In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival.We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability).A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67).Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.). 

Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer

Biomarker concordance between primary colorectal cancer and its metastases

The current understanding on the impact of KRAS on colorectal cancer.

// Camille Boulagnon-Rombi 1, 2 , Christophe Schneider 2, 3 , Chloe Leandri 4 , Albin Jeanne 2, 5 , Virginie Grybek 6 , Aude Marchal Bressenot 2 , Coralie Barbe 7 , Benjamin Marquet 1 , Saviz Nasri 8 , Christelle Coquelet 8 , Caroline Fichel 1 , Nicole Bouland 1 , Arnaud Bonnomet 9 , Reza Kianmanesh 10 , Anne-Sophie Lebre 6 , Olivier Bouche 4 , Marie-Daniele Diebold 1, 2 , Georges Bellon 2, 11 and Stephane Dedieu 2, 3 1 Laboratoire de Biopathologie, Centre Hospitalier Universitaire et Faculte de Medecine, Reims, France 2 CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France 3 Universite de Reims Champagne-Ardenne, UFR Sciences Exactes et Naturelles, Campus Moulin de la Housse, Reims, France 4 Service de Gastro-enterologie et Cancerologie Digestive, Centre Hospitalier Universitaire, Reims, France 5 SATT Nord, Lille, France 6 Laboratoire de Genetique, Centre Hospitalier Universitaire, Reims, France 7 Unite d’Aide Methodologique, Centre Hospitalier Universitaire, Reims, France 8 CRB Tumorotheque de Champagne-Ardenne, Reims, France 9 Plateforme d’Imagerie Cellulaire et Tissulaire, Universite de Reims Champagne-Ardenne, Reims, France 10 Service de Chirurgie Digestive, Centre Hospitalier Universitaire, Reims, France 11 Laboratoire de Biochimie, Centre Hospitalier Universitaire, Reims, France Correspondence to: Camille Boulagnon-Rombi, email: camille.boulagnon@gmail.com Keywords: colorectal cancer; LRP1; miR-205; BRAF; microsatellite instability; Pathology Received: May 11, 2017      Accepted: January 09, 2018      Published: January 13, 2018 ABSTRACT LRP1 (low-density lipoprotein receptor-related protein 1), a multifunctional endocytic receptor, has recently been identified as a hub within a biomarker network for multi-cancer clinical outcome prediction. As its role in colon cancer has not yet been characterized, we here investigate the relationship between LRP1 and outcome. Materials and Methods: LRP1 mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, as well as in stromal and tumor cells obtained after laser capture microdissection. Clinical potential was further investigated by immunohistochemistry in a population-based colon cancer series ( n = 307). LRP1 methylation, mutation and miR-205 expression were evaluated and compared with LRP1 expression levels. Results: LRP1 mRNA levels were significantly lower in colon adenocarcinoma cells compared with colon mucosa and stromal cells obtained after laser capture microdissection. Low LRP1 immunohistochemical expression in adenocarcinomas was associated with higher age, right-sided tumor, loss of CDX2 expression, Annexin A10 expression, CIMP-H, MSI-H and BRAF V600E mutation. Low LRP1 expression correlated with poor clinical outcome, especially in stage IV patients. While LRP1 expression was downregulated by LRP1 mutation, LRP1 promoter was never methylated. Conclusions: Loss of LRP1 expression is associated with worse colon cancer outcomes. Mechanistically, LRP1 mutation modulates LRP1 expression.

/pdf/lrp1-expression-in-colon-cancer-predicts-clinical-outcome-10msky0u4o.pdf

LRP1 expression in colon cancer predicts clinical outcome.

The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K-AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and -3), and BRAF. A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance. Pharmacogenomic research has demonstrated its value in this field, highlighting some tumor mutations that could discriminate responders from non-responders. The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice. The introduction of immunotherapy has paved the way for a new generation of predictive markers, including genome-wide assessment of the tumor landscape. Furthermore, the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine, rendering precision medicine available to every patient.

https://www.mdpi.com/1422-0067/18/7/1522/pdf

Pharmacogenomics of targeted agents for personalization of colorectal cancer treatment

Background/Aims: Whether patients with RAS mutation metastatic colorectal cancer (mCRC) obtain benefits from bevacizumab added to first-line chemotherapy remains unclear. Methods: PubMed, Cochrane Systematic Reviews, the Cochrane Collaboration Central Register of Controlled Clinical Trials, ClinicalTrials.gov, and the American Society of Clinical Oncology and European Society for Medical Oncology databases were searched to identify abstracts for randomized controlled trials (RCTs) evaluating the efficacy of bevacizumab for the first-line treatment of patients with RAS mutations mCRC from inception to the end of April 2016. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated. Results: Ten eligible papers reporting six RCTs were included. In the network meta-analysis of patients with RAS mutations, bevacizumab + chemotherapy prolonged PFS compared with chemotherapy alone (HR 0.75, 95% CI 0.51-1.10), but the difference was not statistically significant. Bevacizumab + chemotherapy did not prolong OS compared with chemotherapy alone (HR 1.10, 95% CI 0.73-1.66). Conclusion: There was insufficient evidence to definitively state that patients with RAS mutations mCRC could benefit from bevacizumab combined with chemotherapy as first-line treatment.

/pdf/efficacy-of-bevacizumab-in-the-first-line-treatment-of-4tqnzse9lj.pdf

Efficacy of Bevacizumab in the First-Line Treatment of Patients with RAS Mutations Metastatic Colorectal Cancer: a Systematic Review and Network Meta-Analysis.

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Efficacy of Bevacizumab in the First-Line Treatment of Patients with RAS Mutations Metastatic Colorectal Cancer: a Systematic Review and Network Meta-Analysis.