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291 results on '"Tinari N."'

52. Timed flat infusion of 5-fluorouracil increases the tolerability of 5-fluorouracil/docetaxel regimen in metastatic breast cancer: a dose-finding study

Author

Ficorella, C, primary, Morelli, M F, additional, Ricevuto, E, additional, Cannita, K, additional, Porzio, G, additional, Baldi, P Lanfiuti, additional, Cianci, G, additional, Rocco, ZC Di, additional, Natoli, C, additional, Tinari, N, additional, Galitiis, F De, additional, Calista, F, additional, and Marchetti, P, additional

Published
2004
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64. Pancreatic Juice 90K and Serum CA 19-9 Combined Determination Can Discriminate between Pancreatic Cancer and Chronic Pancreatitis.

Author

Gentiloni, N., Caradonna, P., Costamagna, G., D'Ostilio, N., Perri, V., Mutignani, M., Febbraro, S., Tinari, N., Iacobelli, S., and Natoli, C.

Subjects
PANCREATIC secretions, CANCER, PANCREATITIS, TUMORS, ANTIGENS
Abstract

Objectives: Differential diagnosis of pancreatic cancer versus chronic pancreatitis may be difficult. The aim of this study is to determine whether a group of tumor-associated antigens could differentiate between the two pathologies. Methods: CA 19-9, TAG-72, CAR-3, and a newly discovered antigen termed "90K" were determined in the serum and in the pancreatic juice of 19 patients with pancreatic cancer, 20 patients with chronic pancreatitis, and seven controls with lithiasis of extrapancreatic bile ducts. Results: The serum antigen levels of all three markers except 90K were significantly higher in pancreatic cancer than in chronic pancreatitis. High correlations were found between serum CA 19-9 and both TAG-72 and CAR-3. 90K did not correlate with other markers. In pancreatic juice, only 90K values were significantly higher in chronic pancreatitis than in pancreatic cancer, and only 90K and CA 19-9 were significantly correlated. At the stepwise discriminant analysis, serum CA 19-9 and pancreatic juice 90K had independent diagnostic roles. Used in combination, they correctly identified 84.2% of pancreatic cancer and 90% of chronic pancreatitis. Conclusions: These data suggest that pancreatic juice 90K and serum CA 19-9 can discriminate between chronic pancreatitis and pancreatic cancer. The data further support the complementary use of tumor-associated antigens along with other diagnostic tools. [ABSTRACT FROM AUTHOR]

Published
1995

72. Pancreatic juice 90K and serum CA 19-9 combined determination can discriminate between pancreatic cancer and chronic pancreatitis

Author

Gentiloni N, Caradonna P, Costamagna G, D'Ostilio N, Perri V, Massimiliano MUTIGNANI, Febbraro S, Tinari N, Iacobelli S, and Natoli C

Subjects
CA-19-9 Antigen, Lipoproteins, Sensitivity and Specificity, Neoplasm Proteins, Diagnosis, Differential, Pancreatic Neoplasms, Pancreatic Juice, Pancreatitis, Antigens, Neoplasm, Chronic Disease, Biomarkers, Tumor, Humans, Carrier Proteins, Glycoproteins
Abstract

Differential diagnosis of pancreatic cancer versus chronic pancreatitis may be difficult. The aim of this study is to determine whether a group of tumor-associated antigens could differentiate between the two pathologies.CA 19-9, TAG-72, CAR-3, and a newly discovered antigen termed "90K" were determined in the serum and in the pancreatic juice of 19 patients with pancreatic cancer, 20 patients with chronic pancreatitis, and seven controls with lithiasis of extrapancreatic bile ducts.The serum antigen levels of all three markers except 90K were significantly higher in pancreatic cancer than in chronic pancreatitis. High correlations were found between serum CA 19-9 and both TAG-72 and CAR-3. 90K did not correlate with other markers. In pancreatic juice, only 90K values were significantly higher in chronic pancreatitis than in pancreatic cancer, and only 90K and CA 19-9 were significantly correlated. At the stepwise discriminant analysis, serum CA 19-9 and pancreatic juice 90K had independent diagnostic roles. Used in combination, they correctly identified 84.2% of pancreatic cancer and 90% of chronic pancreatitis.These data suggest that pancreatic juice 90K and serum CA 19-9 can discriminate between chronic pancreatitis and pancreatic cancer. The data further support the complementary use of tumor-associated antigens along with other diagnostic tools.

75. Developing a decision-making model based on an interdisciplinary oncological care group for the management of colorectal cancer

Author

Genovesi, D., Mazzilli, L., Trignani, M., Di Tommaso, M., Nuzzo, A., Biondi, E., Tinari, N., Martino, M. T., Innocenti, P., Di Sebastiano, P., Mazzola, L., Lanci, C., Neri, M., Laterza, F., Marino, M., Ferrini, G., Spadaccini, A., Filippone, A., Di Giandomenico, E., Marulli, A., Palombo, G., Sparvieri, A., Marchetti, A., Pizzicannella, G., Petrini, F., Di Felice, M., Ottaviani, F., Monteodorisio, A., MARTA DI NICOLA, and Cefaro, G. A.

Subjects
Practice Guidelines as Topic, Disease Management, Humans, Colorectal Neoplasms, Medical Oncology
Abstract

To report our experience on implementation and preliminary results of a decision-making model based on the recommendations of an Interdisciplinary Oncological Care Group developed for the management of colorectal cancer.The multidisciplinary team identified a reference guideline using appraisal of guidelines for research and evaluation (AGREE) tool based on a sequential assessment of the guideline quality. Thereafter, internal guidelines with diagnostic and therapeutic management for early, locally advanced and metastatic colonic and rectal cancer were drafted; organizational aspects, responsibility matrices, protocol actions for each area of specialty involved and indicators for performing audits were also defined.The National Institute for Health and Care Excellence (NICE) UK guideline was the reference for drafting the internal guideline document; from February to November 2013, 125 patients with colorectal cancer were discussed by and taken under the care of the Interdisciplinary Oncological Care Group. The first audit performed in December 2013 revealed optimal adherence to the internal guideline, mainly in terms of uniformity and accuracy of perioperative staging, coordination and timing of multi-modal therapies. To date, all patients under observation are within the diagnostic and therapeutic course, no patient came out from the multidisciplinary "path" and only in 14% of cases have the first recommendations proposed been changed. The selected indicators appear effective and reliable, while at the moment, it is not yet possible to assess the impact of the multidisciplinary team on clinical outcome.Although having a short observation period, our model seems capable of determining optimal uniformity of diagnostic and therapeutic management, to a high degree of patient satisfaction. A longer observation period is necessary in order to confirm these observations and for assessing the impact on clinical outcome.

76. Longitudinal analysis of the 90K glycoprotein in the Italian HIV-seroconversion study: Temporal trend and predictability of the maturity of HIV infection

Author

Dorrucci M, Iacobelli S, BARBARA SULIGOI, Pezzotti P, Sinicco A, Angarano G, Tinari N, and Rezza G

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, Acquired Immunodeficiency Syndrome, Time Factors, Adolescent, Enzyme-Linked Immunosorbent Assay, HIV Infections, Middle Aged, Prognosis, Cohort Studies, Italy, Antigens, Neoplasm, Risk Factors, Antiretroviral Therapy, Highly Active, HIV Seropositivity, Biomarkers, Tumor, Humans, Regression Analysis, Female, Prospective Studies, Carrier Proteins, Glycoproteins, Proportional Hazards Models
Abstract

To evaluate the level of 90K as a predictor of AIDS; to describe 90K levels over time after HIV serconversion; and to evaluate the 90K level as a marker of the maturity of infection.Prospective incident cohort of HIV-infected individuals with documented dates of seroconversion.Cox models were applied to estimate the crude and adjusted relative hazards (RH) of AIDS by level of 90K. Regression models were applied to describe the temporal trend and the correlates of the level of 90K over time after HIV-seroconversion. Logistic models were applied to evaluate the probability of a sample of 90K having been taken within a certain time period after HIV-seroconversion.The study population consisted of 150 participants of the Italian Seroconversion Study. A total of 429 measurements of 90K were taken. Both early and later measurements of 90K were highly predictive of AIDS, also when adjusting for CD4 lymphocyte count and HIV load. The 90K level (U/ml) increased by 10% annually (95% CI: 7%-13%); the increase over time was linear. IDUs had higher 90K levels than heterosexuals and homosexuals over the course of HIV disease. High 90K levels were highly predictive of distant seroconversions (age-adjusted probability, 74%), whereas were poorly predictive of recent seroconversions (age-adjusted probability, 5%); the results were similar for the predictability of CD4 lymphocyte count.The level of 90K is a useful prognostic tool for clinical purposes. As a marker of the maturity of infection, 90K is similar to the CD4 lymphocyte count, with the advantage of being able to use serum instead of fresh whole blood. It has a good capacity to identify distant infections.

78. Elevated serum levels of a 90 kDa tumor-associated antigen in cancer and in infection by human immunodeficiency virus (HIV)

Author

Natoli, C., Tinari, N., D'Egidio, M., Ghinelli, F., Fusco, O., D'Ostilio, N., Grassadonia, A., Ortona, L., Piazza, M., and Iacobelli, S.

Subjects
Tumor antigens -- Physiological aspects, HIV infection -- Physiological aspects
Abstract

AUTHORS: C. Natoli, N. Tinari, M. D'Egidio, F. Ghinelli, O. Fusco, N. D'Ostilio, A. Grassadonia, L. Ortona, M. Piazza and S. Iacobelli. University 'G. D'Annunzio', Chieti, Italy; S. Anna Hospital, [...]

Published
1994

79. A phase I study of recombinant interferon-alpha administered as a 7-day continuous venous infusion at circadian-rhythm modulated rate in patients with cancer

Author

Iacobelli, S., Garufi, C., Irtelli, L., Martino, M.T., Santobuono, F., Vicario, G., Tinari, N., Fiorentino, B., Innocenti, P., and Natoli, C.

Subjects
Interferon alpha -- Dosage and administration, Circadian rhythms -- Effect of chemicals on, Chemotherapy -- Dosage and administration, Business, Health care industry
Abstract

According to the authors' abstract of an article published in American Journal of Clinical Oncology - Cancer Clinical Trials, 'A Phase I trial of interferon-alpha (IFN-alpha) administered at circadian-rhythm modulated [...]

Published
1995

81. Metronomic chemotherapy for advanced breast cancer patients in the real world practice: Final results of the VICTOR-6 study

Author

M.E. Cazzaniga, G. Pinotti, E. Montagna, D. Amoroso, R. Berardi, A. Butera, K. Cagossi, L. Cavanna, M. Ciccarese, S. Cinieri, E. Cretella, E. De Conciliis, A. Febbraro, F. Ferraù, A. Ferzi, G. Fiorentini, A. Fontana, A.R. Gambaro, O. Garrone, V. Gebbia, D. Generali, L. Gianni, F. Giovanardi, A. Grassadonia, V. Leonardi, P. Marchetti, E. Melegari, A. Musolino, M. Nicolini, C. Putzu, F. Riccardi, D. Santini, S. Saracchini, M.G. Sarobba, M.G. Schintu, G. Scognamiglio, P. Spadaro, C. Taverniti, D. Toniolo, P. Tralongo, A. Turletti, R. Valenza, M.R. Valerio, P. Vici, L. Clivio, V. Torri, F. Cicchiello, F. Riva, I. Vallini, M. Mazza, C. Bonfadini, E. Bordin, M. Canicattì, F. Cappuccio, E. Collovà, C. De Angelis, R. Desorte, S. Donati, G. Drudi, D. Galanti, C. Mocerino, L. Orlando, B. Pellegrino, L. Pizzuti, C. Ridolfi, A. Rocca, D. Sarti, I. Spagnoletti, N. Tinari, A. Vandone, L. Vizzini, Cazzaniga M.E., Pinotti G., Montagna E., Amoroso D., Berardi R., Butera A., Cagossi K., Cavanna L., Ciccarese M., Cinieri S., Cretella E., De Conciliis E., Febbraro A., Ferrau F., Ferzi A., Fiorentini G., Fontana A., Gambaro A.R., Garrone O., Gebbia V., Generali D., Gianni L., Giovanardi F., Grassadonia A., Leonardi V., Marchetti P., Melegari E., Musolino A., Nicolini M., Putzu C., Riccardi F., Santini D., Saracchini S., Sarobba M.G., Schintu M.G., Scognamiglio G., Spadaro P., Taverniti C., Toniolo D., Tralongo P., Turletti A., Valenza R., Valerio M.R., Vici P., Clivio L., Torri V., Cicchiello F., Riva F., Vallini I., Mazza M., Bonfadini C., Bordin E., Canicatti M., Cappuccio F., Collova E., De Angelis C., Desorte R., Donati S., Drudi G., Galanti D., Mocerino C., Orlando L., Pellegrino B., Pizzuti L., Ridolfi C., Rocca A., Sarti D., Spagnoletti I., Tinari N., Vandone A., Vizzini L., Cazzaniga, M, Pinotti, G, Montagna, E, Amoroso, D, Berardi, R, Butera, A, Cagossi, K, Cavanna, L, Ciccarese, M, Cinieri, S, Cretella, E, De Conciliis, E, Febbraro, A, Ferrau, F, Ferzi, A, Fiorentini, G, Fontana, A, Gambaro, A, Garrone, O, Gebbia, V, Generali, D, Gianni, L, Giovanardi, F, Grassadonia, A, Leonardi, V, Marchetti, P, Melegari, E, Musolino, A, Nicolini, M, Putzu, C, Riccardi, F, Santini, D, Saracchini, S, Sarobba, M, Schintu, M, Scognamiglio, G, Spadaro, P, Taverniti, C, Toniolo, D, Tralongo, P, Turletti, A, Valenza, R, Valerio, M, Vici, P, Clivio, L, Torri, V, Cicchiello, F, Riva, F, Vallini, I, Mazza, M, Bonfadini, C, Bordin, E, Canicatti, M, Cappuccio, F, Collova, E, De Angelis, C, Desorte, R, Donati, S, Drudi, G, Galanti, D, Mocerino, C, Orlando, L, Pellegrino, B, Pizzuti, L, Ridolfi, C, Rocca, A, Sarti, D, Spagnoletti, I, Tinari, N, Vandone, A, and Vizzini, L

Subjects
Adult, Oncology, medicine.medical_specialty, Cyclophosphamide, Settore MED/06 - Oncologia Medica, Antineoplastic Agents, Breast Neoplasms, Vinorelbine, Drug Administration Schedule, Antineoplastic Agent, Efficacy, Capecitabine, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Retrospective Studie, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, 030212 general & internal medicine, Progression-free survival, Retrospective Studies, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocol, business.industry, Metronomic chemotherapy, General Medicine, Middle Aged, medicine.disease, Metastatic breast cancer, Metronomic Chemotherapy, Survival Rate, Methotrexate, Treatment Outcome, 030220 oncology & carcinogenesis, MED/06 - ONCOLOGIA MEDICA, Female, Surgery, business, Breast Neoplasm, Human, medicine.drug
Abstract

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3–10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8–11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3–15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Published
2019

82. The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial

Author

Pietro Del Medico, Rossana Berardi, Enzo Veltri, Maria Rosaria Valerio, Alessandra Cassano, Daniele Marinelli, Vito Lorusso, Patrizia Vici, Nicola D’Ostilio, Silverio Tomao, Enrico Cortesi, Nicola Tinari, Emilio Bria, Domenico Sergi, Luca Moscetti, Giuseppe Sanguineti, Teresa Gamucci, Claudio Zamagni, Maddalena Barba, Clara Natoli, Theodora Daralioti, Giancarlo Paoletti, Antonino Grassadonia, Marina Elena Cazzaniga, Icro Meattini, Ornella Garrone, Andrea Michelotti, Giuseppina Sarobba, Nicla La Verde, Laura Pizzuti, Letizia Perracchio, Vincenzo Adamo, Giuseppe Tonini, A. Vaccaro, Francesco Giotta, Corrado Ficorella, Maria Agnese Fabbri, Antonio Russo, Paolo Marchetti, Gennaro Ciliberto, Mirco Pistelli, Rosanna Mirabelli, Marco Mazzotta, Daniele Generali, Marcello Maugeri-Saccà, Mario Roselli, Angelo Di Leo, Anna Di Benedetto, Isabella Sperduti, Ida Paris, Eriseld Krasniqi, Carlo Garufi, Lorenzo Livi, Ruggero De Maria, Andrea Botticelli, Domenico Corsi, Pizzuti, L, Barba, M, Mazzotta, M, Krasniqi, E, Maugeri-Sacca, M, Gamucci, T, Berardi, R, Livi, L, Ficorella, C, Natoli, C, Cortesi, E, Generali, D, La Verde, N, Cassano, A, Bria, E, Moscetti, L, Michelotti, A, Adamo, V, Zamagni, C, Tonini, G, Sergi, D, Marinelli, D, Paoletti, G, Tomao, S, Botticelli, A, Marchetti, P, Tinari, N, Grassadonia, A, Valerio, M, Mirabelli, R, Fabbri, M, D'Ostilio, N, Veltri, E, Corsi, D, Garrone, O, Paris, I, Sarobba, G, Meattini, I, Pistelli, M, Giotta, F, Lorusso, V, Garufi, C, Russo, A, Cazzaniga, M, Del Medico, P, Roselli, M, Vaccaro, A, Perracchio, L, di Benedetto, A, Daralioti, T, Sperduti, I, De Maria, R, Di Leo, A, Sanguineti, G, Ciliberto, G, Vici, P, Pizzuti, Laura, Barba, Maddalena, Mazzotta, Marco, Krasniqi, Eriseld, Maugeri-Saccà, Marcello, Gamucci, Teresa, Berardi, Rossana, Livi, Lorenzo, Ficorella, Corrado, Natoli, Clara, Cortesi, Enrico, Generali, Daniele, La Verde, Nicla, Cassano, Alessandra, Bria, Emilio, Moscetti, Luca, Michelotti, Andrea, Adamo, Vincenzo, Zamagni, Claudio, Tonini, Giuseppe, Sergi, Domenico, Marinelli, Daniele, Paoletti, Giancarlo, Tomao, Silverio, Botticelli, Andrea, Marchetti, Paolo, Tinari, Nicola, Grassadonia, Antonino, Valerio, Maria Rosaria, Mirabelli, Rosanna, Fabbri, Maria Agnese, D’Ostilio, Nicola, Veltri, Enzo, Corsi, Domenico, Garrone, Ornella, Paris, Ida, Sarobba, Giuseppina, Meattini, Icro, Pistelli, Mirco, Giotta, Francesco, Lorusso, Vito, Garufi, Carlo, Russo, Antonio, Cazzaniga, Marina, Del Medico, Pietro, Roselli, Mario, Vaccaro, Angela, Perracchio, Letizia, di Benedetto, Anna, Daralioti, Theodora, Sperduti, Isabella, De Maria, Ruggero, Di Leo, Angelo, Sanguineti, Giuseppe, Ciliberto, Gennaro, Vici, Patrizia, Pizzuti L., Barba M., Mazzotta M., Krasniqi E., Maugeri-Sacca M., Gamucci T., Berardi R., Livi L., Ficorella C., Natoli C., Cortesi E., Generali D., La Verde N., Cassano A., Bria E., Moscetti L., Michelotti A., Adamo V., Zamagni C., Tonini G., Sergi D., Marinelli D., Paoletti G., Tomao S., Botticelli A., Marchetti P., Tinari N., Grassadonia A., Valerio M.R., Mirabelli R., Fabbri M.A., D'Ostilio N., Veltri E., Corsi D., Garrone O., Paris I., Sarobba G., Meattini I., Pistelli M., Giotta F., Lorusso V., Garufi C., Russo A., Cazzaniga M., Del Medico P., Roselli M., Vaccaro A., Perracchio L., di Benedetto A., Daralioti T., Sperduti I., De Maria R., Di Leo A., Sanguineti G., Ciliberto G., and Vici P.

Subjects
0301 basic medicine, Oncology, Cancer therapy, Receptor, ErbB-2, medicine.medical_treatment, Ado-Trastuzumab Emtansine, progesterone receptor, Settore MED/06, 0302 clinical medicine, human epidermal growth factor receptor 2 (HER2), Antineoplastic Combined Chemotherapy Protocols, estrogen, Neoplasm Metastasis, skin and connective tissue diseases, Multidisciplinary, Brain Neoplasms, Middle Aged, Prognosis, Metastatic breast cancer, Neoplasm Metastasi, 030220 oncology & carcinogenesis, Medicine, Female, Pertuzumab, metastatic breast cancer, Receptors, Progesterone, Breast Neoplasm, HER2 positivity, medicine.drug, Human, Adult, medicine.medical_specialty, medicine.drug_class, Science, trastuzumab-emtansine, Breast Neoplasms, cancer, Article, Disease-Free Survival, Brain Neoplasm, 03 medical and health sciences, Breast cancer, breast cancer, Settore MED/04 - PATOLOGIA GENERALE, pertuzumab, Internal medicine, Progesterone receptor, medicine, Humans, neoplasms, Aged, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Cancer, medicine.disease, HER2-positive, oncology, radiotherapy, chemotherapy, HER2, Radiation therapy, 030104 developmental biology, Estrogen, business, prognostic relevance
Abstract

Breast cancer (BC) heterogeneity is composite in nature, with a wide variety of factors concurring to define several pathological entities, which differ by clinical presentation, pathologic features, therapy administered, and inherent outcomes1. Additional sources of breast cancer heterogeneity may raise during the disease course. In BC patients whose disease was initially diagnosed in the early stage and subsequently progressed with metastatic involvement of one single or multiple site/s, the molecular characteristics of metastatic lesions do not necessary mimic those of the disease initially diagnosed. A well-depicted molecular landscape is crucial for subtype definition, prognostic evaluation and appropriate therapeutic decisions. Accordingly, current guidelines suggest repeating the immunohistochemical (IHC) assessment in patients with metastatic spread and at least one secondary lesion amenable to biopsy2. Discordance in human epidermal growth factor receptor 2 (HER2) status between the tumor and metastatic lesions is widely acknowledged, and not yet completely unraveled in their biologic meaning and prognostic relevance3–11. The overexpression of HER2 or amplification of the related gene is extensively recognized as a feature associated with more aggressive biological behavior12,13. However, the extent to which changes in HER2 status may affect patients’ prognosis is still a matter of debate14. We herein propose an observational study of HER2-positive metastatic breast cancer (mBC) patients treated with the anti-HER2 targeted agents pertuzumab and/or trastuzumab emtansine (T-DM1). Our research question is whether relevant differences exist in long-term outcomes of patients with concordant HER2 status between the primary tumor and its secondary lesion/s compared to patients whose disease revealed HER2-positivity gain at the IHC assessment of metastatic lesions. In our historical cohorts, we also sought to identify factors associated with HER2-positivity gain at the IHC reassessment, for which an impact on prognosis may be foreseen.

Published
2021

83. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial

Author

Sabino De Placido, Ciro Gallo, Michelino De Laurentiis, Giancarlo Bisagni, Grazia Arpino, Maria Giuseppa Sarobba, Ferdinando Riccardi, Antonio Russo, Lucia Del Mastro, Alessio Aligi Cogoni, Francesco Cognetti, Stefania Gori, Jennifer Foglietta, Antonio Frassoldati, Domenico Amoroso, Lucio Laudadio, Luca Moscetti, Filippo Montemurro, Claudio Verusio, Antonio Bernardo, Vito Lorusso, Adriano Gravina, Gabriella Moretti, Rossella Lauria, Antonella Lai, Carmela Mocerino, Sergio Rizzo, Francesco Nuzzo, Paolo Carlini, Francesco Perrone, Antonello Accurso, Biagio Agostara, Michele Aieta, Oscar Alabiso, Maria Grazia Alicicco, Dino Amadori, Laura Amaducci, Gianna Amiconi, Giustino Antuzzi, Mara Ardine, Antonio Ardizzoia, Caterina Aversa, Giuseppe Badalamenti, Sandro Barni, Carlo Basurto, Rossana Berardi, Cinzia Bergamasco, Paolo Bidoli, Claudia Bighin, Edoardo Biondi, Corrado Boni, Karen Borgonovo, Mario Botta, Stefano Bravi, Paolo Bruzzi, Giuseppe Buono, Alfredo Butera, Alessia Caldara, Giampiero Candeloro, Claudia Cappelletti, Cinzia Cardalesi, Elisabetta Carfora, Anna Cariello, Francesco Carrozza, Giacomo Cartenì, Michele Caruso, Virginia Casadei, Claudia Casanova, Luigi Castori, Luigi Cavanna, Giovanna Cavazzini, Marina Cazzaniga, Mario Chilelli, Paolo Chiodini, Silvia Chiorrini, Fortunato Ciardiello, Mariangela Ciccarese, Saverio Cinieri, Mario Clerico, Mariarosa Coccaro, Mario Comande, Claudia Corbo, Giuseppina Cortino, Stefania Cusenza, Gennaro Daniele, Alfonso Maria D'arco, Giuliana D'auria, Claudio Dazzi, Carmine De Angelis, Filippo de Braud, Gianfranco De Feo, Andrea De Matteis, Michele De Tursi, Anna Di Blasio, Giuseppe di Lucca, Liberato Di Lullo, Francesca Di Rella, Gianfranco Di Renzo, Pia Di Stefano, Aida Di Stefano, Anna Diana, Sara Donati, Agnese Fabbri, Alessandra Fabi, Marina Faedi, Gabriella Farina, Antonio Farris, Antonio Febbraro, Palma Fedele, Piera Federico, Francesco Ferraù, Gianluigi Ferretti, Antonella Ferro, Irene Floriani, Rosachiara Forcignanò, Samantha Forciniti, Valeria Forestieri, Gianni Fornari, Michela Frisinghelli, Vittorio Fusco, Giulia Gallizzi, Antonio Galvano, Antonio Gambardella, Angelo Gambi, Vittorio Gebbia, Erika Gervasi, Mara Ghilardi, Alice Giacobino, Giovanni Giardina, Francesco Giotta, Sara Giraudi, Mario Giuliano, Antonino Grassadonia, Donatella Grasso, Federica Grosso, Lorenzo Guizzaro, Pasquale Incoronato, Lorena Incorvaia, Giovanni Iodice, Nicla La Verde, Vincenzo Labonia, Gabriella Landi, Agnese Latorre, Vita Leonardi, Alessia Levaggi, Gennaro Limite, Linda Lina Bascialla, Lorenzo Livi, Evaristo Maiello, Daniela Mandelli, Ilaria Marcon, Daniela Menon, Michele Montedoro, Lucia Moraca, Anna Moretti, Maria Grazia Morritti, Patrizia Morselli, Antonella Mura, Silvia Mura, Michela Musacchio, Alberto Muzio, Donato Natale, Clara Natoli, Cinzia Nigro, Cecilia Nisticò, Antonio Nuzzo, Michele Orditura, Laura Orlando, Carmen Pacilio, Giuliano Palumbo, Raffaella Palumbo, Felice Pasini, Emanuela Paterno, Antonio Pazzola, Silvia Pelliccioni, Matilde Pensabene, Davide Perroni, Angela Pesenti Gritti, Fausto Petrelli, Maria Carmela Piccirillo, Graziella Pinotti, Claudia Pogliani, Davide Poli, Sonia Prader, Francesco Recchia, Daniele Rizzi, Carmen Romano, Rosalba Rossello, Chiara Rossini, Giuseppina Salvucci, Valeria Sanna, Alessandra Santini, Silvana Saracchini, Clementina Savastano, Giovanni Scambia, Francesco Schettini, Paola Schiavone, Alessio Schirone, Elena Seles, Simona Signoriello, Giuseppe Signoriello, Rosa Rita Silva, Antonia Silvestri, Vittorio Simeon, Ilaria Spagnoletti, Stefano Tamberi, Cristina Teragni, Verena Thalmann, Renato Thomas, Guglielmo Thomas, Amelia Tienghi, Nicola Tinari, Vincenza Tinessa, Federica Tomei, Giuseppe Tonini, Valter Torri, Divina Traficante, Marianna Tudini, Monica Turazza, Roberto Vignoli, Maria Giuseppa Vitale, Alessandra Zacchia, Pasquale Zagarese, Alda Zanni, Laura Zavallone, Maria Zavettieri, Alessandra Zoboli, De Placido, S., Gallo, C., De Laurentiis, M., Bisagni, G., Arpino, G., Sarobba, M. G., Riccardi, F., Russo, A., Del Mastro, L., Cogoni, A. A., Cognetti, F., Gori, S., Foglietta, J., Frassoldati, A., Amoroso, D., Laudadio, L., Moscetti, L., Montemurro, F., Verusio, C., Bernardo, A., Lorusso, V., Gravina, A., Moretti, G., Lauria, R., Lai, A., Mocerino, C., Rizzo, S., Nuzzo, F., Carlini, P., Perrone, F., Accurso, A., Agostara, B., Aieta, M., Alabiso, O., Alicicco, M. G., Amadori, D., Amaducci, L., Amiconi, G., Antuzzi, G., Ardine, M., Ardizzoia, A., Aversa, C., Badalamenti, G., Barni, S., Basurto, C., Berardi, R., Bergamasco, C., Bidoli, P., Bighin, C., Biondi, E., Boni, C., Borgonovo, K., Botta, M., Bravi, S., Bruzzi, P., Buono, G., Butera, A., Caldara, A., Candeloro, G., Cappelletti, C., Cardalesi, C., Carfora, E., Cariello, A., Carrozza, F., Carteni, G., Caruso, M., Casadei, V., Casanova, C., Castori, L., Cavanna, L., Cavazzini, G., Cazzaniga, M., Chilelli, M., Chiodini, P., Chiorrini, S., Ciardiello, F., Ciccarese, M., Cinieri, S., Clerico, M., Coccaro, M., Comande, M., Corbo, C., Cortino, G., Cusenza, S., Daniele, G., D'Arco, A. M., D'Auria, G., Dazzi, C., De Angelis, C., de Braud, F., De Feo, G., De Matteis, Ma., De Tursi, M., Di Blasio, A., di Lucca, G., Di Lullo, L., Di Rella, F., Di Renzo, G., Di Stefano, P., Di Stefano, A., Diana, A., Donati, S., Fabbri, A., Fabi, A., Faedi, M., Farina, G., Farris, A., Febbraro, A., Fedele, P., Federico, P., Ferrau, F., Ferretti, G., Ferro, A., Floriani, I., Forcignano, R., Forciniti, S., Forestieri, V., Fornari, G., Frisinghelli, M., Fusco, V., Gallizzi, G., Galvano, A., Gambardella, A., Gambi, A., Gebbia, V., Gervasi, E., Ghilardi, M., Giacobino, A., Giardina, G., Giotta, F., Giraudi, S., Giuliano, M., Grassadonia, A., Grasso, D., Grosso, F., Guizzaro, L., Incoronato, P., Incorvaia, L., Iodice, G., La Verde, N., Labonia, V., Landi, G., Latorre, A., Leonardi, V., Levaggi, A., Limite, G., Lina Bascialla, L., Livi, L., Maiello, E., Mandelli, D., Marcon, I., Menon, D., Montedoro, M., Moraca, L., Moretti, A., Morritti, M. G., Morselli, P., Mura, A., Mura, S., Musacchio, M., Muzio, A., Natale, D., Natoli, C., Nigro, C., Nistico, C., Nuzzo, A., Orditura, M., Orlando, L., Pacilio, C., Palumbo, G., Palumbo, R., Pasini, F., Paterno, E., Pazzola, A., Pelliccioni, S., Pensabene, M., Perroni, D., Pesenti Gritti, A., Petrelli, F., Piccirillo, M. C., Pinotti, G., Pogliani, C., Poli, D., Prader, S., Recchia, F., Rizzi, D., Romano, C., Rossello, R., Rossini, C., Salvucci, G., Sanna, V., Santini, A., Saracchini, S., Savastano, C., Scambia, G., Schettini, F., Schiavone, P., Schirone, A., Seles, E., Signoriello, S., Signoriello, G., Silva, R. R., Silvestri, A., Simeon, V., Spagnoletti, I., Tamberi, S., Teragni, C., Thalmann, V., Thomas, R., Thomas, G., Tienghi, A., Tinari, N., Tinessa, V., Tomei, F., Tonini, G., Torri, V., Traficante, D., Tudini, M., Turazza, M., Vignoli, R., Vitale, M. G., Zacchia, A., Zagarese, P., Zanni, A., Zavallone, L., Zavettieri, M., Zoboli, A., De Placido, Sabino, Gallo, Ciro, De Laurentiis, Michelino, Bisagni, Giancarlo, Arpino, Grazia, Sarobba, Maria Giuseppa, Riccardi, Ferdinando, Russo, Antonio, Del Mastro, Lucia, Cogoni, Alessio Aligi, Cognetti, Francesco, Gori, Stefania, Foglietta, Jennifer, Frassoldati, Antonio, Amoroso, Domenico, Laudadio, Lucio, Moscetti, Luca, Montemurro, Filippo, Verusio, Claudio, Bernardo, Antonio, Lorusso, Vito, Gravina, Adriano, Moretti, Gabriella, Lauria, Rossella, Lai, Antonella, Mocerino, Carmen, Rizzo, Sergio, Nuzzo, Francesco, Carlini, Paolo, Perrone, Francesco, Accurso, Antonello, Agostara, Biagio, Aieta, Michele, Alabiso, Oscar, Alicicco, Maria Grazia, Amadori, Dino, Amaducci, Laura, Amiconi, Gianna, Antuzzi, Giustino, Ardine, Mara, Ardizzoia, Antonio, Aversa, Caterina, Badalamenti, Giuseppe, Barni, Sandro, Basurto, Carlo, Berardi, Rossana, Bergamasco, Cinzia, Bidoli, Paolo, Bighin, Claudia, Biondi, Edoardo, Boni, Corrado, Borgonovo, Karen, Botta, Mario, Bravi, Stefano, Bruzzi, Paolo, Buono, Giuseppe, Butera, Alfredo, Caldara, Alessia, Candeloro, Giampiero, Cappelletti, Claudia, Cardalesi, Cinzia, Carfora, Elisabetta, Cariello, Anna, Carrozza, Francesco, Cartenì, Giacomo, Caruso, Michele, Casadei, Virginia, Casanova, Claudia, Castori, Luigi, Cavanna, Luigi, Cavazzini, Giovanna, Cazzaniga, Marina, Chilelli, Mario, Chiodini, Paolo, Chiorrini, Silvia, Ciardiello, Fortunato, Ciccarese, Mariangela, Cinieri, Saverio, Clerico, Mario, Coccaro, Mariarosa, Comande, Mario, Corbo, Claudia, Cortino, Giuseppina, Cusenza, Stefania, Daniele, Gennaro, D'arco, Alfonso Maria, D'auria, Giuliana, Dazzi, Claudio, De Angelis, Carmine, de Braud, Filippo, De Feo, Gianfranco, De Matteis, Andrea, De Tursi, Michele, Di Blasio, Anna, di Lucca, Giuseppe, Di Lullo, Liberato, Di Rella, Francesca, Di Renzo, Gianfranco, Di Stefano, Pia, Di Stefano, Aida, Diana, Anna, Donati, Sara, Fabbri, Agnese, Fabi, Alessandra, Faedi, Marina, Farina, Gabriella, Farris, Antonio, Febbraro, Antonio, Fedele, Palma, Federico, Piera, Ferraù, Francesco, Ferretti, Gianluigi, Ferro, Antonella, Floriani, Irene, Forcignanò, Rosachiara, Forciniti, Samantha, Forestieri, Valeria, Fornari, Gianni, Frisinghelli, Michela, Fusco, Vittorio, Gallizzi, Giulia, Galvano, Antonio, Gambardella, Antonio, Gambi, Angelo, Gebbia, Vittorio, Gervasi, Erika, Ghilardi, Mara, Giacobino, Alice, Giardina, Giovanni, Giotta, Francesco, Giraudi, Sara, Giuliano, Mario, Grassadonia, Antonino, Grasso, Donatella, Grosso, Federica, Guizzaro, Lorenzo, Incoronato, Pasquale, Incorvaia, Lorena, Iodice, Giovanni, La Verde, Nicla, Labonia, Vincenzo, Landi, Gabriella, Latorre, Agnese, Leonardi, Vita, Levaggi, Alessia, Limite, Gennaro, Lina Bascialla, Linda, Livi, Lorenzo, Maiello, Evaristo, Mandelli, Daniela, Marcon, Ilaria, Menon, Daniela, Montedoro, Michele, Moraca, Lucia, Moretti, Anna, Morritti, Maria Grazia, Morselli, Patrizia, Mura, Antonella, Mura, Silvia, Musacchio, Michela, Muzio, Alberto, Natale, Donato, Natoli, Clara, Nigro, Cinzia, Nisticò, Cecilia, Nuzzo, Antonio, Orditura, Michele, Orlando, Laura, Pacilio, Carmen, Palumbo, Giuliano, Palumbo, Raffaella, Pasini, Felice, Paterno, Emanuela, Pazzola, Antonio, Pelliccioni, Silvia, Pensabene, Matilde, Perroni, Davide, Pesenti Gritti, Angela, Petrelli, Fausto, Piccirillo, Maria Carmela, Pinotti, Graziella, Pogliani, Claudia, Poli, Davide, Prader, Sonia, Recchia, Francesco, Rizzi, Daniele, Romano, Carmen, Rossello, Rosalba, Rossini, Chiara, Salvucci, Giuseppina, Sanna, Valeria, Santini, Alessandra, Saracchini, Silvana, Savastano, Clementina, Scambia, Giovanni, Schettini, Francesco, Schiavone, Paola, Schirone, Alessio, Seles, Elena, Signoriello, Simona, Signoriello, Giuseppe, Silva, Rosa Rita, Silvestri, Antonia, Simeon, Vittorio, Spagnoletti, Ilaria, Tamberi, Stefano, Teragni, Cristina, Thalmann, Verena, Thomas, Renato, Thomas, Guglielmo, Tienghi, Amelia, Tinari, Nicola, Tinessa, Vincenza, Tomei, Federica, Tonini, Giuseppe, Torri, Valter, Traficante, Divina, Tudini, Marianna, Turazza, Monica, Vignoli, Roberto, Vitale, Maria Giuseppa, Zacchia, Alessandra, Zagarese, Pasquale, Zanni, Alda, Zavallone, Laura, Zavettieri, Maria, Zoboli, Alessandra, Mocerino, Carmela, D'Arco, Alfonso Maria, D'Auria, Giuliana, De Placido, S, Gallo, C, De Laurentiis, M, Bisagni, G, Arpino, G, Sarobba, M, Riccardi, F, Russo, A, Del Mastro, L, Cogoni, A, Cognetti, F, Gori, S, Foglietta, J, Frassoldati, A, Amoroso, D, Laudadio, L, Moscetti, L, Montemurro, F, Verusio, C, Bernardo, A, Lorusso, V, Gravina, A, Moretti, G, Lauria, R, Lai, A, Mocerino, C, Rizzo, S, Nuzzo, F, Carlini, P, Perrone, F, Accurso, A, Agostara, B, Aieta, M, Alabiso, O, Alicicco, M, Amadori, D, Amaducci, L, Amiconi, G, Antuzzi, G, Ardine, M, Ardizzoia, A, Aversa, C, Badalamenti, G, Barni, S, Basurto, C, Berardi, R, Bergamasco, C, Bidoli, P, Bighin, C, Biondi, E, Boni, C, Borgonovo, K, Botta, M, Bravi, S, Bruzzi, P, Buono, G, Butera, A, Caldara, A, Candeloro, G, Cappelletti, C, Cardalesi, C, Carfora, E, Cariello, A, Carrozza, F, Carteni, G, Caruso, M, Casadei, V, Casanova, C, Castori, L, Cavanna, L, Cavazzini, G, Cazzaniga, M, Chilelli, M, Chiodini, P, Chiorrini, S, Ciardiello, F, Ciccarese, M, Cinieri, S, Clerico, M, Coccaro, M, Comande, M, Corbo, C, Cortino, G, Cusenza, S, Daniele, G, D'Arco, A, D'Auria, G, Dazzi, C, De Angelis, C, de Braud, F, De Feo, G, De Matteis, A, De Tursi, M, Di Blasio, A, di Lucca, G, Di Lullo, L, Di Rella, F, Di Renzo, G, Di Stefano, P, Di Stefano, A, Diana, A, Donati, S, Fabbri, A, Fabi, A, Faedi, M, Farina, G, Farris, A, Febbraro, A, Fedele, P, Federico, P, Ferrau, F, Ferretti, G, Ferro, A, Floriani, I, Forcignano, R, Forciniti, S, Forestieri, V, Fornari, G, Frisinghelli, M, Fusco, V, Gallizzi, G, Galvano, A, Gambardella, A, Gambi, A, Gebbia, V, Gervasi, E, Ghilardi, M, Giacobino, A, Giardina, G, Giotta, F, Giraudi, S, Giuliano, M, Grassadonia, A, Grasso, D, Grosso, F, Guizzaro, L, Incoronato, P, Incorvaia, L, Iodice, G, La Verde, N, Labonia, V, Landi, G, Latorre, A, Leonardi, V, Levaggi, A, Limite, G, Lina Bascialla, L, Livi, L, Maiello, E, Mandelli, D, Marcon, I, Menon, D, Montedoro, M, Moraca, L, Moretti, A, Morritti, M, Morselli, P, Mura, A, Mura, S, Musacchio, M, Muzio, A, Natale, D, Natoli, C, Nigro, C, Nistico, C, Nuzzo, A, Orditura, M, Orlando, L, Pacilio, C, Palumbo, G, Palumbo, R, Pasini, F, Paterno, E, Pazzola, A, Pelliccioni, S, Pensabene, M, Perroni, D, Pesenti Gritti, A, Petrelli, F, Piccirillo, M, Pinotti, G, Pogliani, C, Poli, D, Prader, S, Recchia, F, Rizzi, D, Romano, C, Rossello, R, Rossini, C, Salvucci, G, Sanna, V, Santini, A, Saracchini, S, Savastano, C, Scambia, G, Schettini, F, Schiavone, P, Schirone, A, Seles, E, Signoriello, S, Signoriello, G, Silva, R, Silvestri, A, Simeon, V, Spagnoletti, I, Tamberi, S, Teragni, C, Thalmann, V, Thomas, R, Thomas, G, Tienghi, A, Tinari, N, Tinessa, V, Tomei, F, Tonini, G, Torri, V, Traficante, D, Tudini, M, Turazza, M, Vignoli, R, Vitale, M, Zacchia, A, Zagarese, P, Zanni, A, Zavallone, L, Zavettieri, M, and Zoboli, A

Subjects
Oncology, Receptor, ErbB-2, Settore MED/06 - Oncologia Medica, letrozole, law.invention, Adjuvant anastrozole, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Exemestane, law, exemestane, tamoxifen, breast cancer, Antineoplastic Combined Chemotherapy Protocols, 030212 general & internal medicine, Aromatase Inhibitors, Letrozole, Hazard ratio, Middle Aged, Receptors, Estrogen, Tolerability, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, Receptors, Progesterone, Breast Neoplasm, Human, medicine.drug, medicine.medical_specialty, Socio-culturale, Anastrozole, Breast Neoplasms, Disease-Free Survival, Drug Administration Schedule, 03 medical and health sciences, Breast cancer, Internal medicine, medicine, Aromatase Inhibitor, Humans, Aged, Antineoplastic Combined Chemotherapy Protocol, Androstadiene, business.industry, medicine.disease, Androstadienes, chemistry, business, Tamoxifen
Abstract

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

Published
2018

84. 3D-Informed Targeting of the Trop-2 Signal-Activation Site Drives Selective Cancer Vulnerability

Author

Emanuela Guerra, Marco Trerotola, Valeria Relli, Rossano Lattanzio, Romina Tripaldi, Martina Ceci, Khouloud Boujnah, Ludovica Pantalone, Andrea Sacchetti, Kristina M. Havas, Pasquale Simeone, Nicole Travali, Patrizia Querzoli, Massimo Pedriali, Pietro Roversi, Manuela Iezzi, Nicola Tinari, Laura Antolini, Saverio Alberti, Guerra, E, Trerotola, M, Relli, V, Lattanzio, R, Tripaldi, R, Ceci, M, Boujnah, K, Pantalone, L, Sacchetti, A, Havas, K, Simeone, P, Travali, N, Querzoli, P, Pedriali, M, Roversi, P, Iezzi, M, Tinari, N, Antolini, L, and Alberti, S

Subjects
Cancer Research, Oncology, trop-2
Abstract

Next-generation Trop-2–targeted therapy against advanced cancers is hampered by expression of Trop-2 in normal tissues. We discovered that Trop-2 undergoes proteolytic activation by ADAM10 in cancer cells, leading to the exposure of a previously inaccessible protein groove flanked by two N-glycosylation sites. We designed a recognition strategy for this region, to drive selective cancer vulnerability in patients. Most undiscriminating anti–Trop-2 mAbs recognize a single immunodominant epitope. Hence, we removed it by deletion mutagenesis. Cancer-specific, glycosylation-prone mAbs were selected by ELISA, bio-layer interferometry, flow cytometry, confocal microscopy for differential binding to cleaved/activated, wild-type and glycosylation site–mutagenized Trop-2. The resulting 2G10 mAb family binds Trop-2–expressing cancer cells, but not Trop-2 on normal cells. We humanized 2G10 by state-of-the-art complementarity determining region grafting/re-modeling, yielding Hu2G10. This antibody binds cancer-specific, cleaved/activated Trop-2 with Kd < 10−12 mol/L, and uncleaved/wtTrop-2 in normal cells with Kd 3.16×10−8 mol/L, thus promising an unprecedented therapeutic index in patients. In vivo, Hu2G10 ablates growth of Trop-2–expressing breast, colon, prostate cancers, but shows no evidence of systemic toxicity, paving the way for a paradigm shift in Trop-2–targeted therapy.

Published
2023

85. A perspective analysis: microRNAs, glucose metabolism, and drug resistance in colon cancer stem cells

Author

Feliciano Protasi, Nicola Tinari, Sara Pagotto, Giorgio Stassi, Maria Luisa Colorito, Angelo Veronese, Simone Di Franco, Tiziana Apuzzo, Annalisa Nicotra, Rosa Visone, Pagotto S., Colorito M.L., Nicotra A., Apuzzo T., Tinari N., Protasi F., Stassi G., Visone R., Di Franco S., and Veronese A.

Subjects
cancer stem cell, Cancer Research, Colorectal cancer, Drug resistance, Carbohydrate metabolism, Text mining, Cell Line, Tumor, microRNA, Humans, Medicine, Molecular Biology, business.industry, Perspective (graphical), medicine.disease, 2-DG, Gene Expression Regulation, Neoplastic, MicroRNAs, Glucose, colon cancer, Drug Resistance, Neoplasm, Colonic Neoplasms, Neoplastic Stem Cells, Cancer research, Molecular Medicine, Settore MED/46 - Scienze Tecniche Di Medicina Di Laboratorio, Stem cell, business, metabolism
Abstract

Metabolism sustains the stemness of Cancer Stem Cells (CSCs), affecting, in turn, tumor heterogeneity, metastatic potential, and therapy resistance. Therefore, it is appealing to target CSCs metabolism as a new therapeutic approach. Consequently, we paid considerable attention to the anti-apoptotic microRNA miR-483-3p, that we reported being regulated by glucose metabolism in liver cancer cells. We investigated the therapeutic potential of targeting miR-483-3p by using the anti-glucose metabolism 2-deoxyglucose (2-DG) molecule in tumor Xenograft mouse model originating from two different Colon-Cancer Stem Cell lines (CCSC lines). We show that 2-DG treatment does not affect CCSCs during tumor formation in immunocompromised mouse models despite its ability to increase the CCSCs apoptotic rate in vitro and decrease miR-483-3p expression in both in vitro and in vivo experimental conditions. The promising in vitro data contrast with in vivo results that show the inefficacy of the treatment. We think that, in our immuno-compromised mouse model, to inhibit the glucose metabolism could become not only ineffective but also counterproductive by creating a selective pressure on the most fitting tumoral clones.

Published
2021

86. Trop-2, Na +/K + ATPase, CD9, PKCα, cofilin assemble a membrane signaling super-complex that drives colorectal cancer growth and invasion

Author

Emanuela Guerra, Valeria Relli, Martina Ceci, Romina Tripaldi, Pasquale Simeone, Anna Laura Aloisi, Ludovica Pantalone, Rossana La Sorda, Rossano Lattanzio, Andrea Sacchetti, Kristina Havas, Simone Guarnieri, Daniele Vergara, Isabelle Fournier, Michel Salzet, Nicola Tinari, Mauro Piantelli, Marco Trerotola, Saverio Alberti, Guerra, E, Relli, V, Ceci, M, Tripaldi, R, Simeone, P, Aloisi, Al, Pantalone, L, La Sorda, R, Lattanzio, R, Sacchetti, A, Havas, K, Guarnieri, S, Vergara, D, Fournier, I, Salzet, M, Tinari, N, Piantelli, M, Trerotola, M, Alberti, S., and Pathology

Subjects
Cancer Research, SDG 3 - Good Health and Well-being, Genetics, Molecular Biology
Abstract

Trop-2 is a transmembrane signal transducer that is overexpressed in most human cancers, and drives malignant progression. To gain knowledge on the higher-order molecular mechanisms that drive Trop-2 signaling, we applied next-generation sequencing, proteomics, and high-resolution microscopy to models and primary cases of human colorectal cancer (CRC). We had previously shown that Trop-2 induces a Ca2+ signal. We reveal here that Trop-2 binds the cell membrane Na+/K+-ATPase, and that clustering of Trop-2 induces an intracellular Ca2+ rise followed by membrane translocation of PKCα, which in turn phosphorylates the Trop-2 cytoplasmic tail. This feed-forward signaling is promoted by the binding of Trop-2 to the PKCα membrane-anchor CD9. CRISPR-based inactivation of CD9 in CRC cells shows that CD9 is required by Trop-2 for recruiting PKCα and cofilin-1 to the cell membrane. This induces malignant progression through proteolytic cleavage of E-cadherin, remodeling of the β-actin cytoskeleton, and activation of Akt and ERK. The interaction between Trop-2 and CD9 was validated in vivo in murine models of CRC growth and invasion. Overexpression of the components of this Trop-2-driven super-complex significantly worsened disease-free and overall survival of CRC patients, supporting a pivotal relevance in CRC malignant progression. Our findings demonstrate a previously unsuspected layer of cancer growth regulation, which is dormant in normal tissues, and is activated by Trop-2 in cancer cells.

Published
2022

87. PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting

Author

Angela Maione, Nicola Tinari, Paola Pinnarò, Enzo Maria Ruggeri, Isabella Sperduti, Olivia Bacciu, Emanuela Risi, Icro Meattini, Federica Tomao, Luca Marchetti, Nicola D’Ostilio, Patrizia Vici, Lorenza Landi, Giuseppina Sarobba, Lucia Mentuccia, Elisabetta Landucci, Emilio Bria, A.F. Scinto, Gennaro Ciliberto, Laura Pizzuti, Elena Fiorio, Andrea Michelotti, Ida Paris, Simonetta Stani, Antonio Russo, Clara Natoli, Rosa Saltarelli, Alessandra Cassano, Paolo Marchetti, Maria Agnese Fabbri, Daniele Marinelli, Ferdinando Riccardi, Mauro Minelli, Corrado Ficorella, Anna Ceribelli, Maria Rosaria Valerio, Maddalena Barba, Jennifer Foglietta, Maria Mauri, Teresa Gamucci, Luca Moscetti, Beatrice Taurelli Salimbeni, Fabio Pelle, Daniele Santini, Andrea Botticelli, Vito Lorusso, Mirco Pistelli, Giacomo Barchiesi, Francesco Giotta, Eriseld Krasniqi, Antonino Grassadonia, Simone Scagnoli, Valentina Sini, Katia Cannita, Flavia Cavicchi, Michele De Tursi, Mimma Raffaele, Marco Mazzotta, Sonia Cappelli, Paola Scavina, Francesca Sofia Di Lisa, Giuliana D’Auria, Armando Orlandi, Marcello Maugeri-Saccà, Federico Cappuzzo, Claudio Botti, Nello Salesi, Lorenzo Livi, Beatrice Fratini, Giulia Bon, Silverio Tomao, Giuseppe Sanguineti, Enzo Veltri, Domenico Corsi, Enrico Cortesi, Rossana Berardi, Laura Iezzi, Rosalinda Rossi, Giuseppe Tonini, Elisabetta Maria Capomolla, Pizzuti L., Krasniqi E., Sperduti I., Barba M., Gamucci T., Mauri M., Veltri E.M., Meattini I., Berardi R., Di Lisa F.S., Natoli C., Pistelli M., Iezzi L., Risi E., D'Ostilio N., Tomao S., Ficorella C., Cannita K., Riccardi F., Cassano A., Bria E., Fabbri M.A., Mazzotta M., Barchiesi G., Botticelli A., D'Auria G., Ceribelli A., Michelotti A., Russo A., Salimbeni B.T., Sarobba G., Giotta F., Paris I., Saltarelli R., Marinelli D., Corsi D., Capomolla E.M., Sini V., Moscetti L., Mentuccia L., Tonini G., Raffaele M., Marchetti L., Minelli M., Ruggeri E.M., Scavina P., Bacciu O., Salesi N., Livi L., Tinari N., Grassadonia A., Fedele Scinto A., Rossi R., Valerio M.R., Landucci E., Stani S., Fratini B., Maugeri-Sacca M., De Tursi M., Maione A., Santini D., Orlandi A., Lorusso V., Cortesi E., Sanguineti G., Pinnaro P., Cappuzzo F., Landi L., Botti C., Tomao F., Cappelli S., Bon G., Pelle F., Cavicchi F., Fiorio E., Foglietta J., Scagnoli S., Marchetti P., Ciliberto G., and Vici P.

Subjects
Oncology, medicine.medical_specialty, Advanced breast, T-DM1, Treatment outcome, Lapatinib, Breast cancer, pertuzumab, Internal medicine, Medicine, lapatinib, RC254-282, advanced breast cancer, business.industry, Human epidermal growth factor, HER2-positive, sequence, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, medicine.disease, Observational study, Pertuzumab, business, medicine.drug
Abstract

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Published
2021

88. Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) in Luminal Breast Cancer: A Retrospective Analysis in the Neoadjuvant Setting

Author

Marco Mazzotta, Nicola Tinari, Eriseld Krasniqi, Laura Iezzi, A. Amodio, Clara Natoli, Laura Pizzuti, Giuseppe Cicero, Maddalena Barba, Vincenzo Graziano, Patrizia Vici, Antonino Grassadonia, Daniele Marinelli, Grassadonia A., Graziano V., Iezzi L., Vici P., Barba M., Pizzuti L., Cicero G., Krasniqi E., Mazzotta M., Marinelli D., Amodio A., Natoli C., Tinari N., Graziano, Vincenzo [0000-0001-7656-824X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Adult, medicine.medical_specialty, Multivariate analysis, Neutrophils, QH301-705.5, medicine.medical_treatment, Breast Neoplasms, Article, Disease-Free Survival, predictive/prognostic biomarkers, 03 medical and health sciences, 0302 clinical medicine, Text mining, Breast cancer, luminal breast cancer, Internal medicine, Medicine, Humans, Lymphocytes, Neutrophil to lymphocyte ratio, Biology (General), Neoadjuvant therapy, Aged, Retrospective Studies, Chemotherapy, business.industry, Proportional hazards model, allergology, fungi, Luminal breast cancer, Neoadjuvant chemotherapy, Neutrophil to lymphocyte ratio (NLR), Predictive/prognostic biomarkers, Female, Ki-67 Antigen, Middle Aged, Multivariate Analysis, Prognosis, Treatment Outcome, Neoadjuvant Therapy, Histology, General Medicine, medicine.disease, neutrophil to lymphocyte ratio (NLR), 030104 developmental biology, 030220 oncology & carcinogenesis, Population study, business, neoadjuvant chemotherapy
Abstract

The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan–Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65–10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25–15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.

Published
2021

89. Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence

Author

Aangela Vaccaro, Antonio Giordano, Marina Elena Cazzaniga, Antonio Russo, Maddalena Barba, Emilio Bria, Corrado Ficorella, Claudio Botti, Nicla La Verde, Clara Natoli, Valentina Magri, Loretta D'Onofrio, Carlo Garufi, Ruggero De Maria, Maria Rosaria Valerio, Gennaro Ciliberto, Mario Roselli, A. Fabbri, Emanuela Magnolfi, Giuseppina Rosaria Rita Ricciardi, Patrizia Vici, Alessandra Cassano, Emanuela Risi, Isabella Sperduti, Daniele Generali, Daniele Marinelli, Vito Lorusso, Teresa Gamucci, Lorenzo Livi, Giuseppe Tonini, Antonino Grassadonia, Editta Baldini, Marco Mazzotta, Luca Moscetti, Silverio Tomao, Claudio Zamagni, Silvia Carpano, Ornella Garrone, Icro Meattini, Giuseppe Sanguineti, Eriseld Krasniqi, Lucia Mentuccia, Katia Cannita, Daniele Santini, Rossana Mirabelli, Enzo Veltri, Domenico Sergi, Aandrea Michelotti, Alice Villa, Nicola Tinari, Vincenzo Adamo, A. Botticelli, Ramy Kayal, Mirco Pistelli, Domenico Corsi, Pietro Del Medico, Rossana Berardi, Enrico Cortesi, Giacomo Barchiesi, Alain Gelibter, Ida Paris, Elisa Landucci, Pia Di Stefano, Laura Pizzuti, Paolo Marchetti, Luisa Carbognin, Francesco Giotta, A.F. Scinto, Krasniqi, E, Pizzuti, L, Barchiesi, G, Sergi, D, Carpano, S, Botti, C, Kayal, R, Sanguineti, G, Marchetti, P, Botticelli, A, Marinelli, D, Gamucci, T, Natoli, C, Grassadonia, A, Tinari, N, Tomao, S, Tonini, G, Santini, D, Michelotti, A, Mentuccia, L, Vaccaro, A, Magnolfi, E, Gelibter, A, Magri, V, Cortesi, E, D'Onofrio, L, Cassano, A, Cazzaniga, M, Moscetti, L, Fabbri, A, Scinto, A, Corsi, D, Carbognin, L, Bria, E, La Verde, N, Garufi, C, Di Stefano, P, Mirabelli, R, Veltri, E, Paris, I, Giotta, F, Lorusso, V, Landucci, E, Ficorella, C, Roselli, M, Adamo, V, Ricciardi, G, Russo, A, Valerio, M, Berardi, R, Pistelli, M, Cannita, K, Zamagni, C, Garrone, O, Baldini, E, Livi, L, Meattini, I, Del Medico, P, Generali, D, De Maria, R, Risi, E, Ciliberto, G, Villa, A, Sperduti, I, Mazzotta, M, Barba, M, Giordano, A, Vici, P, Eriseld K., Laura P., Giacomo B., Domenico S., Silvia C., Claudio B., Ramy K., Giuseppe S., Paolo M., Andrea B., Daniele M., Teresa G., Clara N., Antonino G., Nicola T., Silverio T., Giuseppe T., Daniele S., Aandrea M., Lucia M., Aangela V., Emanuela M., Alain G., Valentina M., Enrico C., Loretta D., Alessandra C., Marina C., Luca M., Agnese F., Angelo Fedele S., Domenico C., Luisa C., Emilio B., Nicla L.V., Carlo G., Pia D.S., Rossana M., Enzo V., Ida P., Francesco G., Vito L., Elisa L., Corrado F., Mario R., Vincenzo A., Giuseppina R., Antonio R., Maria Rosaria V., Rossana B., Mirco P., Katia C., Claudio Z., Ornella G., Editta B., Lorenzo L., Icro M., Pietro D.M., Daniele G., Ruggero D.M., Emanuela R., Gennaro C., Alice V., Isabella S., Marco M., Maddalena B., Antonio G., and Patrizia V.

Subjects
0301 basic medicine, Oncology, Physiology, Receptor, ErbB-2, Clinical Biochemistry, Ado-Trastuzumab Emtansine, Settore MED/06, body mass index, HER2-positive metastatic breast cancer, pertuzumab, trastuzumab emtansine, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, Aged, 80 and over, education.field_of_study, Univariate analysis, Middle Aged, Metastatic breast cancer, Progression-Free Survival, Quartile, 030220 oncology & carcinogenesis, Disease Progression, Female, Pertuzumab, medicine.drug, Adult, medicine.medical_specialty, Population, Breast Neoplasms, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Breast cancer, Settore MED/04 - PATOLOGIA GENERALE, Internal medicine, medicine, Humans, Obesity, education, Aged, business.industry, nutritional and metabolic diseases, Cell Biology, Overweight, medicine.disease, 030104 developmental biology, chemistry, Trastuzumab emtansine, MED/06 - ONCOLOGIA MEDICA, business, Body mass index
Abstract

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

Published
2020

90. Evaluation of Second-line Anti-VEGF after First-line Anti-EGFR Based Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Multicenter 'SLAVE' Study

Author

Teresa Troiani, Claudia Angela Maria Fulgenzi, Giampaolo Tortora, N. Zanaletti, Alessandra Boccaccino, Emanuela Dell'Aquila, Daniele Santini, P. Vitale, Pasquale Lombardi, Michele De Tursi, Susana Rosello Keranen, Filippo Merloni, Olga Venditti, Maria Alessandra Calegari, Alessandra Emiliani, Federica Zoratto, Federica Mazzuca, Marco Maria Germani, Domenico Corsi, Riccardo Giampieri, Simona Delle Monache, Lisa Salvatore, Giampiero Porzio, Marisol Huerta Alvaro, Michele Ghidini, Pietro Di Marino, Alessandro Parisi, Alice Indini, Ina Valeria Zurlo, Paolo Marchetti, Daniele Rossini, Mario Occhipinti, Michela Roberto, Ingrid Garajová, Alessio Cortellini, Floriana Camarda, Katia Cannita, Nicola Tinari, Corrado Ficorella, Parisi, A., Cortellini, A., Cannita, K., Venditti, O., Camarda, F., Calegari, M. A., Salvatore, L., Tortora, G., Rossini, D., Germani, M. M., Boccaccino, A., Dell'Aquila, E., Fulgenzi, C., Santini, D., De Tursi, M., Tinari, N., Di Marino, P., Lombardi, P., Keranen, S. R., Alvaro, M. H., Zurlo, I. V., Corsi, D. C., Emiliani, A., Zanaletti, N., Troiani, T., Vitale, P., Giampieri, R., Merloni, F., Occhipinti, M. A., Marchetti, P., Roberto, M., Mazzuca, F., Ghidini, M., Indini, A., Garajova, I., Zoratto, F., Monache, S. D., Porzio, G., and Ficorella, C.

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Bevacizumab, Colorectal cancer, Anti-angiogenic, Cetuximab, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Panitumumab, Progression-free survival, Aflibercept, RAS wild-type mCRC, Performance status, business.industry, anti-angiogenics, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Regimen, 030104 developmental biology, 030220 oncology & carcinogenesis, second-line treatment, business, aflibercept, bevacizumab, cetuximab, panitumumab, ras wild-type mcrc, medicine.drug
Abstract

Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated. Methods: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles. Results: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7&ndash, 34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95&ndash, 1.89), p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3&ndash, 18.1) and 12.7 (95%CI: 8.8&ndash, 17.5) months, respectively (HR= 1.31 (95%CI: 0.89&ndash, 1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02&ndash, 2.03), p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99&ndash, 2.17), p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively (p = 0.0001). Conclusion: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed.

Published
2020
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91. Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting

Author

Isacco Desideri, G. Tonini, Emanuela Magnolfi, L. Pizzuti, Jennifer Foglietta, Marina Elena Cazzaniga, Adamo, Patrizia Vici, Enrico Cortesi, Emanuela Risi, G. D'Auria, Loretta D'Onofrio, Mario Roselli, Isabella Sperduti, N. Tinari, Nicola D’Ostilio, A. Vaccaro, Icro Meattini, Federica Tomao, Giacomo Barchiesi, B Di Cocco, F Cardillo, Enzo Veltri, Claudia Omarini, Mirco Pistelli, Clara Natoli, Carlo Garufi, E. Landucci, M. Mauri, Rosanna Mirabelli, Federico Piacentini, Domenico Corsi, A.F. Scinto, Alice Villa, Alain Gelibter, C. De Angelis, Marco Mazzotta, Gennaro Ciliberto, Claudio Zamagni, Giuseppe Sanguineti, Fiorentino Izzo, Elizabeth H. Baldini, Rossana Berardi, Grr Ricciardi, Maddalena Barba, Ornella Garrone, Ida Paris, Luisa Carbognin, A. Botticelli, Giuseppina Sarobba, Silverio Tomao, Antonio Astone, Lucia Mentuccia, P Del Medico, Lorusso, Daniele Santini, M. Della Giulia, Riccardo Samaritani, Francesco Giotta, Alessandra Cassano, Laura Iezzi, Maria Agnese Fabbri, R De Maria, Eriseld Krasniqi, Raffaele Giusti, Sini, Lorenzo Livi, Ernesto Rossi, Andrea Michelotti, Emilio Bria, A Di Leo, Luca Moscetti, Corrado Ficorella, Antonino Grassadonia, Roberta Sarmiento, Katia Cannita, Filippo Greco, Sandro Barni, Elena Fiorio, Teresa Gamucci, Magri, Antonio Russo, M. De Tursi, N. La Verde, Daniele Generali, Paolo Marchetti, Pizzuti, L, Krasniqi, E, Barchiesi, G, Della Giulia, M, Izzo, F, Sanguineti, G, Marchetti, P, Mazzotta, M, Giusti, R, Botticelli, A, Gamucci, T, Natoli, C, Grassadonia, A, Tinari, N, Iezzi, L, Tomao, S, Tomao, F, Tonini, G, Santini, D, Astone, A, Michelotti, A, De Angelis, C, Mentuccia, L, Vaccaro, A, Magnolfi, E, Gelibter, A, Magri, V, Cortesi, E, D'Onofrio, L, Cassano, A, Rossi, E, Cazzaniga, M, Moscetti, L, Omarini, C, Piacentini, F, Fabbri, M, Scinto, A, Corsi, D, Carbognin, L, Bria, E, La Verde, N, Samaritani, R, Garufi, C, Barni, S, Mirabelli, R, Sarmiento, R, Veltri, E, D'Auria, G, Paris, I, Giotta, F, Lorusso, V, Cardillo, F, Landucci, E, Mauri, M, Ficorella, C, Roselli, M, Adamo, V, Ricciardi, G, Russo, A, Berardi, R, Pistelli, M, Fiorio, E, Cannita, K, Sini, V, D'Ostilio, N, Foglietta, J, Greco, F, Zamagni, C, Garrone, O, Di Cocco, B, Baldini, E, Livi, L, Desideri, I, Meattini, I, Sarobba, G, Del Medico, P, De Tursi, M, Generali, D, De Maria, R, Risi, E, Ciliberto, G, Sperduti, I, Villa, A, Barba, M, Di Leo, A, and Vici, P

Subjects
Oncology, Cancer Research, Multivariate analysis, Settore MED/06 - Oncologia Medica, Receptor, ErbB-2, T-DM1, Estrogen receptor, 0302 clinical medicine, ErbB-2, Trastuzumab, Receptors, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Molecular Targeted Therapy, Neoplasm Metastasis, Cancer Therapy and Prevention, Progesterone, Aged, 80 and over, advanced breast cancer, Tumor, real world, Middle Aged, Prognosis, Metastatic breast cancer, Immunohistochemistry, Gene Expression Regulation, Neoplastic, trastuzumab, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, HER2 positive, pertuzumab, Adult, Aged, Biomarkers, Tumor, Breast Neoplasms, Humans, Neoplasm Staging, Receptors, Progesterone, Pertuzumab, medicine.drug, Receptor, medicine.medical_specialty, T‐DM1, chemotherapy, 03 medical and health sciences, Breast cancer, Settore MED/04 - PATOLOGIA GENERALE, Internal medicine, medicine, Neoplastic, business.industry, medicine.disease, Estrogen, Settore CHIM/08 - Chimica Farmaceutica, Gene Expression Regulation, MED/06 - ONCOLOGIA MEDICA, business, Biomarkers, Hormone
Abstract

We analyzed data from 738 HER2‐positive metastatic breast cancer (mbc) patients treated with pertuzumab‐based regimens and/or T‐DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression‐free survival at first‐line (mPFS1) was 12 months. Pertuzumab as first‐line conferred longer mPFS1 compared to other first‐line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second‐line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T‐DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs‐negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T‐DM1 in second‐line after pertuzumab were significantly lower compared to pertuzumab‐naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment‐related outcomes of HER2‐positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2‐positive (mbc) patients., What's new? About half of breast cancers positive for human epidermal growth factor (HER2) also express hormone receptors but the impact of hormone receptor status on the success of HER2‐directed treatments is not fully explored. Here the authors retrospectively assessed tumor behavior and treatment outcomes in 738 women with HER2+ metastatic breast cancer treated with new generation anti‐HER2 agents. Distinct hormone receptor expression patterns significantly affected the progression free and overall survival, justifying further studies to define optimal treatment regimens and the interplay between hormone receptor and HER2 signaling.

Published
2020

92. Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor-positive, advanced breast cancer: A real-world experience

Author

Michele De Tursi, Marco Mazzotta, Armando Orlandi, Marina Elena Cazzaniga, Enrico Cortesi, Maddalena Barba, Laura Iezzi, Giuseppe Tonini, E. Landucci, Lucio Laudadio, Domenico Sergi, Alessandra Cassano, Giuseppe Sanguineti, Nicla La Verde, Riccardo Samaritani, Patrizia Seminara, Antonio Russo, Claudio Zamagni, Simone Scagnoli, Valentina Magri, Ramy Kayal, Enzo Veltri, Francesca Aroldi, Clara Natoli, Ilaria Portarena, Samantha Forciniti, Laura Ferrari, Lucia Mentuccia, Gennaro Ciliberto, Daniele Santini, Teresa Gamucci, Filippo Greco, Silvia Carpano, Mario Roselli, Sandro Barni, A. Fabbri, Isabella Sperduti, A. Vaccaro, Ida Paris, Daniela Rubino, Ruggero De Maria, Patrizia Vici, Claudia De Angelis, Giulia Pomati, Luisa Carbognin, Simona Vallarelli, Antonino Grassadonia, Mirco Pistelli, A.F. Scinto, Katia Cannita, Andrea Michelotti, Domenico Corsi, E. Capomolla, Corrado Ficorella, Nicola Tinari, Vito Lorusso, Rossana Berardi, Andrea Botticelli, Antonio Giordano, Silverio Tomao, Laura Pizzuti, Paolo Marchetti, Maria Giuseppina Sarobba, Valentina Sini, Luca Moscetti, Lucrezia Diodati, Maria Vincenza Mancini, Luciano Mariani, Pizzuti, L, Giordano, A, Michelotti, A, Mazzotta, M, Natoli, C, Gamucci, T, De Angelis, C, Landucci, E, Diodati, L, Iezzi, L, Mentuccia, L, Fabbri, A, Barba, M, Sanguineti, G, Marchetti, P, Tomao, S, Mariani, L, Paris, I, Lorusso, V, Vallarelli, S, Cassano, A, Airoldi, F, Orlandi, A, Moscetti, L, Sergi, D, Sarobba, M, Tonini, G, Santini, D, Sini, V, Veltri, E, Vaccaro, A, Ferrari, L, De Tursi, M, Tinari, N, Grassadonia, A, Greco, F, Botticelli, A, La Verde, N, Zamagni, C, Rubino, D, Cortesi, E, Magri, V, Pomati, G, Scagnoli, S, Capomolla, E, Kayal, R, Scinto, A, Corsi, D, Cazzaniga, M, Laudadio, L, Forciniti, S, Mancini, M, Carbognin, L, Seminara, P, Barni, S, Samaritani, R, Roselli, M, Portarena, I, Russo, A, Ficorella, C, Cannita, K, Carpano, S, Pistelli, M, Berardi, R, De Maria, R, Sperduti, I, Ciliberto, G, Vici, P, Pizzuti, Laura, Giordano, Antonio, Michelotti, Andrea, Mazzotta, Marco, Natoli, Clara, Gamucci, Teresa, De Angelis, Claudia, Landucci, Elisabetta, Diodati, Lucrezia, Iezzi, Laura, Mentuccia, Lucia, Fabbri, Agnese, Barba, Maddalena, Sanguineti, Giuseppe, Marchetti, Paolo, Tomao, Silverio, Mariani, Luciano, Paris, Ida, Lorusso, Vito, Vallarelli, Simona, Cassano, Alessandra, Airoldi, Francesca, Orlandi, Armando, Moscetti, Luca, Sergi, Domenico, Sarobba, Maria Giuseppina, Tonini, Giuseppe, Santini, Daniele, Sini, Valentina, Veltri, Enzo, Vaccaro, Angela, Ferrari, Laura, De Tursi, Michele, Tinari, Nicola, Grassadonia, Antonino, Greco, Filippo, Botticelli, Andrea, La Verde, Nicla, Zamagni, Claudio, Rubino, Daniela, Cortesi, Enrico, Magri, Valentina, Pomati, Giulia, Scagnoli, Simone, Capomolla, Elisabetta, Kayal, Ramy, Scinto, Angelo Fedele, Corsi, Domenico, Cazzaniga, Marina, Laudadio, Lucio, Forciniti, Samantha, Mancini, Maria, Carbognin, Luisa, Seminara, Patrizia, Barni, Sandro, Samaritani, Riccardo, Roselli, Mario, Portarena, Ilaria, Russo, Antonio, Ficorella, Corrado, Cannita, Katia, Carpano, Silvia, Pistelli, Mirco, Berardi, Rossana, De Maria, Ruggero, Sperduti, Isabella, Ciliberto, Gennaro, and Vici, Patrizia

Subjects
Male, 0301 basic medicine, Oncology, Pyridines, Receptor, ErbB-2, Physiology, Clinical Biochemistry, Piperazines, chemistry.chemical_compound, 0302 clinical medicine, Exemestane, Antineoplastic Combined Chemotherapy Protocols, advanced breast cancer, hormonal therapy, endocrine resistance, palbociclib, real-world setting, Breast, Aged, 80 and over, advanced breast cancer, hormonal therapy, Middle Aged, Treatment Outcome, Receptors, Estrogen, 030220 oncology & carcinogenesis, Toxicity, Female, Receptors, Progesterone, medicine.drug, Adult, Cell Biology, medicine.medical_specialty, Breast Neoplasms, Palbociclib, Neutropenia, Disease-Free Survival, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, Everolimus, Settore MED/06 - ONCOLOGIA MEDICA, business.industry, Cancer, medicine.disease, Confidence interval, 030104 developmental biology, chemistry, MED/06 - ONCOLOGIA MEDICA, business, Hormone
Abstract

Data from 423 human epidermal growth factor receptor 2-negative (HER2−), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6–35.4) and clinical benefit was 52.7% (95% CI, 48–57.5). ORR was negatively affected by prior exposure to everolimus/exemestane (p = 0.002) and favorably influenced by early line-treatment (p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8–16) and median overall survival was 24 months (95% CI, 17–30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2−, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.

Published
2019

93. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: When overweight becomes favorable

Author

Mario Occhipinti, Gian Carlo Antonini Cappellini, Marco Filetti, Giampiero Porzio, Clara Natoli, Andrea De Giglio, Francesca Rastelli, Federica Zoratto, Silvia Rinaldi, Cecilia Anesi, Sebastiano Buti, Rita Chiari, Fabiana Perrone, Francesco Atzori, Pietro Di Marino, Andrea Botticelli, Enzo Veltri, Melissa Bersanelli, Federica Pergolesi, Nicola Tinari, Alessio Cortellini, Paolo A. Ascierto, Corrado Ficorella, Daniele Santini, Alain Gelibter, Marianna Tudini, Rossana Berardi, Maria Concetta Fargnoli, Tea Zeppola, Rosa Rita Silva, Marcello Tiseo, Riccardo Marconcini, Daniela Iacono, Raffaele Giusti, Federica De Galitiis, Annagrazia Pireddu, Paolo Marchetti, Alessandro Parisi, Francesco Malorgio, Maria Giuseppa Vitale, Michele De Tursi, Maria Michiara, Marco Russano, Biagio Ricciuti, Katia Cannita, Cortellini A., Bersanelli M., Buti S., Cannita K., Santini D., Perrone F., Giusti R., Tiseo M., Michiara M., Di Marino P., Tinari N., De Tursi M., Zoratto F., Veltri E., Marconcini R., Malorgio F., Russano M., Anesi C., Zeppola T., Filetti M., Marchetti P., Botticelli A., Antonini Cappellini G.C., De Galitiis F., Vitale M.G., Rastelli F., Pergolesi F., Berardi R., Rinaldi S., Tudini M., Silva R.R., Pireddu A., Atzori F., Chiari R., Ricciuti B., De Giglio A., Iacono D., Gelibter A., Occhipinti M.A., Parisi A., Porzio G., Fargnoli M.C., Ascierto P.A., Ficorella C., and Natoli C.

Subjects
Male, 0301 basic medicine, Cancer Research, Programmed Cell Death 1 Receptor, Kaplan-Meier Estimate, Anti-PD-1/PD-L1, Overweight, Gastroenterology, B7-H1 Antigen, Body Mass Index, Antineoplastic Agents, Immunological, 0302 clinical medicine, BMI, Cancer, Immunotherapy, Obesity, Immunology and Allergy, Immunology, Molecular Medicine, Oncology, Pharmacology, Renal cell carcinoma, Neoplasms, Molecular Targeted Therapy, Aged, 80 and over, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Underweight, medicine.symptom, Research Article, Adult, medicine.medical_specialty, lcsh:RC254-282, Young Adult, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Aged, Neoplasm Staging, Proportional Hazards Models, business.industry, nutritional and metabolic diseases, Retrospective cohort study, medicine.disease, Clinical trial, 030104 developmental biology, business, Body mass index
Abstract

Background Recent evidence suggested a potential correlation between overweight and the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients. Patients and methods We conducted a retrospective study of advanced cancer patients consecutively treated with anti-PD-1/PD-L1 inhibitors, in order to compare clinical outcomes according to baseline BMI levels as primary analysis. Based on their BMI, patients were categorized into overweight/obese (≥ 25) and non-overweight (

Published
2019

94. Unknown primary tumors

Author

Pier Giorgio Natali, Sergio Palmeri, Stefano Iacobelli, Nicola Tinari, Marco Salvatore, Matteo Landriscina, Clara Natoli, O. Nappi, M. Zilli, V. Ramazzotti, Patrizio Giacomini, Natoli,C, Ramazzotti,V, Nappi,O, Giacomini,P, Palmeri,S, Salvatore,M, Landriscina,M, Zilli,M, Natali,PG, Tinari,N, and Iacobelli,S

Subjects
Cancer Research, business.industry, Gene Expression Profiling, Biological entity, MEDLINE, Treatment options, Signs and symptoms, Bioinformatics, Functional imaging, MicroRNAs, Oncology, Unknown primary tumors, UPT, Immunology, Unknown Primary Tumors, Genetics, Unknown primary, Animals, Humans, Neoplasms, Unknown Primary, Medicine, business, Site of origin
Abstract

An unknown primary tumor (UPT) is defined by the presence of a metastatic cancer without a known primary site of origin despite a standardized diagnostic workup. Clinically, UPTs show rapid progression and early dissemination, with signs and symptoms related to the metastatic site. The molecular bases of their biology remain largely unknown, with no evidence as to whether they represent a distinct biological entity. Immunohistochemistry remain the best diagnostic tool in term of cost-effectiveness, but the time-consuming "algorithmic process" it relies on has led to the application of new molecular techniques for the identification of the primary site of UPTs. For example, several microarray or miRNA classifications of UPTs have been used, with an accuracy in the prediction of the primary site as high as 90%. It should be noted that validating a prediction of tissue origin is challenging in these patients, since most of them will never have a primary site identified. Moreover, prospective studies to determine whether selection of treatment options based on such profiling methods actually improves patient outcome are still missing. In the last few years functional imaging (i.e. FDG-PET/CT) has gained a main role in the detection of the site of origin of UPTs and is currently recommended by the European Association of Nuclear Medicine. However, despite recent refinements in the diagnostic workup, the site of origin of UPT often remains elusive. As a consequence, treatment of patients with UPT is still empirical and inadequate.

Published
2011

95. P-101 - A real-life multicenter study on body weight loss and body mass index in advanced Gastric Cancer patients treated with Ramucirumab-based second-line therapy.

Author

Parisi, A., Cortellini, A., Roberto, M., Venditti, O., Santini, D., Dell'Aquila, E., Stellato, M., Marchetti, P., Occhipinti, M., Zoratto, F., Mazzuca, F., Tinari, N., De Tursi, M., Iezzi, L., Natoli, C., Ratti, M., Pizzo, C., Ghidini, M., Ficorella, C., and Cannita, K.

Subjects
*BODY mass index, *BODY weight, *WEIGHT loss, *CANCER patients
Published
2019
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96. DNA Damage Response in Early Breast Cancer: A Phase III Cohort in the Phobos Study.

Author

Krasniqi E, Ercolani C, Di Benedetto A, Di Lisa FS, Filomeno L, Arcuri T, Botti C, Pelle F, Cavicchi F, Cappelli S, Barba M, Pizzuti L, Maugeri-Saccà M, Moscetti L, Grassadonia A, Tinari N, Sanguineti G, Takanen S, Fragnito D, Terrenato I, Buglioni S, Perracchio L, Latorre A, De Maria R, Pallocca M, Ciliberto G, Giotta F, and Vici P

Abstract

We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical-pathological factors.

Published
2024
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97. The Crucial Role of Hereditary Cancer Panel Testing in Unaffected Individuals with a Strong Family History of Cancer: A Retrospective Study of a Cohort of 103 Healthy Subjects.

Author

Pilenzi L, Anaclerio F, Dell'Elice A, Minelli M, Giansante R, Cicirelli M, Tinari N, Grassadonia A, Pantalone A, Grossi S, Canale N, Bruno A, Calabrese G, Ballerini P, Stuppia L, and Antonucci I

Abstract

Hereditary cancer syndromes caused by germline mutations account for 5-10% of all cancers. The finding of a genetic mutation could have far-reaching consequences for pharmaceutical therapy, personalized prevention strategies, and cascade testing. According to the National Comprehensive Cancer Network's (NCCN) and the Italian Association of Medical Oncology (AIOM) guidelines, unaffected family members should be tested only if the affected one is unavailable. This article explores whether germline genetic testing may be offered to high-risk families for hereditary cancer even if a living affected relative is missing. A retrospective study was carried out on 103 healthy subjects tested from 2017 to 2023. We enrolled all subjects with at least two first- or second-degree relatives affected by breast, ovarian, pancreatic, gastric, prostate, or colorectal cancer. All subjects were tested by Next Generation Sequencing (NGS) multi-gene panel of 27 cancer-associated genes. In the study population, 5 (about 5%) pathogenic/likely pathogenic variants (PVs/LPVs) were found, while 40 (42%) had a Variant of Uncertain Significance (VUS). This study highlights the importance of genetic testing for individuals with a strong family history of hereditary malignancies. This approach would allow women who tested positive to receive tailored treatment and prevention strategies based on their personal mutation status., Competing Interests: The authors declare no conflicts of interest.

Published
2024
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98. Multi-omics staging of locally advanced rectal cancer predicts treatment response: a pilot study.

Author

Cicalini I, Chiarelli AM, Chiacchiaretta P, Perpetuini D, Rosa C, Mastrodicasa D, d'Annibale M, Trebeschi S, Serafini FL, Cocco G, Narciso M, Corvino A, Cinalli S, Genovesi D, Lanuti P, Valentinuzzi S, Pieragostino D, Brocco D, Beets-Tan RGH, Tinari N, Sensi SL, Stuppia L, Del Boccio P, Caulo M, and Delli Pizzi A

Subjects
Adult, Aged, Female, Humans, Male, Middle Aged, Machine Learning, Magnetic Resonance Imaging methods, Metabolomics, Pilot Projects, Predictive Value of Tests, Sensitivity and Specificity, Treatment Outcome, Multiomics, Neoplasm Staging, Rectal Neoplasms diagnostic imaging, Rectal Neoplasms pathology, Rectal Neoplasms therapy
Abstract

Treatment response assessment of rectal cancer patients is a critical component of personalized cancer care and it allows to identify suitable candidates for organ-preserving strategies. This pilot study employed a novel multi-omics approach combining MRI-based radiomic features and untargeted metabolomics to infer treatment response at staging. The metabolic signature highlighted how tumor cell viability is predictively down-regulated, while the response to oxidative stress was up-regulated in responder patients, showing significantly reduced oxoproline values at baseline compared to non-responder patients (p-value < 10 -4 ). Tumors with a high degree of texture homogeneity, as assessed by radiomics, were more likely to achieve a major pathological response (p-value < 10 -3 ). A machine learning classifier was implemented to summarize the multi-omics information and discriminate responders and non-responders. Combining all available radiomic and metabolomic features, the classifier delivered an AUC of 0.864 (± 0.083, p-value < 10 -3 ) with a best-point sensitivity of 90.9% and a specificity of 81.8%. Our results suggest that a multi-omics approach, integrating radiomics and metabolomic data, can enhance the predictive value of standard MRI and could help to avoid unnecessary surgical treatments and their associated long-term complications., (© 2024. The Author(s).)

Published
2024
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99. Phylogenetic conservation of Trop-2 across species-rodent and primate genomics model anti-Trop-2 therapy for pre-clinical benchmarks.

Author

Guerra E, Trerotola M, Relli V, Lattanzio R, Boujnah K, Travali N, Moschella A, Todaro P, Pierdomenico L, Di Pietro R, Tinari N, and Alberti S

Abstract

A phylogenetic conservation analysis of Trop-2 across vertebrate species showed a high degree of sequence conservation, permitting to explore multiple models as pre-clinical benchmarks. Sequence divergence and incomplete conservation of expression patterns were observed in mouse and rat. Primate Trop-2 sequences were found to be 95%-100% identical to the human sequence. Comparative three-dimension primate Trop-2 structures were obtained with AlphaFold and homology modeling. This revealed high structure conservation of Trop-2 (0.66 ProMod3 GMQE, 0.80-0.86 ± 0.05 QMEANDisCo scores), with conservative amino acid changes at variant sites. Primate TACSTD2/TROP2 cDNAs were cloned and transfectants for individual ORF were shown to be efficiently recognized by humanized anti-Trop-2 monoclonal antibodies (Hu2G10, Hu2EF). Immunohistochemistry analysis of Macaca mulatta (rhesus monkey) tissues showed Trop-2 expression patterns that closely followed those in human tissues. This led us to test Trop-2 targeting in vivo in Macaca fascicularis (cynomolgus monkey) . Intravenously injected Hu2G10 and Hu2EF were well tolerated from 5 to 10 mg/kg. Neither neurological, respiratory, digestive, urinary symptoms, nor biochemical or hematological toxicities were detected during 28-day observation. Blood serum pharmacokinetic (PK) studies were conducted utilizing anti-idiotypic antibodies in capture-ELISA assays. Hu2G10 (t 1/2 = 6.5 days) and Hu2EF (t 1/2 = 5.5 days) were stable in plasma, and were detectable in the circulation up to 3 weeks after the infusion. These findings validate primates as reliable models for Hu2G10 and Hu2EF toxicity and PK, and support the use of these antibodies as next-generation anti-Trop-2 immunotherapy tools., Competing Interests: EG is an inventor in patents WO201687651 and WO201784763, and a partner in Mediterranea Theranostic Srl. MT is an inventor in patent WO201784763. SA is an inventor in patents WO201089782, WO201687651 and WO201784763, and is founder and CEO of Oncoxx Biotech Srl and Mediterranea Theranostic Srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Guerra, Trerotola, Relli, Lattanzio, Boujnah, Travali, Moschella, Todaro, Pierdomenico, Di Pietro, Tinari and Alberti.)

Published
2024
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100. Clinical Outcomes of HER2-Negative Metastatic Breast Cancer Patients in Italy in the Last Decade: Results of the GIM 13-AMBRA Study.

Author

Cazzaniga ME, Pronzato P, Amoroso D, Bernardo A, Biganzoli L, Bisagni G, Blasi L, Bria E, Cognetti F, Crinò L, De Laurentiis M, Del Mastro L, De Placido S, Beano A, Ferraù F, Foladore S, Forcignanò R, Gamucci T, Garrone O, Gennari A, Giordano M, Giotta F, Giovanardi F, Latini L, Livi L, Marchetti P, Mattioli R, Michelotti A, Montemurro F, Putzu C, Riccardi F, Ricciardi G, Romagnoli E, Sarobba G, Spazzapan S, Tagliaferri P, Tinari N, Tonini G, Turletti A, Verusio C, Zambelli A, and Mustacchi G

Abstract

GIM 13-AMBRA is a longitudinal cohort study aimed at describing therapeutic strategies and the relative outcome parameters in 939 HER2-ve MBC patients. Taxanes-based regimens, or taxanes + targeted agents, mainly Bevacizumab, were the preferred first choice in both Luminal (30.2%) and TNBC (33.3%) patients. The median PFS1 was 12.5 months (95% CI 16.79-19.64), without any significant difference according to subtypes, while the median Time to first Treatment Change (TTC1) was significantly lower in TNBC patients (7.7 months-95% CI 5.7-9.2) in comparison to Luminal A (13.2 months, 95% CI 11.7-15.1) and Luminal B patients (11.8 months, 95% CI 10.3-12.8). PFS2 was significantly shorter in TNBC patients (5.5 months, 95% CI 4.3-6.5 vs. Luminal A-9.4, 95% CI 8.1-10.7, and Luminal B-7.7 95% CI 6.8-8.2, F-Ratio 4.30, p = 0.014). TTC2 was significantly lower in patients with TNBC than in those with the other two subtypes. The median OS1 was 35.2 months (95% CI 30.8-37.4) for Luminal A patients, which was significantly higher than that for both Luminal B (28.9 months, 95% CI 26.2-31.2) and TNBC (18.5 months, 95% CI 16-20.1, F-ratio 7.44, p = 0.0006). The GIM 13-AMBRA study is one of the largest collections ever published in Italy and provides useful results in terms of time outcomes for first, second, and further lines of treatment in HER2- MBC patients.

Published
2023
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