Search

Introduction: Low molecular weight heparin (LMWH) has been the backbone of the treatment of cancer associated thrombosis (CAT). Direct-acting oral anticoagulants (DOACs) have shown efficacy and safety not inferior to LMWH and guidelines included DOACs as an option for CAT treatment. Nevertheless, DOACs are still poorly prescribed in patients with cancer. The aim of this survey was to better understand prescription patterns of anticoagulants, in particular of DOACs, especially in gynecological cancers (GCs). Methods: Our survey was made up of 21 questions, the last four questions addressed to medical doctors (MDs) involved in GCs. An invitation to complete the survey was sent by e-mail to 691 MITO (Multicentre Italian Trials in Ovarian cancer and gynaecologic malignancies) and 2093 AIOM (Associazione Italiana di Oncologia Medica) members. Results: Overall, 113 MDs completed the questionnaire, 69 involved in GCs. Most respondents (46, 41%) were aged 30-40 years old, worked in public hospitals (59, 52.2%), were medical oncologists (86, 76.1%). LMWH was the preferred choice for the treatment of CAT (104, 92%). However, 89 respondents (78.8%) prescribed or asked to prescribe a DOAC for CAT. The major concern about DOACs was the difficulty in verifying the therapeutic effect and the absence of antidotes in case of bleeding (37.9%). In patients with GCs, DOACs were used with niraparib, olaparib, rucaparib and immune checkpoint inhibitors (ICIs) in less than 10 patients by 23%, 20%, 9% and 10.2% of respondents, respectively. Conclusion: The responders are aware of the Direct-acting oral anticoagulants option and would like to use them

AimsPoly (ADP-ribose) polymerase (PARP) inhibitors (PARPIs) represent a standard of care for the clinical management of high-grade serous ovarian cancer (HGSOC). The recognition of homologous recombination deficiency (HRD) has emerged as a predictive biomarker of response for first-line PARPIs treatment in patients with HGOSC. On the other hand, this test is extremely complex and therefore it is often externalised. Regrettably, the reliability of outsourced HRD testing can be troubled by inconclusive results and high rejection rates. In this methodological study, we assessed the technical feasibility, interassay and interlaboratory reproducibility of in-house HRD testing using three different commercially available next-generation sequencing assays.MethodsA total of n=20 epithelial ovarian cancer samples previously analysed with MyChoice CDx were subjected to HRD retesting using three different platforms in three different major pathology laboratories, that is, SOPHiA DDM HRD Solution, HRD focus and Oncomine homologous recombination repair pathway predesigned panel. Concordance was calculated by Cohen’s (dual) and Fleiss (triple) κ coefficients.ResultsIn-houseBRCA1/2molecular testing yielded a concordance rate >90.0% among all participating centres. HRD scores were successfully calculated by each institution with a concordance rate of 76.5%. Concerning the external gold standard test, the overall percentage of agreement ranged from 80.0% to 90.0% with a positive percentage agreement ranging from 75.0% to 80.0% and a negative percentage agreement ranging from 80.0% to 100%.ConclusionsIn-house testing for HRD can be reliably performed with commercially available next-generation sequencing assays.

Background Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. Patients and methods We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. Results Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00–3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004–0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. Conclusions In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.

The

Peritoneal carcinomatosis (PC) from ovarian cancer (OC) has poor prognosis and is in need for innovative therapies. Such clinical condition displays a composite structure with floating cell aggregates within ascites and solid-like masses invading the peritoneum. A deep understanding of the dynamics is thus crucial to propose more effective treatments. Chimeric antigen receptor (CAR)-based immunotherapies are emerging as promising approaches, and ex vivo expanded cytokine-induced killer lymphocytes (CIK), intrinsically endowed with HLA-independent antitumor activity, are a valid platform to be exploited against solid tumors. Appropriate preclinical models, recapitulating the clinical complexity, are needed in the perspective of clinical translation. Here we explored the activity of mesothelin (MSLN) CAR-redirected CIK (CAR.CIK) against advanced OC, by developing 3D models resembling PC structural complexity. CAR.CIK were generated from patients’ PBMC (n=11), engineered with 2nd generation MSLN-CAR with 4-1BB costimulation. As tumor targets we employed and characterized a panel of ascites-derived OC cell lines (aOC). Anti-aOC CAR.CIK killing ability was evaluated mostly by flow cytometry. CAR.CIK were successfully generated with a mean CAR expression of 42%. MSLN was highly expressed (>75%) in 5/6 aOC. CAR.CIK effectively killed tumor targets in standard 2D assays, even at very low effector/target ratios (E/T), with significant improvement compared to unmodified CIK (NTD.CIK): 78% vs 36%, 46% vs 15% respectively at 5:1 and 1:2 E/T (p In order to recapitulate the clinical complexity we generated 3D aOC spheroids, either floating in liquid medium or embedded in a 3D hydrogel and co-cultured with CAR.CIK. To measure CAR.CIK activity we employed live-imaging and image processing. CAR.CIK were found to localize faster than NTD.CIK in both liquid and solid settings. Recruitment kinetics of CAR.CIK on aOC aggregates in liquid was significantly faster in shaking cultures, reminiscent of spontaneous patient movement, than in absence of flow. Even in the 3D solid setting, CAR.CIK were functionally more efficient and localized faster on aOC spheroids than NTD.CIK. Our data indicate that MSLN-CAR.CIK are effective against aOC in both 2D and 3D settings. Kinetics measurements in 3D show that recruitment in liquid requires shorter times when coupled to fluid flow. The solid setting is instead characterized by slower kinetics but CAR.CIK anti-tumor activity remains comparable to the liquid condition. The kinetics of recruitment should therefore be considered when assessing CAR.CIK killing. Our findings provide reliable translational bases for clinical studies to explore intraperitoneal cellular immunotherapy with CAR.CIK against OC PC. Citation Format: Federica Galvagno, Valeria Leuci, Chiara Donini, Annamaria Massa, Ramona Rotolo, Sonia Capellero, Alessia Proment, Letizia Vitali, Valentina Tuninetti, Martina Olivero, Elisa Vigna, Giorgio Valabrega, Luca Primo, Alberto Puliafito, Dario Sangiolo. Anti-mesothelin CAR.CIK lymphocytes are effective against ovarian cancer in 3D models of peritoneal carcinomatosis [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 3194.

The prognosis of invasive cervical cancer (CC) remains poor, with a treatment approach that has remained the same for several decades. Lately, a better understanding of the interactions between the disease and the host immune system has allowed researchers to focus on the employment of immune therapy in various clinical settings. The most advanced strategy is immune checkpoint inhibitors (ICIs) with numerous phase II and III trials recently concluded with very encouraging results, assessing single agent therapy, combinations with chemotherapy and radiotherapy. Apart from ICIs, several other compounds have gained the spotlight. Tumor Infiltrating Lymphocytes (TILs) due to their highly selective tumoricidal effect and manageable adverse effect profile have received the FDA’s Breakthrough Therapy designation in 2019. The antibody drug conjugate (ADC) Tisotumab-Vedotin has shown activity in metastatic CC relapsed after at least one line of chemotherapy, with a phase III trial currently actively enrolling patients. Moreover, the deeper understanding of the ever-changing immune landscape of CC carcinogenesis has resulted in the development of active therapeutic vaccines. This review highlights the different immunotherapeutic strategies being explored reflects on what role immunotherapy might have in therapeutic algorithms of CC and addresses the role of predictive biomarkers.

Low grade serous carcinoma of the ovary and peritoneum (LGSC) is characterized by low response rates to chemotherapy and by MAPK pathway alterations. Phase II/III clinical trials tested different MEK inhibitors (MEKis) in this complex malignancy, with heterogenous results. Purpose of this systematic review and meta-analysis is to define activity and efficacy of these agents and explore differences in clinical outcomes related to RAS/RAF mutational status.In March 2022, we searched Pubmed, Web of Science, Scopus, and the major conference proceedings (ASCO, ESMO) for randomized and non-randomized clinical trials evaluating MEKi as single agent in recurrent LGSC. The screening was performed independently by two reviewers. Objective response rate (ORR) and progression-free survival (PFS) data were extracted, and RevMan 5.3 software was used for statistical analysis.A total of 4 clinical trials involving 648 patients were included. In the intention-to-treat population, use of a MEK inhibitor was not associated with a significant improvement in PFS, with a pooled Hazard Ratio equal to 0.75 (95 % CI: 0.30 - 1.86, P = 0.54). Heterogeneity was significant (IAlthough no statistically significant improvement in PFS was demonstrated, the available data show clear signals of activity, at least for some MEKis.

The MET oncogene encodes a tyrosine kinase (TK) receptor. Its activation protects cells from death but also stimulates DNA damage response by triggering excess replicative stress. Transcriptomic classification of cancer cell lines based on MET expression showed that response to the PARP inhibitor (PARPi) olaparib is poorer in MET overexpressing cell lines. Accordingly, a high MET expressing lung carcinoma cell line was sensitized to PARPi by MET TK inhibition. This was not linked solely to MET overexpression: other MET overexpressing cell lines were biochemically but not functionally responsive to combined inhibition. Moreover, exogenously induced MET overexpression was unable to induce resistance to PARPi. The MET overexpressing cell line, responsive to the combined PARP and MET inhibition, carried a heterozygous mutation of the ATM gene and showed an attenuated response of ATM to PARPi. Among the downstream targets of ATM activation, NuMA was phosphorylated only in response to the combined PARP and MET inhibition. Given the role played by NuMA in mitosis, data show that the latter is affected by MET and PARP inhibition in cells with haploinsufficient ATM. This is important as ATM heterozygous mutation is frequently found in human cancer and in lung carcinomas in particular.

Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Cancer cells float in peritoneal fluid, named ascites, together with a definitely higher number of non neo-neoplastic cells, as single cells or multicellular aggregates. The aim of this work is to uncover the features that make these aggregates the metastasizing units. Immunofluorescence revealed that aggregates are made almost exclusively of ovarian cancer cells expressing the specific nuclear PAX8 protein. The same cells expressed epithelial and mesenchymal markers, such as EPCAM and αSMA, respectively. Expression of fibronectin further supported a hybrid epithelia-mesenchymal phenotype, that is maintained when aggregates are cultivated and proliferate. Hematopoietic cells as well as macrophages are negligible in the aggregates, while abundant in the ascitic fluid confirming their prominent role in establishing an eco-system necessary for the survival of ovarian cancer cells. Using ovarian cancer cell lines, we show that cells forming 3D structures neo-expressed thoroughly fibronectin and αSMA. Functional assays showed that αSMA and fibronectin are necessary for the compaction and survival of 3D structures. Altogether these data show that metastasizing units display a hybrid phenotype that allows maintenance of the 3D structures and the plasticity necessary for implant and seeding into peritoneal lining.

BackgroundThe term uterine smooth muscle tumor of uncertain malignant potential (STUMP) indicates a rare, equivocal entity between benign leiomyomas and leiomyosarcomas. In the present study, we evaluated a comprehensive range of clinical, surgical, and pathological features in a large multicenter series of patients with STUMP to identify risk factors for recurrence.MethodsThis is a retrospective study performed by collecting consecutive cases diagnosed between January 2000 and December 2020 in five tertiary centers. Associations between STUMP recurrence and clinicopathological characteristics as well as surgical treatment modality were investigated.ResultsEighty-seven patients affected by STUMP were considered. Of them, 18 cases (20.7%) recurred: 11 as leiomyosarcoma (LMS) and 7 as STUMP. The mean time to recurrence was 79 months. We found that fragmentation/morcellation, epithelioid features, high mitotic count, Ki-67 value > 20%, progesterone receptor (PR) < 83%, and p16 diffuse expression were associated with higher risk of recurrence and shorter recurrence-free survival (RFS). Furthermore, morcellation/fragmentation and mitotic count remained independent risk factors for recurrence and shorter RFS after multivariate analysis, while the presence of epithelioid features was an independent risk factor for recurrence only.ConclusionsOur results suggest that morcellation is associated with risk of recurrence and shorter RFS, thus it should be avoided if a STUMP is suspected preoperatively. Epithelioid features, high proliferation activity, low PR expression, and diffuse p16 expression are also unfavorable prognostic factors, so patients presenting these features should be closely followed up.

Low-grade serous ovarian and peritoneal cancer (LGSC) is a rare disease and few data on the clinical and genomic landscape have been published.A retrospective analysis of patients diagnosed with LGSC between 1996 and 2019 was conducted in MITO centers. Objective Response Rate (ORR) to treatments, progression-free survival (PFS) and overall survival (OS) were assessed. Additionally, the tumor molecular profile of 56 patients was evaluated using the Next Generation Sequencing (NGS) FoundationOne CDX (Foundation Medicine®).A total of 128 patients with complete clinical data and pathologically confirmed diagnosis of LGSC were identified. ORR to first and subsequent therapies were 23.7% and 33.7%, respectively. PFS was 43.9 months (95% CI:32.4-53.1) and OS was 105.4 months (95% CI: 82.7-not reached). The most common gene alterations were: KRAS (n = 12, 21%), CDKN2A/B (n = 11, 20%), NRAS (n = 8, 14%), FANCA (n = 8, 14%), NF1 (n = 7, 13%) and BRAF (n = 6, 11%). Unexpectedly, pathogenetic BRCA1 (n = 2, 4%), BRCA2 (n = 1, 2%) and PALB2 (n = 1, 2%) mutations were found.MITO 22 suggests that LGSC is an heterogenous disease for both its clinical behavior in response to standard therapies and its molecular alterations. Future prospective studies should test treatments according to biological and molecular tumor's characteristics.This study is registered under NCT02408536 on ClinicalTrials.gov .

Background: There is compelling need for novel biomarkers to predict response to PARP inhibitors (PARPi) in BRCA wild-type (WT) ovarian cancer (OC). Methods: MITO 37 is a multicenter retrospective study aiming at correlating Ki67 expression at diagnosis with a clinical outcome following platinum treatment and PARPi maintenance. Clinical data were collected from high grade serous or endometroid BRCAWT OC treated with niraparib or rucaparib maintenance between 2010–2021 in 15 centers. Ki67 expression was assessed locally by certified pathologists on formalin-fixed paraffin embedded (FFPE) tissues. Median Ki67 was used as a cut-off. Results: A total of 136 patients were eligible and included in the analysis. Median Ki67 was 45.7% (range 1.0–99.9). The best response to platinum according to median Ki67 was 26.5% vs. 39.7% complete response (CR), 69.1% vs. 58.8% partial response (PR), 4.4% vs. 1.5% stable disease (SD). The best response to PARPi according to median Ki67 was 19.1% vs. 36.8% CR, 26.5% vs. 26.5% PR, 26.5 vs. 25% SD, 27.9% vs. 16.2% progressive disease (PD). No statistically significant differences in progression free survival (PFS) and overall survival (OS) were identified between low and high Ki67. PFS and OS are in line with registration trials. Conclusions: Ki67 at diagnosis did not discriminate responders to PARPi.

ObjectiveCOVID-19 is a global public health emergency. The increasing spread of COVID-19 presents challenges for the clinical care of patients with gynecological tumors. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) performed a survey to evaluate the impact of the COVID-19 pandemic on medical treatment of gynecological cancer, with a focus on chemotherapy and oral treatment with poly(ADP)-ribose polymerase inhibitors (PARP-i).MethodsThe survey consisted of a self-administered online questionnaire, sent via email between November 2020 and January 2021 to all members of MITO group.ResultsForty-nine centers completed the questionnaire. The majority of respondents (83%) use screening tests to determine COVID-19 status in patients who were to undergo chemotherapy or oral medications. All respondents to our survey continued cancer therapy in patients who tested negative for COVID-19 during the pandemic. Seventy-three percent of respondents declared they stopped treatment with chemotherapy or PARP-i only after a positive swab and resumed therapy when negative tests were confirmed.ConclusionsCOVID-19 positivity impacted patterns of treatment in patients diagnosed with ovarian cancer within the MITO group. Further investigations are needed to evaluate whether these modifications influence oncological clinical outcomes.

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.

LBA5504 Background: Trabectedin demonstrated antitumor activity when administered as single agent in relapsed platinum sensitive ovarian cancer (OC), with an overall response rate (ORR) ranging from 26 to 43% and a median PFS of 5 months. In addition, trabectedin showed 39.4% RR, 4.5 months median progression free survival (PFS) and 18 months median overall survival (OS) in a single arm phase 2 trial in recurrent BRCA mutated and/or the BRCAness phenotype OC patients. Methods: In this open-label, phase III, randomized trial, we assigned recurrent OC patients harboring BRCA 1/2 mutations or with BRCAness phenotype (defined as patients who had received and responded to at least 2 previous platinum-based treatments) to receive trabectedin 1.3 mg/mq q 21d or physician’s choice chemotherapy (among carboplatin, gemcitabine, weekly paclitaxel, pegylated liposomal doxorubicine or topotecan). The primary endpoint was OS. Secondary endpoints were PFS, ORR and Duration of Response (DoR). The sample size was calculated based on the assumption that trabectedin would increase median OS from 10 to 15 months (two-sided log-rank test at the error alfa= 0.05 and a power of 80%). Medians and lifetables were computed using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards model was used to assess the effect of treatment. Results: Two hundred and forty-four patients were randomized and analyzed based on the intent-to-treat principle. At a median follow up of 40 months, the median PFS was 4.4 and 4.9 months (HR= 1.03 p=0.848) and median OS was 17.9 and 15.8 months (HR=1.15 p=0.304), in the control and experimental arm, respectively. ORR was 20.2% in the group of patients receiving standard chemotherapies and 15.4% in the group of patients treated with trabectedin. No superior effect was reported for Trabectedin in the pre-specified sub-group analysis according to BRCA mutational status, type of chemotherapy and platinum-free interval. No new signal of toxicity were reported for all the chemotherapies employed. Conclusions: Trabectedin as single agent does not improve survival outcomes when compared to standard chemotherapy in BRCA mut and BRCAness phenotype OC patients. Clinical trial information: NCT02993705.

IntroductionThe role of cytoreductive surgery in the poly-ADP ribose polymerase inhibitors era is not fully investigated. We evaluated the impact of surgery performed prior to platinum-based chemotherapy followed by olaparib maintenance in platinum-sensitive BRCA-mutated recurrent ovarian cancer.MethodsThis retrospective study included platinum-sensitive recurrent ovarian cancer BRCA-mutated patients from 13 Multicenter Italian Trials in Ovarian cancer and gynecological malignancies centers treated between September 2015 and May 2019. The primary outcomes were progression-free survival and overall survival. Data on post-progression treatment was also assessed.ResultsAmong 209 patients, 72 patients (34.5%) underwent cytoreductive surgery followed by platinum-based chemotherapy and olaparib maintenance, while 137 patients (65.5%) underwent chemotherapy treatment alone. After a median follow-up of 37.3 months (95% CI: 33.4 to 40.8), median progression-free survival in the surgery group was not reached, compared with 11 months in patients receiving chemotherapy alone (P12 months, between 6 and 12 months, and ConclusionCytoreductive surgery performed before platinum therapy and olaparib maintenance was associated with longer progression-free survival and overall survival in BRCA-mutated platinum-sensitive relapsed ovarian cancer patients. In accordance with our preliminary results, the response rate to chemotherapy given after progression during olaparib was associated with platinum-free interval.

After more than 30 years of a one-size-fits-all approach in the management of advanced ovarian cancer, in 2018 the SOLO1 trial results have introduced a new era of personalized medicine. A deeper knowledge of ovarian cancer biology and the development of new drugs targeting specific molecular pathways have led to biomarker-driven phase 3 trials with practice changing results. Thereafter, platinum-based combinations are no longer the only therapeutic options available in first line setting and poly-ADP ribose polymerase inhibitors maintenance therapy has become the mainstay in patients with tumor harboring a homologous recombination defect. However, most of the recent therapeutic breakthroughs regard high grade serous carcinoma, the most frequent ovarian cancer subtype, and only few improvements have occurred in the management of less common histotypes. Moving towards the next challenges, we aimed to investigate and review new potential molecular targets in ovarian cancer, according to histotype, starting from promising molecular drivers and matched drugs that have been investigated in early and late-stage clinical trials or conceptualized in preclinical studies.

BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is often incomplete. METHODS To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI's approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS). RESULTS Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ���2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (���6 months) and about 40% were ongoing at a median follow-up of 369 days [194-695] or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p��=��0.67 and 0.19 for LC and Mel, respectively). CONCLUSIONS Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up.

Ovarian cancer is still the most lethal gynecologic malignancy with a median five-year survival of 48%, including the less malignant and early diagnosed cases [...]

Background Carboplatin-paclitaxel is standard systemic anticancer therapy for recurrent or advanced EC for which surgery and/or radiation are not curative. Dostarlimab (TSR-042) is an anti-programmed cell death (PD)-1 humanised monoclonal antibody that has demonstrated antitumour activity and an acceptable safety profile in patients (pts) with recurrent or advanced EC in the GARNET trial. The RUBY trial will evaluate the efficacy and safety of dostarlimab in combination with carboplatin-paclitaxel in recurrent or primary advanced EC compared with carboplatin-paclitaxel alone. Trial Design This is a global, randomised, double-blind, multicenter, placebo-controlled study. Eligible pts must have first recurrent or primary stage III or stage IV EC with a low potential for cure by radiation therapy or surgery alone or in combination. Pts with carcinosarcoma are eligible for enrolment. 470 pts will be enrolled from approximately 160 sites in the ENGOT countries, United States, and Canada. Stratification factors are DNA mismatch repair status (proficient [p], or deficient [d] MMR), prior external pelvic radiotherapy (yes or no), and disease status (recurrent, primary stage III or primary stage IV). Pts will be randomised 1:1 to receive combination dostarlimab 500 mg or placebo + carboplatin AUC 5 + paclitaxel 175 mg/m2 every 3 weeks for 6 cycles followed by dostarlimab 1000 mg or placebo monotherapy every 6 weeks for up to 3 years in the absence of progressive disease, death, unacceptable toxicity, or patient/physician decision to withdraw from the study. The primary endpoint is progression-free survival (PFS) as assessed by the investigator in the all-comers population and the dMMR population per RECIST version 1.1. Secondary efficacy endpoints are PFS assessed by blinded independent central review per RECIST version 1.1, overall survival, objective response rate, duration of response, disease control rate, safety and tolerability, and patient-reported outcomes. Disclosures Sponsor: GlaxoSmithKline, Waltham, MA, USA NCT number: NCT03981796 Encore statement: This data is presented on behalf of the original authors with their permission. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 29–31, 2020, Virtual. Dr. Mirza reports personal fees and other from Karyopharm Therapeutics; Personal fees and other from Sera Prognostics and Roche; Grants and Personal fees from AstraZeneca, Clovis Oncology, Pfizer, GSK, Genmab, BioCad, Sotio, Boehringer Ingelheim, Geneos Therapeutics, Merck, Oncology Venture, Seattle Genetics, Sera Prognostics,Takeda Pharmaceutical Company Ltd, and Zailab. Dr. Coleman reports consulting fees from Merck, Reoche/Genentech, AstraZeneca, Oncomed/Mateo, Novocure, Oncosec, Janssen, Clovis, Tesaro/GSK, Abbvie, Eisai, Arrivive, and Oncoquest; grants from Merck, Roche/Genentech, V-Foundation, AstraZeneca, Janssen, Clovis, Genmab and Abbvie; and honoraria/reimbursement from Merck, Roche/Genentech, AstraZeneca, Oncomed/Mateo, Novocure, Oncosec, Janssen, Clovis, Tesaro/GSK, Eisai, Arrivive and OncoQuest. Dr. Slomovitz reports consulting/advisory fees from GlaxoSmithKline. Dr. Powell reports consulting/advisory fees from Roche/Genentech, AstraZeneca, Tesaro, and Clovis Oncology; and speakers’ bureau at Genentech/Roche, AstraZeneca, Tesaro and Clovis Oncology. Drs. Hanker and Valabrega have nothing to disclose. Drs. Im, Walker, and Guo are employees of GlaxoSmithKline.

Niraparib efficacy, safety, and QOL were similar in compared age groups. Implementation of an ISD regimen improved rates of grade ≥3 thrombocytopenia events in older patients.

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting. We evaluated all consecutive patients undergoing cytoreduction for platinum-resistance over an 8-year period (2010&ndash, 2018) in two different centers. Fifty patients (median age 52.5 years, range 34&ndash, 75) were included, the median number of previous chemotherapy lines was three (range 1&ndash, 7) and the median number of previous surgeries was one (range 1&ndash, 4). Completeness of cytoreduction (CC = 0) was achieved in 22 patients (44%). Rates of major operative morbidity and 30-day mortality were 38% and 8%, respectively. Median follow-up was 35 months. The absence of tumor residual (CC = 0) was associated with a significantly better overall survival (OS) compared to the CC &gt, 0 subgroup (median OS 32.9 months (95%CI 21.6&ndash, 44.2) vs. 4.8 months (95% CI n.a.&ndash, 9.8), hazard ratio (HR) 4.21 (95%CI 2.07&ndash, 8.60), p &lt, 0.001). Optimal cytoreduction is feasible and associated with promising OS in selected, heavily pre-treated PROCs. Further prospective studies are required to better define the role of surgery in platinum-resistant disease.

Objective Around 15% of epithelial ovarian cancer (EOC) patients (pts) harbor a germline BRCA1 or 2 mutation, showing different features than BRCA wild-type pts. The clinical and pathological features of an Italian BRCA mutated EOC cohort were described. Methods We retrospectively analyzed clinical, pathological and mutational data from a cohort of Italian BRCA mutated EOC pts. treated in 15 MITO centers between 1995 and 2017. Results Three-hundred thirty-one pts. were recorded. Two-hundred forty (72%) and 91 (27.5%) pts. harbored a BRCA1 and BRCA2 mutation, respectively. Median age at diagnosis was 52 years. The most frequent diagnosis was a high grade serous FIGO III or IV EOC and platinum doublet in first-line was administered to almost all pts. Fifty-three % of them had no residual disease (R = 0) at surgery. Median progression-free-survival (mPFS) after first-line chemotherapy was 29 months. Expected percentage of pts. alive at 5 years was 72.5% (CI 60.2–80.8%) and R = 0 predicted a significantly longer overall survival (OS). Sixty-six pts. (19,9%) had both an EOC and a breast cancer (BC) diagnosis. The first diagnosis was BC in 81,8% of cases with a mean interval between the two diagnoses (IBTDs) of 132.4 months. Mutational data show that the founder mutation c.5266dupC in BRCA1 was the most frequently recorded. Conclusions This is the largest Italian BRCA mutEOC cohort. The only predictor of longer OS was R = 0. EOC pts. that developed subsequently a BC are long-term survivors.

With this review, we provide the state of the art concerning brain metastases (BMs) from ovarian cancer (OC), a rare condition. Clinical, pathological, and molecular features, treatment options, and future perspectives are comprehensively discussed. Overall, a diagnosis of high-grade serous OC and an advanced disease stage are common features among patients who develop brain metastases. BRCA1 and BRCA2 gene mutations, as well as the expression of androgen receptors in the primary tumor, are emerging risk and prognostic factors which could allow one to identify categories of patients at greater risk of BMs, who could benefit from a tailored follow-up. Based on present data, a multidisciplinary approach combining surgery, radiotherapy, and chemotherapy seem to be the best approach for patients with good performance status, although the median overall survival (

Epithelial ovarian cancer (EOC) is the most common cause of death among gynecological malignancies. Despite surgical and pharmacological efforts to improve patients' outcome, persistent and recurrent EOC remains an un-eradicable disease. Chimeric associated antigens (CAR) T cells are T lymphocytes expressing an engineered T cell receptor that activate the immune response after an MHC unrestricted recognition of specific antigens, including tumor associated antigens (TAAs). CART cells have been shown to be effective in the treatment of hematologic tumors even if frequently associated with potentially severe toxicity and high production costs.In this review, we will focus on preclinical and clinical studies evaluating CART activity in EOC in order to identify possible difficulties and advantages of their use in this particular setting.The pattern of diffusion within the peritoneal cavity, the tumor microenvironment and the high rate of TAAs make EOC a particularly interesting model for CART cells use. Data from preclinical studies indicate a potential activity of CARTs in EOC, but robust clinical data are still awaited. Further studies are needed to determine the best methods of administration and the most effective CAR type to treat EOC patients.

// Gloria Mittica 1, 2, * , Eleonora Ghisoni 1, 2, * , Gaia Giannone 1, 2 , Massimo Aglietta 1, 2 , Sofia Genta 1, 2 and Giorgio Valabrega 1, 2 1 Department of Oncology, University of Turin, Turin, Italy 2 Division of Medical Oncology-1, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy * These authors contributed equally to this work Correspondence to: Giorgio Valabrega, email: giorgio.valabrega@ircc.it Keywords: endometrial cancer, immunotherapy, tumor infiltrating lymphocytes (TILs), polymerase epsilon (POLE)-ultra-mutated, microsatellite instability (MSI) Received: June 08, 2017 Accepted: July 26, 2017 Published: August 08, 2017 ABSTRACT Context: Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. Materials and Methods: We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords ‘endometrial cancer’ and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. Results: POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Conclusions: Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

// Gloria Mittica 1, 2, * , Rebecca Senetta 3, * , Giulia Scotto 1 , Massimo Aglietta 1, 2 , Furio Maggiorotto 4 , Eleonora Ghisoni 1, 2 , Sofia Genta 1, 2 , Renzo Boldorini 5 , Claudia Manini 6 , Isabella Morra 7 , Roberta Buosi 8 , Anna Sapino 3, 9 , Paola Cassoni 9, * and Giorgio Valabrega 1, 2, * 1 Department of Oncology, University of Turin, Turin, Italy 2 Division of Medical Oncology-1, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy 3 Unit of Pathology Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy 4 Division of Gynecologic Oncology, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy 5 Department of Health Science, University of Eastern Piedmont “Amedeo Avogadro”, Novara, Italy 6 Unit of Pathology, Giovanni Bosco Hospital, Turin, Italy 7 Unit of Pathology, Citta della Salute e della Scienza, Turin, Italy 8 Division of Oncology, Santo Spirito Hospital, Casale Monferrato, Italy 9 Department of Medical Sciences, University of Turin, Turin, Italy * These authors have contributed equally to this work Correspondence to: Giorgio Valabrega, email: giorgio.valabrega@ircc.it Keywords: androgen receptor, ovarian cancer, brain metastases Received: November 24, 2016 Accepted: March 17, 2017 Published: April 12, 2017 ABSTRACT Brain metastases are uncommon localizations in epithelial ovarian cancer (EOC), their reported incidence is increasing and no predictive biomarkers have been identified yet. Goals of this study were: i) to define a possible association between Estrogen Receptor (ER), Progesterone Receptor (PR), Androgen Receptor (AR),human EGF receptor 2 (HER2) and brain progression in EOC patients, and ii) to identify differences in ER, PR, AR and HER2 protein expression from primary EOC and its matched resected brain metastasis. A retrospective series of 11 EOC with matched brain metastasis surgically removed was collected. For comparison, a “Control dataset” of 22 patients, without evidence of brain involvement after an adequate follow up was matched. ER, PR, AR and HER2 status were analyzed by means of immunohistochemistry forCases (both primary and metastatic lesions) and Controls. Univariate analysis showed that AR status was significantly associated with brain localization, both considered as discrete variable (cut-off: 10%, p =0.013) and as continuous one ( p =0.035). Multivariate analysis confirmed this trend ( p =0.053). When considered as continuous variables, ER and AR showed greater expression in primary tumors in comparison with brain metastases ( p =0.013 and p =0.032, respectively). In our series, AR predicts brain involvement, with a 9.5 times higher propensity for AR-negative EOC. Moreover, brain dissemination is probably the result of progressive dedifferentiation of primary tumor, shown by reduction of ER and AR expression in metastases. Further studies are required, in order to anticipate and improve multimodal treatment of brain metastases.