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Milano, Italy

Sinicrope F.A.,Mayo Medical School | Foster N.R.,Mayo Medical School | Marsoni S.,SENDO Foundation | Monges G.,Institute Paoli Calmettes | And 6 more authors.
Journal of the National Cancer Institute

Background Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and examined the impact of 5-fluorouracil (FU)-based adjuvant therapy on recurrence variables.MethodsWe included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using χ2 or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided.ResultsIn this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P <. 001), delayed TTR (P <. 001), and fewer distant recurrences (22% vs 12%; P <. 001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P =. 005) and improved DFS (P =. 035) and OS (P =. 031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P =. 011) and reduced recurrence to all sites for pMMR tumors (P <. 001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU-based treatment compared with sporadic tumors where no benefit was observed (P =. 006). ConclusionsPatients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors. © 2011 The Author. Source

Damia G.,Laboratory of Molecular Pharmacology | Broggini M.,Laboratory of Molecular Pharmacology | Marsoni S.,SENDO Foundation | Venturini S.,Bocconi University | Generali D.,U.O Sperimentale di Patologia Mammaria
Journal of the National Cancer Institute - Monographs

Cancer is a complex cellular disease caused by multiple factors via genetic mutations (hereditary or somatic) or environmental factors. The emerging omics technologies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, and interactomics, are increasingly being used for cancer research and personalized medicine; they have provided new opportunities in the molecular analysis of human cancer with unprecedented speed and detail. The omic approach has brought powerful ability to screen cancer cells at different levels from gene to metabolite and to search for novel drug targets, expounding the drug mechanism of action, identifying adverse effects in unexpected interaction, validating current drug targets, exploring potential applications for novel drugs, and enabling the translation from bench to bedside. As a clinical research tool, the neoadjuvant approach in breast cancer is the perfect setting for individualization of treatment based on clinical, pathological, image-guided, or molecular assessment, based on the omics techniques of tumors during treatment; neoadjuvant treatment offers the ability to discern treatment effect in vivo and may allow smaller trials targeting specific breast cancer subtypes. © The Author 2011. Published by Oxford University Press. All rights reserved. Source

Mandala M.,Ospedali Riuniti | Grosso F.,Ospedale Santi Antonio e Biagio | Vitalini C.,SENDO Foundation | Corradino I.,SENDO Foundation | And 6 more authors.
British Journal of Cancer

Background: To investigate, retrospectively, the role of tumour histotype and antiangiogenic drugs for venous thromboembolism (VTE) development in advanced cancer patients treated in phase I studies.Methods:Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organisation) were considered.Results:Data of 1415 patients were included in the analysis: 526 (37.2%) patients were males, median age was 57.3 years (range: 13-85). Fifty-six (3.96%) patients developed a VTE. At multivariate analysis gynaecologic (hazard ratio (HR): 2.8, 95% confidence interval (CI): 1.29-6.23, P=0.009) and gastrointestinal tumours (HR: 3.23, 95% CI: 1.18-8.87, P=0.023) as well as combination regimens of cytotoxic and antiangiogenic agents (HR: 2.6, 95% CI: 1.11-6.30, P=0.028), white blood cell 11 000 l 1 (HR: 2.59, 95% CI: 1.10-6.09, P=0.028) and haemoglobin10 g dl 1 (HR: 3.1, 95% CI: 1.07-8.94, P=0.037) were statistically correlated with VTE development. Venous thromboembolism was the fourth most common cause of drug discontinuation. The median time from first drug administration to discontinuation was 1.4 for VTE and 2.3 months for the other adverse events (P=0.02).Conclusion:Venous thromboembolism is a relatively common complication among patients treated in the context of phase I studies, and may lead to early drug discontinuation. A greater risk of developing VTE is associated with the diagnosis of gynaecologic and gastrointestinal tumours and the combined use of chemotherapy and antiangiogenic drugs. © 2012 Cancer Research UK All rights reserved. Source

Rojo F.,Cancer Research Program | Gracias E.,National Institute of Oncology and Radiobiology | Villena N.,Cancer Research Program | Cruz T.,National Institute of Oncology and Radiobiology | And 16 more authors.
Clinical Cancer Research

Purpose: To assess the pharmacodynamic effects of nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody with intermediate affinity for the receptor, in skin and tumor tissues from head and neck cancer patients. Experimental design: Pharmacodynamic study in patients with advanced squamous cell carcinoma of the head and neck, unsuitable for chemoradiotherapy, enrolled in a single-center trial. Patients received 8 weekly infusions of nimotuzumab. The first nimotuzumab infusion was administered 1 week before starting radiation, whereas the remaining doses were administered concomitantly with irradiation. Paired biopsies were taken from skin and primary tumors, before (pretherapy) and 1 week (on single-agent therapy) after first infusion. Immunohistochemistry was conducted to assay the effects of nimotuzumab on total and phosphorylated EGFR, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), p-AKT, and proliferation (Ki-67). Results: Nimotuzumab was well tolerated and there was no evidence of skin rash. Objective response was achieved in 9 of 10 patients. The pharmacodynamic assays showed inhibition of p-EGFR in both skin and tumor (P = 0.042 in skin and P = 0.034 in tumor). No significant changes in p-ERK1/2, p-AKT, or Ki-67 were detected in skin. In addition, lymphocytic infiltrates, folliculitis, or perifolliculitis were not observed. In tumor samples, there was an upregulation of p-AKT (P = 0.043), a reduction in proliferation index (P = 0.012), and a nonsignificant trend toward a decrease of p-ERK1/2 (P = 0.091). Conclusions: The pharmacodynamic data confirmed the ability of nimotuzumab to decrease EGFR phosphorylation. Downstream effects were observed in tumor cells but not in skin, a finding that may help to explain the lack of skin rash in patients treated with nimotuzumab. ©2010 AACR. Source

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