[Venous thromboembolism and breast cancer]. / Maladie thromboembolique veineuse et cancer du sein.

Breast cancer is the most common cancer in women. Patients with breast cancer have a 4-fold increased risk of venous thromboembolism (VTE) compared to age- and sex-matched controls without cancer. VTE remains the second leading cause of death in cancer patients and an independent risk factor for mortality. In women with breast cancer, the main risk factors for developing VTE are increasing age, obesity, disease stage, central catheter placement and cancer treatments, including surgery, chemotherapy, hormonotherapy and cyclin-dependent kinase 4/6 inhibitors. In women receiving tamoxifen, the risk of VTE is particularly increased within the first 6 months after initiation of hormonotherapy, although some evidence suggests that this risk may persist through the first 2 years of treatment. The risk of VTE appears to be lower in patients receiving aromatase inhibitors. In breast cancer patients receiving cyclin-dependent kinase 4/6 inhibitors, the rate of VTE is approximately 6%. Current clinical practice guidelines for the treatment and prevention of VTE in patients with cancer suggest that thromboprophylaxis should not be used routinely in ambulatory cancer patients receiving chemotherapy or hormonotherapy. The risk-benefit ratio of thromboprophylaxis should be assessed on a case-by-case basis and be the subject of multidisciplinary discussion.

Therapeutic Strategies for Patients with Advanced Small Bowel Adenocarcinoma: Current Knowledge and Perspectives.

Small bowel adenocarcinoma (SBA) is diagnosed at an advanced (unresectable or metastatic) tumor stage in approximately one-third of cases. This is partly due to the non-specific symptomatology and limitations in endoscopic and radiologic detection methods. In this context, the prognosis remains poor and systemic chemotherapy appears to benefit patients when compared to best supportive care alone, despite the absence of randomized controlled trials. The results of a recent large prospective cohort (ARCAD-NADEGE) reported that the absence of chemotherapy was a predictive factor for a lower overall survival (OS) even though poor differentiation and SBA associated with Crohn's disease correlate with poor prognosis. In retrospective series, the median OS ranges from approximately 9 to 18 months with current treatment approaches. A combination of a fluoropyrimidine and oxaliplatin (FOLFOX or CAPOX) appears to be the most utilized and effective first-line chemotherapy regimen. Other front-line alternatives are the combination of 5-FU and cisplatin or fluoropyrimidine and irinotecan (FOLFIRI). In second-line, FOLFIRI is an effective option after progression on platinum-based therapy. Taxane-based therapy appears to be an alternative option, but further evaluation in larger series is needed. To a limited extent, the role of surgical resection for metastatic disease appears to be a valid option, though this approach has not been evaluated in prospective clinical studies. Due to the rareness of the disease, inclusion in clinical trials should be prioritized, and there is hope that targeted therapies and immunotherapy may enter the therapeutic arsenal for these patients.

Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives.

Gastrointestinal (GI) cancers are major health burdens worldwide and biomarkers are needed to improve the management of these diseases along their evolution. Circulating tumor DNA (ctDNA) is a promising non-invasive blood and other bodily-fluid-based biomarker in cancer management that can help clinicians in various cases for the detection, diagnosis, prognosis, monitoring and personalization of treatment in digestive oncology. In addition to the well-studied prognostic role of ctDNA, the main real-world applications appear to be the assessment of minimal residual disease to further guide adjuvant therapy and predict relapse, but also the monitoring of clonal evolution to tailor treatments in metastatic setting. Other challenges such as predicting response to treatment including immune checkpoint inhibitors could also be among the potential applications of ctDNA. Although the level of advancement of ctDNA development in the different tumor localizations is still inhomogeneous, it might be now reliable enough to be soon used in clinical routine for colorectal cancers and shows promising results in other GI cancers.

Plasma clearance of RAS mutation under therapeutic pressure is a rare event in metastatic colorectal cancer.

In metastatic colorectal cancer (mCRC), circulating tumor DNA (ctDNA) monitoring can be used to genotype tumors and track clonal evolution. We investigated the clearance of RAS mutated clones under chemotherapy pressure by ctDNA analysis in patients with a RAS mutated mCRC. Patients with a RAS mutated tumor included in the prospective PLACOL study were monitored for ctDNA. Analyses were based on optimized targeted next-generation sequencing and/or droplet-based digital polymerase chain reaction (ddPCR). For plasma samples without detectable mutations at progression disease, we tested the methylation status of WIF1 and NPY genes using methylation-ddPCR (met-ddPCR) to validate the presence of ctDNA. Among the 36 patients with positive plasma samples for RAS mutations at inclusion, 28 (77.8%) remained RAS positive at disease progression and 8 (22.2%) became negative. Subsequent met-ddPCR for methylated markers showed that only two out of the eight patients with RAS negative plasma had detectable ctDNA at progression. Therefore, only 2 samples among 36 were confirmed for clearance of RAS mutation in our series. In conclusion, this study suggests that the clearance of RAS mutations in patients treated by chemotherapy for a RAS mutated mCRC is a rare event. Monitoring tumor mutations in plasma samples should be combined with a strict control of the presence of ctDNA. The therapeutic impacts of RAS clearance need to be further explored.

Role of circulating tumor DNA in the management of patients with colorectal cancer.

Colorectal cancer is a major health burden with a prognosis that has been improved with the progresses in diagnosis and the advance of chemotherapy and personalized medicine. However, because of intra-tumor heterogeneity, clonal evolution and selection, tumors often develop resistance to treatments. "Liquid biopsy" is a minimally invasive method, based on analysis of tumor-specific material in peripheral blood samples of patients. Analysis of tumor specific genetic or epigenetic alterations in cell-free circulating nucleic acids may reflect the molecular heterogeneity of the underlying disease process and serial testing could allow to monitor its temporal genomic changing without using re-biopsy. In this review, we focused on the role of circulating tumor DNA (ctDNA) as a biomarker in the management of patients with colorectal cancer at early and advanced stages. Through recent studies, we described its promising clinical applications for diagnosis, detection of recurrence after surgery and monitoring for tumor response or therapeutic resistance in metastatic setting. Such recent developments offer new perspectives for personalized medicine in colorectal cancer but still needs some standardized detection methods and further studies to validate its use in clinical routine.

Gly388Arg FGFR4 Polymorphism Is Not Predictive of Everolimus Efficacy in Well-Differentiated Digestive Neuroendocrine Tumors.

INTRODUCTION: Preclinical data suggest that the single nucleotide polymorphism substituting a glycine for an arginine in codon 388 of the FGFR4 transmembrane domain may increase the proliferation of xenografted neuroendocrine cell lines and decrease their sensitivity to everolimus by modulating STAT3 signaling and the mTOR pathway. AIM: To evaluate the prognostic and predictive values of this polymorphism on everolimus efficacy in patients treated for digestive neuroendocrine tumor (NET). PATIENTS AND METHODS: This monocentric retrospective cohort included patients with small bowel NET (SBNET) and pancreatic NET (PNET) treated with everolimus (2006-2013). The patients were genotyped by classical sequencing, and mTOR pathway activity was assessed by immunochemistry on formalin-fixed paraffin-embedded samples (PTEN/pPTEN/pAKT/pmTOR/pS6/p4EBP1). RESULTS: Forty-one patients (21 males, median age 57 years) with PNET (n = 28), SBNET (n = 12) or NET of unknown origin (n = 1), grade 1 (n = 8), 2 (n = 27), 3 (n = 3) or unknown grade (n = 3), were studied. At least one 388Arg allele was found in 14/23 PNET and 10/11 SBNET. Progression-free survival in the whole population and the PNET subgroup was not influenced by the presence of one or two 388Arg alleles [HR = 1.31 (0.58-2.99), p = 0.52 and HR = 1.11 (0.45-2.73), p = 0.82, respectively]. Similarly, overall survival was not influenced. Finally, mTOR pathway molecule expression was not modified by the presence of at least one 388Arg allele. CONCLUSION: The Gly388Arg FGFR4 polymorphism does not seem to have a prognostic value in digestive NET. In addition, it neither predicts the response to everolimus nor modifies the activation of the mTOR pathway.