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Murviel-lès-Montpellier, France

Tabernero J.,Autonomous University of Barcelona | Lenz H.-J.,University of Southern California | Siena S.,Niguarda Cancer Center | Siena S.,University of Milan | And 17 more authors.
The Lancet Oncology | Year: 2015

Background: Tumour mutational status is an important determinant of the response of metastatic colorectal cancer to targeted treatments. However, the genotype of the tissue obtained at the time of diagnosis might not accurately represent tumour genotype after multiple lines of treatment. This retrospective exploratory analysis investigated the clinical activity of regorafenib in biomarker subgroups of the CORRECT study population defined by tumour mutational status or plasma protein levels. Methods: We used BEAMing technology to identify KRAS, PIK3CA, and BRAF mutations in DNA obtained from the plasma of 503 patients with metastatic colorectal cancer who enrolled in the CORRECT trial. We quantified total human genomic DNA isolated from plasma samples for 503 patients using a modified version of human long interspersed nuclear element-1 (LINE-1) quantitive real-time PCR. We also measured the concentration of 15 proteins of interest-angiopoietin 2, interleukin 6, interleukin 8, placental growth factor, soluble TIE-1, soluble VEGFR1, VEGF-A, VEGF-C, VEGF-D, VEGF-A isoform 121, bone morphogenetic protein 7, macrophage colony-stimulating factor, stromal cell-derived factor-1, tissue inhibitor of metalloproteinase 2, and von Willebrand factor-in plasma samples from 611 patients. We did correlative analyses of overall survival and progression-free survival in patient subgroups based on mutational status, circulating DNA concentration, and protein concentrations. The CORRECT trial was registered with ClinicalTrials.gov, number NCT01103323. Findings: Tumour-associated mutations were readily detected with BEAMing of plasma DNA, with KRAS mutations identified in 349 (69%) of 503 patients, PIK3CA mutations in 84 (17%) of 503 patients, and BRAF mutations in 17 (3%) of 502 patients. We did not do correlative analysis based on BRAF genotype because of the low mutational frequency detected for this gene. Some of the most prevalent individual hot-spot mutations we identified included: KRAS (KRAS G12D, 116 [28%] of 413 mutations; G12V, 72 [17%]; and G13D, 67 [16%]) and PIK3CA (PIK3CA E542K, 27 [30%] of 89 mutations; E545K, 37 [42%]; and H1047R, 12 [14%]). 41 (48%) of 86 patients who had received anti-EGFR therapy and whose archival tumour tissue DNA was KRAS wild-type in BEAMing analysis were identified as having KRAS mutations in BEAMing analysis of fresh plasma DNA. Correlative analyses suggest a clinical benefit favouring regorafenib across patient subgroups defined by KRAS and PIK3CA mutational status (progression-free survival with regorafenib vs placebo: hazard ratio [HR] 0·52, 95% CI 0·35-0·76 for KRAS wild-type; HR 0·51, 95% CI 0·40-0·65 for KRAS mutant [KRAS wild type vs mutant, pinteraction=0·74]; HR 0·50, 95% CI 0·40-0·63 for PIK3CA wild-type; HR 0·54, 95% CI 0·32-0·89 for PIK3CA mutant [PIK3CA wild-type vs mutant, pinteraction=0·85]) or circulating DNA concentration (progression-free survival with regorafenib vs placebo: HR 0·53, 95% CI 0·40-0·71, for low circulating DNA concentrations; HR 0·52, 95% CI 0·40-0·70, for high circulating DNA concentrations; low vs high circulating DNA, pinteraction=0·601). With the exception of von Willebrand factor, assessed with the median cutoff method, plasma protein concentrations were also not associated with regorafenib activity in terms of progression-free survival. In univariable analyses, the only plasma protein that was associated with overall survival was TIE-1, high concentrations of which were associated with longer overall survival compared with low TIE-1 concentrations. This association was not significant in multivariable analyses. Interpretation: BEAMing of circulating DNA could be a viable approach for non-invasive analysis of tumour genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue. Additionally, the results show that regorafenib seems to be consistently associated with a clinical benefit in a range of patient subgroups based on mutational status and protein biomarker concentrations. Funding: Bayer HealthCare Pharmaceuticals. © 2015 Elsevier Ltd.

Loupakis F.,Istituto Toscano Tumori | Stein A.,University of Hamburg | Ychou M.,ICM Val DAurelle | Hermann F.,Hoffmann-La Roche | And 2 more authors.
Targeted Oncology | Year: 2015

Colorectal cancer is the third most common cancer worldwide. A significant proportion of patients presents with unresectable metastatic disease or develops metachronous metastases following surgical resection of the primary tumor. The prognosis of the disease has improved over the past two decades, with extended multimodality treatment options and the development of increasingly intensified chemotherapy regimens that now typically include targeted biologics. A recent advance in therapy is a treatment regimen composed of three chemotherapeutic agents (i.e., triplet chemotherapy: 5-fluorouracil [5-FU]/leucovorin [LV], oxaliplatin, and irinotecan; FOLFOXIRI) in combination with the vascular endothelial growth factor inhibitor bevacizumab. This regimen has been shown to elicit significantly improved objective response rates and median progression-free survival compared with 5-FU/LV and irinotecan in combination with bevacizumab. However, triplet chemotherapy has been associated with increased rates of chemotherapy-related adverse events, and treatment-emergent adverse events should be properly managed to minimize treatment interruption or discontinuation. We present herein a review of clinical studies evaluating the safety and efficacy of FOLFOXIRI with bevacizumab in metastatic colorectal cancer, and propose a practical guide for the management of adverse events associated with the regimen. [MediaObject not available: see fulltext.] © 2015 The Author(s)

Denost Q.,Bordeaux University Hospital Center | Faucheron J.L.,Michallon University Hospital | Lefevre J.H.,University Pierre and Marie Curie | Panis Y.,University Paris Diderot | And 5 more authors.
European Journal of Surgical Oncology | Year: 2015

Background There is a significant worldwide variation in practice regarding the criteria for operative intervention and overall management in patients with locally recurrent rectal cancer (LRRC). A survival benefit has been described for patients with clear resection margins in patients undergoing surgery for LRRC which is seen as an important surgical quality indicator. Methods A prospective French national database was established in 2008 which recorded procedures undertaken for locally recurrent rectal cancer (LRRC). Overall and Disease-Free Survival (OS, DFS) were assessed retrospectively. We report the variability and the heterogeneity of LRRC management in France as well as 5-year oncological outcomes. Results In this national report, 104 questionnaires were completed at 29 French surgical centres with a high variability of cases-loaded. Patients had preoperative treatment in 86% of cases. Surgical procedures included APER (36%), LAR (25%), Hartmann's procedure (21%) and pelvic exenterations (15.5%). Four patients had a low sacrectomy (S4/S5). There were no postoperative deaths and overall morbidity was 41%. R0 was achieved in 60%, R1 and R2 in 29% and 11%, respectively. R0 resection resulted in a 5-year OS of 35% compared to 12% and 0% for respectively R1 and R2 (OR = 2.04; 95% CI: 1.4-2.98; p < 0.001). OS was similar between R2 and non-resected patients (OR = 1.47; 95% CI: 0.58-3.76; p = 0.418). Conclusions Our data is in accordance with the literature except the rate of extended resection procedures. This underlines the selective character of operative indications for LRRC in France as well as the care variability and the absence of optimal clinical pathway regarding these patients. © 2015 Elsevier Ltd.

Zhu A.X.,Harvard University | Kudo M.,Kinki University | Assenat E.,ICM Val DAurelle | Cattan S.,University of Lille Nord de France | And 18 more authors.
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE: To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS: EVOLVE-1was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS: Everolimus, 7.5mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. MAIN OUTCOMES AND MEASURES: The primary end pointwas overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). RESULTS: No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95%CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8%vs 3.3%, respectively), asthenia (7.8%vs 5.5%, respectively), and decreased appetite (6.1%vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. CONCLUSIONS AND RELEVANCE: Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01035229 Copyright 2014 American Medical Association. All rights reserved.

Colombo P.-E.,ICM Val DAurelle | Vincent-Salomon A.,University Pierre and Marie Curie | Chateau M.-C.,ICM Val DAurelle | Mourregot A.,ICM Val DAurelle | And 5 more authors.
Bulletin du Cancer | Year: 2014

Diagnostics of high-risk breast lesions have increased these last years with the augmentation of breast percutaneous biopsies. They are lesions that confer an enlarged risk of breast cancer, either because of an increased probability of finding cancer after open surgery, a possible evolution toward in situ or invasive cancer, or because of an increased probability of developing breast cancer over the long term. Much progress has been made these last years in their histological diagnostic, classification and pathogenesis. Nevertheless, no consensus exists to date on the management of these "high-risk" lesions. In particular, surgical indications and follow-up modalities remain controversial for each histological type. In this review, the principal factors that could impact surgical decision and long-term follow-up are discussed with areas of controversy highlighted. Copyright © 2014 John Libbey Eurotext.

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