade B) is recommended. Laparoscopic exploration for multiple biopsies (grade A) and to evaluate carcinomatosis score (at least using the Fagotti score) (grade C) are recommended to estimate the possibility of a complete surgery (i.e. no macroscopic residue). Complete medial laparotomy surgery is recommended for advanced cancers (grade B). It is recommended in advanced cancers to perform para-aortic and pelvic lymphadenectomy in case of clinical or radiological suspicion of metastatic lymph node (grade B). In the absence of clinical or radiological lymphadenopathy and in case of complete peritoneal surgery during an initial surgery for advanced cancer, it is possible not to perform a lymphadenectomy because it does not modify the medical treatment and the overall survival (grade B). Primary surgery is recommended when no tumor residue is possible (grade B). After a complete first surgery, it is recommended to deliver 6 cycles of intravenous (grade A) or to propose intraperitoneal (grade B) chemotherapy, to be discussed with patient, according to the benefit/risk ratio. After a complete interval surgery for a FIGO III stage, the hyperthermic intra peritoneal chemotherapy (HIPEC) can be proposed in the same conditions of the OV-HIPEC trial (grade B). In case of tumor residue after surgery or FIGO stage IV, chemotherapy associated with bevacizumab is recommended (grade A).

TPS5604 Background: Gynecological carcinosarcomas (CS) are rare and highly aggressive tumors with a 5-year overall survival (OS) < 10%. After initial treatment majority of patients (pts) relapse and receive diverse chemotherapies (CT) producing modest benefits. The median PFS in relapse after platinum based CT is less than 4 months and median OS less than 1 year. New innovative strategies are urgently needed. Since CS showed high DNA damage response activity and potentially a high tumor mutation load resulting in neo-antigens, a synergy between PARPi and anti-PD1 is expected. Methods: ROCSAN is a multicentric, randomized, open-label, integrated Phase II/III study. In the Phase II, 63 pts with recurrent or progressing endometrial or ovarian CS after at least a first line of platinum-based CT will be randomized (2:2:1) to receive either niraparib in monotherapy, niraparib in combination with dostarlimab or standard CT (paclitaxel, doxorubicine, gemcitabine, topotecan). Stratification factors include the number of previous CT lines (1 vs 2-3), FIGO stage at diagnosis (I-II vs III-IV), CS localisation (ovarian vs endometrial), and performance status (0-1 vs 2). The primary objective of the Phase II is to select the best experimental strategy between niraparib and dostarlimab/niraparib combination based on Response Rate at 4 months (RR-4M by RECIST1.1). A single stage design with a 10% unacceptable RR-4M and a 30% targeted RR-4M was used to determine Phase II sample size, assuming a 10% one sided alpha for each comparison and more than 90% power. A pick-the-winner selection design could be used in case of promising efficacy in each experimental arm. At the interim analysis, an Independent Data Monitoring Committee will make recommendation for the selection of the optimal experimental arm. The Steering committee could then support to continue enrolment for the international Phase III which is calibrated to detect an improvement in median OS from 7 months (Standard CT) to 11.7 months (best experimental arm). Assuming a 5% alpha level and 80% power, 133 additional pts could be randomized (2:1). Secondary endpoints include safety, PFS, PFS2, TTST, ORR, duration of response, patient report outcomes (assessed via EORTC QLQ-C30 OV28, HADS, PRO-CTCAE). A translational program supported by European Community is associated to the clinical study to identify predictive biomarkers of response/resistance to study treatments, to correlate with immune environment, a special focus on genetic instability and the EMT process will be included. Trial is currently recruiting only in France for the phase II part, the first pt was randomized in July 2020. Clinical trial information: NCT 03651206.

5513 Background: Homologous recombination deficiency (HRD), defined as BRCA1/2 mutation ( BRCAmut)or high genomic instability, is currently used to identify patients (pts) with epithelial ovarian cancer (EOC) most likely to benefit from PARP inhibitors. While these genomic tests are useful, they are imperfect: some BRCAm EOC demonstrate primary PARPi resistance and some HR-proficient benefit. Another approach to evaluate HRD is to measure the capacity of tumor cells to recruit nuclear RAD51 foci during S/G2 phase in the presence of double strand DNA damage using multiplexed immunofluorescence (IF) for RAD51, geminin (GMN) and yH2AX. We aimed to describe for the 1st time HRD using this RAD51 functional assay in EOC and correlate RAD51 status to platinum response and BRCAmut. Methods: Tumor samples and clinical data were collected prospectively from pts in the randomized CHIVA trial of neoadjuvant platinum chemotherapy +/- nintedanib. IF for RAD51, GMN, and DAPI was performed on a 3uM slide from FFPE blocks, where feasible, yH2AX was positively scored on a consecutive slide. Tumors were considered RAD51-deficient if < 10% of gem+ tumor cells (TC) had > 5 RAD51+ foci. BRCAmut were identified by NGS. Results: 155 baseline chemotherapy naïve EOC samples were available. All were advanced stage (IIIC/IV), 75% were G3, 7% G2, 2% G1, and 16% grade UK. A contributive RAD51 result was obtained for 90% (139/155) of samples. Contributive NGS results were available for 130 samples. Overall, yH2AX scores were high (median % TC+: 86%, IQR: 56%-100%) confirming the presence of significant basal DNA damage in high grade EOC. Only 8 samples were yH2AX-low, including two of the three G1 tumors. In contrast, 55% (76/155) of samples were considered RAD51-deficient (score < 10%). With regard to outcome, pts with RAD51-deficient tumors had significantly higher overall response rates to neoadjuvant platinum (68% vs 37%, p = 0.04) and significantly longer median progression-free survival (HR 0.50, IC95% 0.25-0.98, p = 0.02). Considering BRCA status, 15% of tumors harbored a deleterious BRCAmut and 67% of these were RAD51-deficient. Importantly among BRCAmut EOC, the RAD51-proficient tumors had significantly poorer response to neoadjuvant chemotherapy (RR = 17% vs 75%, p = 0.02). Conclusions: We evaluated a novel functional assay of HR functionality in advanced EOC. The assay requires minimal tissue and yields contributive results in 90% of cases. Overall, EOC demonstrate high levels of basal DNA damage, yet 55% fail to recruit RAD51 foci during S/G2 cell cycle phase. These RAD51-deficient EOC have improved outcome after neoadjuvant platinum. Conversely, the RAD51 assay also identified a small subset of RAD51-high BRCAmut tumors with poor platinum response. Whether this RAD51 functional assay may also predict PARP inhibitor benefit is currently being investigated.