TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy

Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan–Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT

Molecular determinants of anti-EGFR sensitivity and resistance in metastatic colorectal cancer

Since 2004, the clinical impact of monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) on patients with metastatic colorectal cancer (MCRC) has been clearly established. The combination of these biological agents with conventional chemotherapy has led to a significant improvement in response rate, progression-free survival and overall survival in first-line as well as in second- or third-line treatment of MCRC. However, the high variability of response and outcome in MCRC patients treated with these anti-EGFR mAbs has highlighted the need of identifying clinical and/or molecular predictive markers to ensure appropriate use of targeted therapies. The presence of somatic KRAS mutations has been clearly identified as a predictive marker of resistance to anti-EGFR in MCRC, and the use of anti-EGFR mAbs is now restricted to patients with no detectable KRAS mutation. Several studies have indicated that amplification of EGFR, overexpression of the EGFR ligands and inactivation of the anti-oncogene TP53 are associated with sensitivity to anti-EGFR mAbs, whereas mutations of BRAF and PIK3CA and loss of PTEN expression are associated with resistance. Besides these somatic variations, germline polymorphisms such as those affecting genes involved in the EGFR pathway or within the immunoglobulin receptors may also modulate response to anti-EGFR mAbs. Until now, all these markers are not completely validated and only KRAS genotyping is mandatory in routine practice for use of the anti-EGFR mAbs in MCRC

Efficacité et tolérance du Bevacizumab en association à une chimiothérapie conventionnellle dans le traitement du cancer colo-rectal métastasique

Introduction : Les essais randomisés évaluant le bevacizumab dans le traitement du CCR métastatique incluent des populations très sélectionnées, différentes des populations rencontrées dans la pratique. Objectifs : Evaluer le bénéfice clinique et la tolérance du bevacizumab au sein de la population traitée dans notre centre. Patients et méthodes : Les patients traités par bevacizumab en lère ou rie ligne de chimiothérapie pour un CCR métastatique entre 2006 et 2010 ont été inclus rétrospectivement dans l'étude et comparés à un groupe traité par chimiothérapie seule entre 2002 et 2006. L'efficacité de la chimiothérapie de lère et 2ème ligne en termes de taux de réponse, survie sans progression et survie globale, et la tolérance du traitement ont été analysées. Résultats : Entre 2006 et 2010, 75 patients ont été traités par bevacizumab associé à une chimiothérapie conventionnelle dans notre centre : 54 patients en 1 ère ligne et 21 patients en rie ligne. Soixante et un patients traités par chimiothérapie seule ont été analysés. Le taux de réponse objective était supérieur dans le groupe traité par bevacizumab en 1 ère ligne (25/54 soit 46.3% vs 19/61 soit 31.1%, p=0.09), ainsi que la médiane de survie sans progression (13 mois vs 8 mois, 1)=0.0047) et la médiane de survie globale (24 mois vs 19 mois, p-0.094). La tolérance du traitement est restée acceptable. Conclusion : Le bénéfice clinique et l'absence de surtoxicité retrouvés dans notre population sont cohérents avec les résultats décrits dans les essais cliniques.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

Bevacizumab+chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial-PRODIGE 20 study results

IF 11.855International audienceBackground :Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population.Patients and methods :Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator’s choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria.Results :About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75–91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT).Conclusion :Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria

Prognostic factor analysis for elderly patients treated for metastatic colorectal cancer in the randomized phase II trial PRODIGE 20

International audienc