Bulletin du cancer
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Traditional cancer therapies, such as treatment with anthracyclines and chest radiation, are known to induce cardiovascular complications. Currently, the increase of cancer therapies will involve new mechanisms such as cancer immunotherapies, also called immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 inhibitors). These treatments have shown long-term remissions in subgroup of cancers, including melanomas, non-small-cell lung cancer, urothelial carcinoma, renal cell carcinoma, squamous cell carcinoma of the head and neck and colorectal cancer. ⋯ A cardiologist's opinion must be requested in emergency to discuss both a transthoracic echocardiography and the appropriate treatment (stopping immunotherapy, adding immunosuppressive treatment such as corticoids) and the monitoring in an intensive care unit. Cardiac MRI and endomyocardial biopsies may help to approach the final diagnosis. In this situation, other cancer therapies may be discussed.
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Microsatellite instability (MSI) is a molecular indicator of defective DNA mismatch repair (dMMR) and is observed in approximately 5% of metastatic colorectal cancers (mCRC). MSI is a major predictive biomarker for the efficacy of immune checkpoint inhibitors (ICKi) amongst mCRC patients. After summarizing the literature about the efficacy of conventional cytotoxic regimens, we will highlight studies that have demonstrated the clinical activity of ICKi for patients with chemoresistant MSI/dMMR mCRC. Then we will focus on ongoing clinical trials and emerging challenges for the treatment of patients with MSI/dMMR mCRC.
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Microsatellite instability (MSI), which is caused by deficiency of the DNA mismatch repair (MMR) system, is the molecular abnormality observed in tumors associated with Lynch syndrome. Lynch syndrome represents one of the most frequent conditions of cancer predisposition in human, thus requiring specific care and genetic counseling. Moreover, research has recently focused increasingly on MMR deficiency due to its positive predictive value for the efficacy of immune checkpoints inhibitors (ICKi) in metastatic tumors, regardless of their primary origin. ⋯ To date, there is no recommendation for the detection of dMMR/MSI in other primary tumors. In this review, we will present a comprehensive overview of the methods used for evaluation of tumor dMMR/MSI status in colorectal cancer, as well as in other tumor sites. We will see that the evaluation of this status remains challenging in some clinical settings, with the need to improve the above methods in these specific contexts.
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In the last few years, immunotherapy has revolutionized the oncology landscape by targeting the host immune system. Blocking immune checkpoints such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its ligand (PD-L1 or B7-H1), has proven its efficacy in several solid cancers. Recently, several clinical studies have demonstrated a significant improvement in clinical response to the anti-PD-1-based immunotherapy in a subset of patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient tumors that accumulate short insertion/deletion mutations notably in coding microsatellites regions of the genome. ⋯ The current review will summarize how and why MMR deficiency has emerged as an important predictor of sensitivity for immunotherapy-based strategies. We will also discuss tumor-cell intrinsic genetic and immune-related features of MSI tumors that can modulate immune checkpoint blockade response and explain primary and/or acquired resistance to anti-PD-1 therapy. Finally, we will also discuss about emerging scores which can define more precisely the immune context of the tumor microenvironment and thus better evaluate prognosis and predict response to Immune Checkpoint Blockade.
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The offer of anti-cancer drugs has recently been disrupted by the introduction of checkpoint inhibitors on the market. Currently, one anti-CTLA-4, two anti-PD-1 and two anti-PD-L1 are authorized in the European Union, in seven different types of cancer. The clinical development of these therapies is still in full swing: in July 2017, more than 1 500 clinical trials were evaluating anti-PD-1, anti-PD-L1 and anti-CTLA-4 drugs in about twenty different locations and this number continues to increase. ⋯ In addition, the expenses associated with ipilimumab, nivolumab and pembrolizumab are substantial and almost tripled in one year, going from 120 million euros in 2015 to more than 340 million euros in 2016. This raises the question of the ability of the current healthcare system to maintain equitable access to innovation and best treatments for all patients. For all these reasons, the French National Cancer Institute decided to dedicate its thematic annual report on these innovative immunotherapies, targeting in particular checkpoint inhibitors and CAR-T cells, in order to produce an inventory of current data and an analysis regarding the different issues associated with these therapies.