17 results on '"Rachiglio, A. M."'
Search Results
2. Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies
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Rachiglio, A. M., Forgione, L., Pasquale, R., Barone, Carlo Antonio, Maiello, E., Antonuzzo, L., Cassata, A., Tonini, G., Bordonaro, R., Rosati, G., Zaniboni, Alberto, Lonardi, S., Ferrari, D., Frassineti, G. L., Tamberi, S., Pisconti, S., Di Fabio, F., Roma, C., Orlandi, Armando, Latiano, T., Damato, A., Tortora, Giampaolo, Pinto, C., Normanno, N., Barone C. A., Zaniboni A., Orlandi A. (ORCID:0000-0001-5253-4678), Tortora G. (ORCID:0000-0002-1378-4962), Rachiglio, A. M., Forgione, L., Pasquale, R., Barone, Carlo Antonio, Maiello, E., Antonuzzo, L., Cassata, A., Tonini, G., Bordonaro, R., Rosati, G., Zaniboni, Alberto, Lonardi, S., Ferrari, D., Frassineti, G. L., Tamberi, S., Pisconti, S., Di Fabio, F., Roma, C., Orlandi, Armando, Latiano, T., Damato, A., Tortora, Giampaolo, Pinto, C., Normanno, N., Barone C. A., Zaniboni A., Orlandi A. (ORCID:0000-0001-5253-4678), and Tortora G. (ORCID:0000-0002-1378-4962)
- Abstract
Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the IdyllaTM ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.
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- 2022
3. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial
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Normanno, N., Rachiglio, A. M., Lambiase, M., Martinelli, E., Fenizia, F., Esposito, C., Roma, C., Troiani, T., Rizzi, D., Tatangelo, F., Botti, G., Maiello, E., Colucci, G., and Ciardiello, F.
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- 2015
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- View/download PDF
4. Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial
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Ciardiello, F., Normanno, N., Maiello, E., Martinelli, E., Troiani, T., Pisconti, S., Giuliani, F., Barone, C., Cartenì, G., Rachiglio, A. M., Montesarchio, V., Tonini, G., Rizzi, D., Cinieri, S., Bordonaro, R., Febbraro, A., De Vita, F., Orditura, M., Fenizia, F., Lambiase, M., Rinaldi, A., Tatangelo, F., Botti, G., and Colucci, G.
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- 2014
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5. Targeted sequencing analysis of cell-free DNA from metastatic non-small-cell lung cancer patients: clinical and biological implications
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Pasquale, Raffaella, primary, Forgione, Laura, additional, Roma, Cristin, additional, Fenizia, Francesca, additional, Bergantino, Francesca, additional, Rachiglio, Anna M., additional, De Luca, Antonella, additional, Gallo, Marianna, additional, Maiello, Monica R., additional, Palumbo, Giuliano, additional, Morabito, Alessandro, additional, Azzaro, Rosa, additional, and Normanno, Nicola, additional
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- 2020
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6. MAPK signaling is involved in intrinsic and acquired resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib
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Normanno, N., Maiello, M. R., Antonella De Luca, Carotenuto, A., Rachiglio, A. M., and D Alessio, A.
7. Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol
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Francesco Izzo, Anna Maria Trotta, Vittorio Albino, Lucrezia Silvestro, Antonio Avallone, Raffaele Palaia, Gerardo Botti, Monica Capozzi, Paolo Chiodini, Rossana Casaretti, Carmine Picone, Stefania Scala, Nicola Normanno, Mario Tamburini, Andrea Belli, Crescenzo D'Alterio, Anna Maria Rachiglio, Massimiliano Di Marzo, Guglielmo Nasti, Paolo Delrio, Cristin Roma, Anna Nappi, Carmela Romano, Antonella Petrillo, Antonino Cassata, Gianfranco De Feo, Alessandro Ottaiano, Salvatore Tafuto, Maria Napolitano, Alfonso Amore, Alfonso De Stefano, Ugo Pace, Luigi Portella, Ottaiano, A., Scala, S., Normanno, N., Napolitano, M., Capozzi, M., Rachiglio, A. M., Roma, C., Trotta, A. M., D'Alterio, C., Portella, L., Romano, C., Cassata, A., Casaretti, R., Silvestro, L., Nappi, A., Tafuto, S., Avallone, A., De Stefano, A., Tamburini, M., Picone, C., Petrillo, A., Izzo, F., Palaia, R., Albino, V., Amore, A., Belli, A., Pace, U., Di Marzo, M., Chiodini, P., Botti, G., De Feo, G., Delrio, P., and Nasti, G.
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Antibody-dependent cell-mediated cytotoxicity ,Colorectal cancer ,Phase II study ,Cetuximab ,medicine.disease_cause ,Irinotecan ,Fluorouracule ,lcsh:RC254-282 ,03 medical and health sciences ,Study Protocol ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,FcγR ,Genetics ,Medicine ,Panitumumab ,Humans ,Epidermal growth factor receptor ,neoplasms ,Colorectal Cancer ,Polymorphism, Genetic ,biology ,business.industry ,Receptors, IgG ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,digestive system diseases ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,biology.protein ,KRAS ,Fluorouracil ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
Background Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients’ selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. Methods/design CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses’ duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients’ cetuximab-mediated ADCC and characterize the tumor microenvironment. Discussion The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results’ interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. Trial registration The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number (NCT03874062).
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- 2019
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8. Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives
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Teresa Troiani, Giulia Martini, F. De Vita, Claudia Cardone, Tiziana Latiano, Fortunato Ciardiello, Evaristo Maiello, Nicola Normanno, Erika Martinelli, Anna Maria Rachiglio, Pietro Paolo Vitiello, Davide Ciardiello, Martinelli, E., Ciardiello, D., Martini, G., Troiani, T., Cardone, C., Vitiello, P. P., Normanno, N., Rachiglio, A. M., Maiello, E., Latiano, T., De Vita, F., and Ciardiello, F.
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Colorectal cancer ,Cetuximab ,Antineoplastic Agents ,Translational research ,Context (language use) ,medicine.disease_cause ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,anti-epidermal growth factor receptor monoclonal antibodie ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Panitumumab ,Epidermal growth factor receptor ,Liquid biopsy ,predictive biomarker ,molecular selection ,biology ,liquid biopsy ,business.industry ,metastatic colorectal cancer ,rechallenge therapy ,Hematology ,medicine.disease ,digestive system diseases ,ErbB Receptors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,KRAS ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.
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- 2020
9. Genomic Profiling of KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer Patients Reveals Novel Mutations in Genes Potentially Associated with Resistance to Anti-EGFR Agents
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Alessia Iannaccone, Daniela Frezzetti, Anna Maria Rachiglio, Marianeve Carotenuto, Evaristo Maiello, Antonella De Luca, Cristin Roma, Matilde Lambiase, Francesca Fenizia, Nicola Normanno, Fortunato Ciardiello, E. Martinelli, Claudia Cardone, Rachiglio, A. M., Lambiase, M., Fenizia, F., Roma, C., Cardone, C., Iannaccone, A., De Luca, A., Carotenuto, M., Frezzetti, D., Martinelli, E., Maiello, E., Ciardiello, F., and Normanno, N.
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0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,Colorectal cancer ,anti-EGFR monoclonal antibodies ,colorectal cancer ,medicine.disease_cause ,lcsh:RC254-282 ,resistance ,03 medical and health sciences ,0302 clinical medicine ,MAP2K1 ,Anti-EGFR monoclonal antibodie ,medicine ,Progression-free survival ,Copy-number variation ,neoplasms ,Cetuximab ,business.industry ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,digestive system diseases ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,FOLFIRI ,KRAS ,genomic profiling ,business ,medicine.drug - Abstract
Previous findings suggest that metastatic colorectal carcinoma (mCRC) patients with KRAS/NRAS/BRAF/PIK3CA wild-type (quadruple-wt) tumors are highly sensitive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). However, additional molecular alterations might be involved in the de novo resistance to these drugs. We performed a comprehensive molecular profiling of 21 quadruple-wt tumors from mCRC patients enrolled in the &ldquo, Cetuximab After Progression in KRAS wild-type colorectal cancer patients&rdquo, (CAPRI-GOIM) trial of first line FOLFIRI plus cetuximab. Tumor samples were analyzed with a targeted sequencing panel covering single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and gene fusions in 143 cancer-related genes. The analysis revealed in all 21 patients the presence of at least one SNV/Indel and in 10/21 cases (48%) the presence of at least one CNV. Furthermore, 17/21 (81%) patients had co-existing SNVs/Indels in different genes. Quadruple-wt mCRC from patients with the shorter progression free survival (PFS) were enriched with peculiar genetic alterations in KRAS, FBXW7, MAP2K1, and NF1 genes as compared with patients with longer PFS. These data suggest that a wide genetic profiling of quadruple-wt mCRC patients might help to identify novel markers of de novo resistance to anti-EGFR MoAbs.
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- 2019
10. RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial
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Silvana Leo, A. Rinaldi, Francesco Giuliani, Salvatore Pisconti, R. Esposito Abate, Alessia Iannaccone, Fortunato Ciardiello, Matilde Lambiase, Anna Maria Rachiglio, Evaristo Maiello, E. Martinelli, Nicola Normanno, M. Biglietto, Laura Forgione, Teresa Troiani, Tiziana Latiano, Roberto Bordonaro, Claudia Cardone, D. Rizzi, Alessandra Sacco, Normanno, N., Esposito Abate, R., Lambiase, M., Forgione, L., Cardone, C., Iannaccone, A., Sacco, A., Rachiglio, A. M., Martinelli, E., Rizzi, D., Pisconti, S., Biglietto, M., Bordonaro, R., Troiani, T., Latiano, T. P., Giuliani, F., Leo, S., Rinaldi, A., Maiello, E., and Ciardiello, F.
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0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,medicine.medical_specialty ,Pathology ,Colorectal cancer ,medicine.drug_class ,Colon carcinoma ,Leucovorin ,Cetuximab ,NRAS ,medicine.disease_cause ,Monoclonal antibody ,Gastroenterology ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Anti-EGFR monoclonal antibodie ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,KRAS ,Humans ,Digital polymerase chain reaction ,Liquid biopsy ,Neoplasm Metastasis ,Alleles ,business.industry ,Liquid Biopsy ,Hematology ,medicine.disease ,Progression-Free Survival ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,FOLFIRI ,Camptothecin ,Fluorouracil ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
Background Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy. Patients and methods In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing. Results A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P
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- 2017
11. Clinical activity and tolerability of FOLFIRI and cetuximab in elderly patients with metastatic colorectal cancer in the CAPRI-GOIM first-line trial
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Andrea Onetti Muda, Guido Giordano, Gianni Simone, Pietro Micheli, C. Barone, Giacomo Cartenì, Fabiana Tatangelo, Laura Longhitano, Vincenzo Rosario Iaffaioli, Alessandra Cassano, M. Biglietto, Anna Nappi, Sabrina Rossi, A.R. Bordonaro, A. Rinaldi, Francesco Sponziello, G. Modoni, GabrieleDi Maggio, Matilde Lambiase, Oscar Nappi, Claudia Cardone, Antonella Marino, Mirko Montrone, Sandro Barni, Michele Orditura, Antonio Febbraro, Paolo Graziano, Saverio Cinieri, Guglielmo Nasti, Fortunato Ciardiello, Evaristo Maiello, D. Rizzi, Vincenzo Sforza, Stefano Cordio, F. De Vita, Erika Martinelli, S. Romito, Vincenzo Montesarchio, Giuseppe Tonini, Annamaria Sebastio, Salvatore Pisconti, Nicola Normanno, Tiziana Guarino, Giuseppe Colucci, Francesco Giuliani, Anna Maria Rachiglio, Gerardo Botti, Nicoletta Chicchinelli, Tiziana Latiano, Teresa Troiani, Vito Lorusso, Michele Aieta, Silvana Leo, Giuseppe Grimaldi, Eugenio Tommaselli, Luigi Leo, Cinzia Chiarazzo, Mario Manusia, Martinelli, E, Cardone, C, Troiani, T, Normanno, N, Pisconti, S, Sforza, V, Bordonaro, A R, Rachiglio, A M, Lambiase, M, Latiano, T P, Modoni, G, Cordio, S, Giuliani, F, Biglietto, M, Montesarchio, V, Barone, C, Tonini, G, Cinieri, Enrico, Febbraro, A, Rizzi, D, De Vita, F, Orditura, M, Colucci, G, Maiello, E, and Ciardiello, F
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Oncology ,Cancer Research ,medicine.medical_specialty ,Population ,colorectal cancer ,medicine.disease_cause ,elderly ,FOLFIRI ,FOLFOX ,Internal medicine ,cetuximab ,Medicine ,education ,neoplasms ,Original Research ,education.field_of_study ,Cetuximab ,business.industry ,digestive system diseases ,Oxaliplatin ,Irinotecan ,Tolerability ,NGS ,KRAS ,business ,medicine.drug - Abstract
In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. Background: In the cetuximab after progression in KRAS wild-type colorectal cancer patients ( CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups.Methods: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by agegroups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (>= 65; >= 70 and >= 75 years).Results: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were > 65 years, 86 > 70 years and 35 > 75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were > 65 years, 46 > 70 and 17 > 75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were >= 65 years; 29 were >= 70; 9 were >= 75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade >= 3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients >= 75 years and grade >= 3 fatigue (31% vs 20%, p=0.01) in patients < 75 years.Conclusions: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade >= 3 diarrhoea and neutropaenia in patients >= 75 years and grade >= 3 fatigue in patients < 75 years.
- Published
- 2017
12. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial
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Giuseppe Perrone, Mario Manusia, Erika Martinelli, Eugenio Tommaselli, Salvatore Pisconti, A. Perrino, M. Biglietto, Giuseppe Colucci, A. Cardarelli, A. Onetti Muda, Francesco Giuliani, Guido Rindi, Guglielmo Nasti, D. Rizzi, Anna Maria Rachiglio, Saverio Cinieri, Evaristo Maiello, Antonio Febbraro, Fortunato Ciardiello, Gianni Simone, Giacomo Cartenì, E. Montesarchio, Matilde Lambiase, Fabiana Tatangelo, Teresa Troiani, Nicola Normanno, G. Botti, Daniela Cabibi, A. Rinaldi, Alessia Iannaccone, Pietro Micheli, C. Barone, Oscar Nappi, Antonio Russo, Cristin Roma, Roberto Bordonaro, Claudia Esposito, Annamaria Sebastio, Francesca Fenizia, Paolo Graziano, S. Romito, Giuseppe Tonini, Pantaleo Bufo, Tiziana Latiano, Nicoletta Chicchinelli, P. Giaccone, M. Criscuolo, Normanno, Nicola, Rachiglio, A.M., Lambiase, M., Martinelli, E., Fenizia, F., Esposito, C., Roma, C., Troiani, T., Rizzi, D., Tatangelo, F., Botti, G., Maiello, E., Colucci, G., Ciardiello, F., Giuliani, F., Simone, G., Febbraro, A., Tommaselli, E., Cinieri, S., Criscuolo, M., Rinaldi, A., Bordonaro, R., Manusia, M., Romito, S., Bufo, P., Cartenì, G., Biglietto, M., Nappi, O., Montesarchio, E., Micheli, P., Nasti, G., Chicchinelli, N., Iannaccone, A., Russo, A., Cabibi, D., Barone, C., Rindi, G., Tonini, G., Onetti Muda, A., Perrone, G., Latiano, T., Graziano, P., Pisconti, S., Sebastio, A., Normanno, N., and Rachiglio, A. M.
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Oncology ,Neuroblastoma RAS viral oncogene homolog ,Organoplatinum Compounds ,Colorectal cancer ,Settore MED/06 - Oncologia Medica ,Leucovorin ,Cetuximab ,Mutations ,Next-generation sequencing ,Tumor heterogeneity ,Antineoplastic Combined Chemotherapy Protocols ,Camptothecin ,Carcinoma ,Class I Phosphatidylinositol 3-Kinases ,Colorectal Neoplasms ,Drug Resistance, Neoplasm ,Fluorouracil ,GTP Phosphohydrolases ,Gene Frequency ,High-Throughput Nucleotide Sequencing ,Humans ,Membrane Proteins ,Mutation ,Phosphatidylinositol 3-Kinases ,Proto-Oncogene Proteins B-raf ,Proto-Oncogene Proteins p21(ras) ,Treatment Outcome ,Hematology ,Colorectal Neoplasm ,medicine.disease_cause ,GTP Phosphohydrolase ,Membrane Protein ,Class I Phosphatidylinositol 3-Kinase ,colorectal ,FOLFIRI ,KRAS ,medicine.drug ,Human ,medicine.medical_specialty ,Internal medicine ,medicine ,cancer ,neoplasms ,Allele frequency ,Antineoplastic Combined Chemotherapy Protocol ,Settore MED/08 - ANATOMIA PATOLOGICA ,business.industry ,Organoplatinum Compound ,Cancer ,medicine.disease ,digestive system diseases ,Cancer research ,Neoplastic cell ,Phosphatidylinositol 3-Kinase ,business - Abstract
Background: Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. Patients and methods: Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. Results: The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS 33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35). Conclusions: KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.
- Published
- 2015
13. Detection of KRAS mutations in colorectal carcinoma patients with an integrated PCR/sequencing and real-time PCR approach
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Nicola Normanno, Gerardo Botti, Carmine Pinto, R Vincenzo Iaffaioli, Cristin Roma, Fabiana Tatangelo, Oscar Nappi, Anna Maria Rachiglio, Fortunato Ciardiello, Pietro Carotenuto, Carotenuto, P, Roma, C, Rachiglio, Am, Tatangelo, F, Pinto, C, Ciardiello, Fortunato, Nappi, O, Iaffaioli, Rv, Botti, G, Normanno, N., Carotenuto, P., Roma, C., Rachiglio, A. M., Tatangelo, F., Pinto, C., Ciardiello, F., Nappi, O., Iaffaioli, V., and Botti, G.
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medicine.drug_class ,Colorectal cancer ,EGFR ,Mutant ,Reproducibility of Result ,Colorectal Neoplasm ,Biology ,Adenocarcinoma ,Monoclonal antibody ,medicine.disease_cause ,Sensitivity and Specificity ,Cohort Studies ,Proto-Oncogene Proteins p21(ras) ,chemistry.chemical_compound ,colorectal carcinoma ,Proto-Oncogene Proteins ,Genetics ,medicine ,KRAS ,Humans ,Neoplasm Metastasis ,Gene ,Oligonucleotide Array Sequence Analysis ,Pharmacology ,therapy ,Proto-Oncogene Protein ,Oligonucleotide Array Sequence Analysi ,Reverse Transcriptase Polymerase Chain Reaction ,Reproducibility of Results ,medicine.disease ,ras Protein ,Molecular biology ,Neoplasm Metastasi ,Real-time polymerase chain reaction ,chemistry ,Mutation ,ras Proteins ,Molecular Medicine ,DNA fragmentation ,Cohort Studie ,Colorectal Neoplasms ,DNA ,Human - Abstract
Aims: Patients with metastatic colorectal carcinoma (mCRC) carrying activating mutations of the KRAS gene do not benefit from treatment with anti-EGF receptor monoclonal antibodies. Therefore, KRAS mutation testing of mCRC patients is mandatory in the clinical setting to aid in the choice of appropriate therapy. Materials & methods: We developed a cost-effective approach for the determination of KRAS mutations in codons 12 and 13 in clinical practice based on a sensitive PCR/sequencing technique and the commercially available real-time PCR-based Therascreen® kit (DxS Ltd). Results & conclusion: The PCR/sequencing test was able to detect 10% mutant DNA in a background of wild-type DNA. By using this assay, we determined the mutational status of KRAS in 527 out of 540 (97.6%) formalin-fixed paraffin-embedded tissues from mCRC patients. PCR/sequencing was not conclusive in 13 cases, in which low-intensity peaks suggestive of potential mutations were identified. The DxS assay, which showed a sensitivity of 1%, identified mutations in 11 out of 13 inconclusive cases. Interestingly, five of these 11 cases showed high levels of DNA fragmentation. No significant difference was found in the ability of PCR/sequencing and DxS to identify KRAS mutations within 160 cases with more than 30% tumor cells. However, in 24 samples with less than 30% tumor cells, DxS showed an higher sensitivity. In conclusion, our findings suggest that PCR/sequencing can be used for mutational analysis of the majority of tumor samples that have more than 30% tumor cell content, whereas more sensitive and expensive tests should be reserved for inconclusive cases and for samples with a low amount of tumor cells.
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- 2011
14. Optimizing response to gefitinib in the treatment of non-small-cell lung cancer
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Nicola Normanno, Anna Maria Rachiglio, Giuseppe Antinolfi, Pietro Carotenuto, Renato Franco, Alfonso Illiano, Francovito Piantedosi, Alessandro Morabito, Gerardo Botti, Antonella De Luca, Cristin Roma, Raffaella Pasquale, Carotenuto, P, Roma, C, Rachiglio, Am, Pasquale, R, Franco, Renato, Antinolfi, G, Piantedosi, F, Illiano, A, Botti, G, Morabito, A, Normanno, N, De Luca, A., Carotenuto, P., Roma, C., Rachiglio, A. M., Pasquale, R., Franco, R., Antinolfi, G., Piantedosi, F., Illiano, A., Botti, G., Morabito, A., Normanno, N., and de Luca, A.
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,EGFR ,gefitinib ,Review ,NSCLC ,Gefitinib ,Internal medicine ,medicine ,Epidermal growth factor receptor ,Adverse effect ,Lung cancer ,Pathological ,neoplasms ,Pharmacology ,Chemotherapy ,biology ,business.industry ,medicine.disease ,EGFR mutations ,respiratory tract diseases ,Clinical trial ,biology.protein ,Molecular Medicine ,Adenocarcinoma ,EGFR mutation ,business ,medicine.drug - Abstract
The epidermal growth factor receptor (EGFR) is expressed in the majority of non- small-cell lung cancer (NSCLC). However, only a restricted subgroup of NSCLC patients respond to treatment with the EGFR tyrosine kinase inhibitor (EGFR TKI) gefitinib. Clinical trials have demonstrated that patients carrying activating mutations of the EGFR significantly benefit from treatment with gefitinib. In particular, mutations of the EGFR TK domain have been shown to increase the sensitivity of the EGFR to exogenous growth factors and, at the same time, to EGFR TKIs such as gefitinib. EGFR mutations are more frequent in patients with particular clinical and pathological features such as female sex, nonsmoker status, adenocarcinoma histology, and East Asian ethnicity. A close correlation was found between EGFR mutations and response to gefitinib in NSCLC patients. More importantly, randomized Phase III studies have shown the superiority of gefitinib compared with chemotherapy in EGFR mutant patients in the first-line setting. In addition, gefitinib showed a good toxicity profile with an incidence of adverse events that was significantly lower compared with chemotherapy. Therefore, gefitinib is a major breakthrough for the management of EGFR mutant NSCLC patients and represents the first step toward personalized treatment of NSCLC. © 2011 Carotenuto et al, publisher and licensee Dove Medical Press Ltd.
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- 2011
15. Triple negative breast cancer: From molecular portrait to therapeutic intervention
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Amelia D'Alessio, Anna Maria Rachiglio, Cristin Roma, Gerardo Botti, Pietro Carotenuto, Nicola Normanno, Carotenuto, P., Roma, C., Rachiglio, A. M., Botti, G., D'Alessio, A., and Normanno, N.
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Receptor, ErbB-2 ,Estrogen receptor ,Breast Neoplasms ,Target therapy ,Metastasis ,chemistry.chemical_compound ,Breast cancer ,Progesterone receptor ,Genetics ,Medicine ,Humans ,Epidermal growth factor receptor ,Molecular Biology ,Triple-negative breast cancer ,Comparative Genomic Hybridization ,biology ,business.industry ,Gene Expression Profiling ,Chromosome Mapping ,Genes, erbB-2 ,medicine.disease ,Molecular portrait ,Vascular endothelial growth factor ,Gene Expression Regulation, Neoplastic ,chemistry ,Receptors, Estrogen ,Cancer research ,biology.protein ,Neoplastic Stem Cells ,Female ,Gene expression ,Neoplastic Stem Cell ,business ,Triple negative ,Receptors, Progesterone ,Breast Neoplasm ,Brain metastasis ,Human - Abstract
Triple negative breast cancer is a subtype of breast cancer that lacks expression of an estrogen receptor (ER), a progesterone receptor (PR), and HER2. It is characterized by its unique molecular profile, aggressive behavior, and distinct pattern of metastasis. Epidemiological studies show a high prevalence of triple negative breast cancer among younger women and those of African descent. Although sensitive to chemotherapy, early relapse is common, and a predilection for visceral metastasis, including brain metastasis, has been described. Gene-expression profiling approaches demonstrated that triple negative breast cancer is a heterogeneous group of diseases composed of different, molecularly distinct subtypes. Although not synonymous, the majority of triple negative breast cancers carry the "basal-like" molecular profile on gene-expression arrays. However, several studies have shown that triple negative breast cancer includes tumors with a non-basal expression profile and, in particular, the "normal-breast," the "multiple marker negative," and the recently identified "claudin-negative" subtypes. Target-based agents, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly-ADP-ribose polymerase (PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease. © 2010 by Begell House, Inc.
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- 2010
16. Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives.
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Martinelli E, Ciardiello D, Martini G, Troiani T, Cardone C, Vitiello PP, Normanno N, Rachiglio AM, Maiello E, Latiano T, De Vita F, and Ciardiello F
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- Cetuximab therapeutic use, ErbB Receptors genetics, ErbB Receptors metabolism, Humans, Mutation, Panitumumab therapeutic use, Proto-Oncogene Proteins p21(ras) genetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics
- Abstract
Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2020
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17. Clinical activity and tolerability of FOLFIRI and cetuximab in elderly patients with metastatic colorectal cancer in the CAPRI-GOIM first-line trial.
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Martinelli E, Cardone C, Troiani T, Normanno N, Pisconti S, Sforza V, Bordonaro AR, Rachiglio AM, Lambiase M, Latiano TP, Modoni G, Cordio S, Giuliani F, Biglietto M, Montesarchio V, Barone C, Tonini G, Cinieri S, Febbraro A, Rizzi D, De Vita F, Orditura M, Colucci G, Maiello E, Ciardiello F, Iaffaioli V, Nasti G, Nappi A, Botti G, Tatangelo F, Chicchinelli N, Montrone M, Sebastio A, Guarino T, Simone G, Graziano P, Chiarazzo C, Maggio G, Longhitano L, Manusia M, Cartenì G, Nappi O, Micheli P, Leo L, Rossi S, Cassano A, Tommaselli E, Giordano G, Sponziello F, Marino A, Rinaldi A, Romito S, Muda AO, Lorusso V, Leo S, Barni S, Grimaldi G, and Aieta M
- Abstract
Background: In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups., Methods: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (≥65; ≥70 and ≥75 years)., Results: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65 years, 86 >70 years and 35 >75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65 years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were ≥65 years; 29 were ≥70; 9 were ≥75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade ≥3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients ≥75 years and grade ≥3 fatigue (31% vs 20%, p=0.01) in patients <75 years., Conclusions: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade ≥3 diarrhoea and neutropaenia in patients ≥75 years and grade ≥3 fatigue in patients <75 years., Trial Registration Number: 2009-014041-81., Competing Interests: Competing interests: None declared.
- Published
- 2017
- Full Text
- View/download PDF
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