Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer: an update.
- 作者列表："Baraibar I","Ros J","Mulet N","Salvà F","Argilés G","Martini G","Cuadra JL","Sardo E","Ciardiello D","Tabernero J","Élez E
INTRODUCTION:Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (mCRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF and MSI status, and new biomarkers such as HER2 amplification and NTRK fusions have emerged more recently in refractory CRC, supported by overwhelming clinical relevance. These biomarkers can guide treatment management to improve clinical outcomes in these patients. AREAS COVERED:Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory CRC. Molecular alterations are described for classic and novel biomarkers, and data for completed and ongoing studies with targeted and immunotherapies are presented. EXPERT OPINION:Use of targeted therapies based on biomarker testing in CRC has enabled impressive improvements in clinical outcomes in refractory patients. BRAF, MSI, NRAS and KRAS should be tested upfront in all patients given their indisputable therapeutic implications. Other molecular alterations such as HER2 and NTRK are emerging. Testing for these alterations may further improve outcomes for refractory CRC patients. Nonetheless, many key aspects remain to be defined including the optimal timing and technique for testing, the most adequate panel, and whether all patients should be tested for all alterations.
简介: 分子分析导致转移性结直肠癌 (mCRC) 患者的生存期显著延长。临床指南建议检测 KRAS/NRAS 、 BRAF 和 MSI 状态，新的生物标志物如 HER2 扩增和 NTRK 融合最近在难治性 CRC 中出现，得到了压倒性临床相关性的支持。这些生物标志物可以指导治疗管理，以改善这些患者的临床结局。 涵盖领域: 回顾了过去十年的临床前和临床数据，寻找在难治性 CRC 中具有临床意义的已知和新的生物标志物。描述了经典和新型生物标志物的分子改变，并提供了已完成和正在进行的靶向和免疫疗法研究的数据。 专家意见: 在 CRC 中使用基于生物标志物检测的靶向治疗使难治性患者的临床结局有了令人印象深刻的改善。鉴于 BRAF 、 MSI 、 NRAS 和 KRAS 具有无可争辩的治疗意义，应在所有患者中预先进行检测。其他分子改变如 HER2 和 NTRK 正在出现。检测这些改变可能进一步改善难治性 CRC 患者的预后。尽管如此，许多关键方面仍有待确定，包括检测的最佳时机和技术、最合适的 panel 以及是否应检测所有患者的所有改变。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.