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4 results on '"Michele Del Sesto"'

1. Biological and clinical impact of membrane EGFR expression in a subgroup of OC patients from the phase IV ovarian cancer MITO-16A/MANGO-OV2A trial

Author

Luca Forlani, Loris De Cecco, Vittorio Simeon, Biagio Paolini, Marina Bagnoli, Sabrina Chiara Cecere, Anna Spina, Eleonora Citeroni, Eliana Bignotti, Domenica Lorusso, Laura Arenare, Daniela Russo, Carmine De Angelis, Laura Ardighieri, Giosuè Scognamiglio, Michele Del Sesto, Germana Tognon, Daniela Califano, Clorinda Schettino, Paolo Chiodini, Francesco Perrone, Delia Mezzanzanica, Sandro Pignata, and Antonella Tomassetti

Subjects
Ovarian cancer, Bevacizumab, EGFR, Immunohistochemistry, Microarray, Bioinformatics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Validated prognostic biomarkers for anti-angiogenic therapy using the anti-VEGF antibody Bevacizumab in ovarian cancer (OC) patients are still an unmet clinical need. The EGFR can contribute to cancer-associated biological mechanisms in OC cells including angiogenesis, but its targeting gave disappointing results with less than 10% of OC patients treated with anti-EGFR compounds showing a positive response, likely due to a non adequate selection and stratification of EGFR-expressing OC patients. Methods EGFR membrane expression was evaluated by immunohistochemistry in a cohort of 310 OC patients from the MITO-16A/MANGO-OV2A trial, designed to identify prognostic biomarkers of survival in patients treated with first line standard chemotherapy plus bevacizumab. Statistical analyses assessed the association between EGFR and clinical prognostic factors and survival outcomes. A single sample Gene Set Enrichment-like and Ingenuity Pathway Analyses were applied to the gene expression profile of 195 OC samples from the same cohort. In an OC in vitro model, biological experiments were performed to assess specific EGFR activation. Results Based on EGFR-membrane expression, three OC subgroups of patients were identified being the subgroup with strong and homogeneous EGFR membrane localization, indicative of possible EGFR out/in signalling activation, an independent negative prognostic factor for overall survival of patients treated with an anti-angiogenic agent. This OC subgroup resulted statistically enriched of tumors of histotypes different than high grade serous lacking angiogenic molecular characteristics. At molecular level, among the EGFR-related molecular traits identified to be activated only in this patients’ subgroup the crosstalk between EGFR with other RTKs also emerged. In vitro, we also showed a functional cross-talk between EGFR and AXL RTK; upon AXL silencing, the cells resulted more sensitive to EGFR targeting with erlotinib. Conclusions Strong and homogeneous cell membrane localization of EGFR, associated with specific transcriptional traits, can be considered a prognostic biomarker in OC patients and could be useful for a better OC patients’ stratification and the identification of alternative therapeutic target/s in a personalized therapeutic approach.

Published
2023
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2. Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial

Author

Sandro Pignata, Giovanni Scambia, Clorinda Schettino, Laura Arenare, Carmela Pisano, Davide Lombardi, Ugo De Giorgi, Claudia Andreetta, Saverio Cinieri, Carmine De Angelis, Domenico Priolo, Claudia Casanova, Marta Rosati, Filippo Greco, Elena Zafarana, Ilaria Schiavetto, Serafina Mammoliti, Sabrina Chiara Cecere, Vanda Salutari, Simona Scalone, Alberto Farolfi, Marilena Di Napoli, Domenica Lorusso, Piera Gargiulo, Daniela Califano, Daniela Russo, Anna Spina, Rossella De Cecio, Paolo Chiodini, Francesco Perrone, Valentina Accinno, Chiara Altavilla, Giovanna Antonelli, Grazia Artioli, Francesco Avola, Bonifacio Barbara, Valentina Barbato, Michele Bartoletti, Simona Bevilacqua, Roberto Bordonaro, Oriana Borghese, Gaetano Buonfanti, Floriana Camarda, Giuliana Canzanella, Vittoria Carbone, Maria Rita Carbone, Giulia Carlo Stella, Chiara Cassani, Fabrizio Castagna, Monica Cattaneo, Margherita Cinefra, Nicoletta Colombo, Serena Corsetti, Monia Dall'Agata, Maria D'Amico, Gennaro Daniele, Elvira De Marino, Giovanni De Matteis, Sabino De Placido, Gabriella Del Bene, Antonia Del Giudice, Francesca Del Monte, Michele Del Sesto, Maddalena Donini, Giuliana Drudi, Gianluca Falcone, Adolfo Favaretto, Giulia Ferrera, Manuela Florio, Valeria Forestieri, Maria Stella Gallo, Ciro Gallo, Francesca Garibaldi, Fabiana Gerevini, Viola Ghizzoni, Maria Olga Giganti, Anna Gimigliano, Elena Giudice, Nicoletta Gnocchi, Adriano Gravina, Stefano Greggi, Maria Laura Iaia, Annalisa Ilardi, Gelsomina Iovine, Gabriella Ippoliti, Giulia Irollo, Ilenia Isidori, Mariateresa Lapresa, Giuseppe Lavenia, Laura Longhitano, Bortot Lucia, Gabriella Luzi, Sara Mariano, Valentina Marino, Giovanna Marrapese, Marilena Martino, Roberta Matocci, Enrica Mazzoni, Daniela Mercuri, Maria Mirto, Giovanna Mollo, Abbondanza Montinaro, Marta Moscatelli, Anna Maria Mosconi, Lucia Musacchio, Nicoletta Nanni, Pamela Natalucci, Milena Sabrina Nicoloso, Michele Orditura, Gabriella Maria Parma, Rodolfo Passalacqua, Michela Pelone, Maria Teresa Perri, Bruno Perrucci, Alessandra Piancastelli, Maria Carmela Piccirillo, Antonio Piccolo, Stefania Rapisardi, Giorgia Ravaglia, Teresa Ribecco, Caterina Ricci, Marianna Roccio, Fiorella Romano, Daniela Sambataro, Alfonso Savio, Ada Sbriglia, Cono Scaffa, Concetta Sergi, Francesca Sgandurra, Roberto Sorio, Stefano Stabile, Gianna Tabaro, Margherita Tambaro, Stefano Tamberi, Angelica Tecchiato, Angela Maria Trujillo, Eleonora Zaccarelli, Pignata, S, Scambia, G, Schettino, C, Arenare, L, Pisano, C, Lombardi, D, De Giorgi, U, Andreetta, C, Cinieri, S, De Angelis, C, Priolo, D, Casanova, C, Rosati, M, Greco, F, Zafarana, E, Schiavetto, I, Mammoliti, S, Cecere, S, Salutari, V, Scalone, S, Farolfi, A, Di Napoli, M, Lorusso, D, Gargiulo, P, Califano, D, Russo, D, Spina, A, De Cecio, R, Chiodini, P, Perrone, F, Accinno, V, Altavilla, C, Antonelli, G, Artioli, G, Avola, F, Barbara, B, Barbato, V, Bartoletti, M, Bevilacqua, S, Bordonaro, R, Borghese, O, Buonfanti, G, Camarda, F, Canzanella, G, Carbone, V, Carbone, M, Carlo Stella, G, Cassani, C, Castagna, F, Cattaneo, M, Cinefra, M, Colombo, N, Corsetti, S, Dall'Agata, M, D'Amico, M, Daniele, G, De Marino, E, De Matteis, G, De Placido, S, Del Bene, G, Del Giudice, A, Del Monte, F, Del Sesto, M, Donini, M, Drudi, G, Falcone, G, Favaretto, A, Ferrera, G, Florio, M, Forestieri, V, Gallo, M, Gallo, C, Garibaldi, F, Gerevini, F, Ghizzoni, V, Giganti, M, Gimigliano, A, Giudice, E, Gnocchi, N, Gravina, A, Greggi, S, Iaia, M, Ilardi, A, Iovine, G, Ippoliti, G, Irollo, G, Isidori, I, Lapresa, M, Lavenia, G, Longhitano, L, Lucia, B, Luzi, G, Mariano, S, Marino, V, Marrapese, G, Martino, M, Matocci, R, Mazzoni, E, Mercuri, D, and Mirto, M

Subjects
Oncology, Carboplatin
Abstract

Background: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. Methods: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III–IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016–004403–31). Findings: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2–29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7–12·1) in the standard group and 9·6 months (7·2–17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65–0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3–4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). Interpretation: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted.

Published
2023
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3. Clinical characteristics and molecular aspects of low-grade serous ovarian and peritoneal cancer: a multicenter, observational, retrospective analysis of MITO Group (MITO 22)

Author

Lucia Musacchio, Daniela Califano, Michele Bartoletti, Laura Arenare, Domenica Lorusso, Nunzia Simona Losito, Gennaro Cormio, Stefano Greggi, Francesco Raspagliesi, Giorgio Valabrega, Vanda Salutari, Carmela Pisano, Anna Spina, Daniela Russo, Michele Del Sesto, Vincenzo Canzonieri, Francesco Ferraù, Gian Franco Zannoni, Vera Loizzi, Viola Ghizzoni, Claudia Casanova, Valentina Tuninetti, Monika Ducceschi, Vittoria Del Vecchio, Simona Scalone, Domenico Priolo, Francesco Perrone, Giovanni Scambia, Sandro Pignata, Musacchio, Lucia, Califano, Daniela, Bartoletti, Michele, Arenare, Laura, Lorusso, Domenica, Losito, Nunzia Simona, Cormio, Gennaro, Greggi, Stefano, Raspagliesi, Francesco, Valabrega, Giorgio, Salutari, Vanda, Pisano, Carmela, Spina, Anna, Russo, Daniela, Del Sesto, Michele, Canzonieri, Vincenzo, Ferraù, Francesco, Zannoni, Gian Franco, Loizzi, Vera, Ghizzoni, Viola, Casanova, Claudia, Tuninetti, Valentina, Ducceschi, Monika, Del Vecchio, Vittoria, Scalone, Simona, Priolo, Domenico, Perrone, Francesco, Scambia, Giovanni, and Pignata, Sandro

Subjects
Ovarian Neoplasms, Proto-Oncogene Proteins B-raf, Cancer Research, therapy, peritoneal cancer, multicenter, retrospective analysis, serous ovarian, serous ovarian cancer, Cystadenocarcinoma, Serous, Proto-Oncogene Proteins p21(ras), Oncology, MITO Group (MITO 22), Humans, Female, Prospective Studies, observational, serous ovarian, peritoneal cancer, multicenter, observational, retrospective analysis, MITO Group (MITO 22), Peritoneal Neoplasms, Retrospective Studies
Abstract

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 .

Published
2022

4. Evaluation of angiogenesis-related genes as prognostic biomarkers of bevacizumab treated ovarian cancer patients: Results from the phase iv mito16a/mango ov-2 translational study

Author

Gustavo Baldassarre, Nicoletta Colombo, Eliana Bignotti, Vincenzo Canzonieri, Vittorio Simeon, Paolo Chiodini, Sabrina Chiara Cecere, Gian Luca Rampioni Vinciguerra, Daniela Califano, Maria Carmela Piccirillo, Francesca Citron, Giovanni Scambia, Daniela Russo, Marco Montella, Francesco Perrone, Gian Franco Zannoni, Anna Spina, Alessandra Ciucci, Germana Tognon, Clorinda Schettino, Laura Arenare, Nunzia Simona Losito, Michele Del Sesto, Rossella De Cecio, Sandro Pignata, Gabriella Ferrandina, Piera Gargiulo, Giosuè Scognamiglio, Daniela Gallo, Simona Signoriello, Califano, D, Gallo, D, Vinciguerra, G, De Cecio, R, Arenare, L, Signoriello, S, Russo, D, Ferrandina, G, Citron, F, Losito, N, Gargiulo, P, Simeon, V, Scambia, G, Cecere, S, Montella, M, Colombo, N, Tognon, G, Bignotti, E, Zannoni, G, Canzonieri, V, Ciucci, A, Spina, A, Scognamiglio, G, Del Sesto, M, Schettino, C, Piccirillo, M, Perrone, F, Chiodini, P, Pignata, S, Baldassarre, G, Califano, D., Gallo, D., Vinciguerra, G. L. R., De Cecio, R., Arenare, L., Signoriello, S., Russo, D., Ferrandina, G., Citron, F., Losito, N. S., Gargiulo, P., Simeon, V., Scambia, G., Cecere, S. C., Montella, M., Colombo, N., Tognon, G., Bignotti, E., Zannoni, G. F., Canzonieri, V., Ciucci, A., Spina, A., Scognamiglio, G., Del Sesto, M., Schettino, C., Piccirillo, M. C., Perrone, F., Chiodini, P., Pignata, S., and Baldassarre, G.

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Bevacizumab, Angiogenesis, medicine.medical_treatment, Article, law.invention, Bevacizumab treatment, MicroRNAs, Ovarian cancer, Vessel density, Randomized controlled trial, Maintenance therapy, law, Internal medicine, Medicine, RC254-282, Chemotherapy, business.industry, Hazard ratio, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, MicroRNA, medicine.disease, Angiogenesi, Settore MED/40 - GINECOLOGIA E OSTETRICIA, Biomarker (medicine), business, medicine.drug
Abstract

Simple Summary The possibility to identify, with appropriate biomarkers, patients that might mostly benefit from any given treatment is the basis of personalized oncology. Cancer biomarkers should be properly identified and validated on a large number of patients possibly enrolled in dedicated clinical trials. Here, we report the first molecular results of the MITO16A-ManGo-OV2 phase IV trial that was specifically designed to identify prognostic biomarkers of survival in epithelial ovarian cancer patients treated in first line with carboplatin-paclitaxel plus Bevacizumab (NCT01706120), a treatment for which validated predictive or prognostic biomarkers are still lacking. With this work we propose not only novel possible biomarkers for Bevacizumab-treated patients but also a way through which they can be properly collected, analyzed and statistically evaluated in the frame of large multicenter clinical trials. Abstract Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients’ survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials.

Published
2021

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