124PClinicopathological and molecular criteria assessment for the screening of hypermutated proficient mismatch repair (pMMR) colorectal cancers (CRC) with exonucleasic domain POLE (edPOLE) mutations (mt)

AbstractBackgroundMMR Deficiency (dMMR) and edPOLE mutations (mt) are responsible for hypermutated tumoral phenotype. Immunotherapy have shown efficacy in dMMR/high mutation burden patients (pts). One of the French AcS é Nivolumab trial cohorts aims to assess Nivolumab in advanced edPOLE mt tumors. These mt occur in 1-2% of Colorectal Cancer (CRC). We aimed to define the most relevant criterias in CRC to facilitate the screening for inclusion in the AcSé Nivolumab edPOLE cohort.MethodsedPOLE mutational status was evaluated in a cohort of locally advanced/metastatic (LA/M) CRC cancers enriched for BRAF mt, RAS mt, and unusual BRAF/RAS mt using High Resolution Melting PCR on the three hotspots described in the literature (codons 286, 411 and 459). Patients harboring edPOLE mt were then analyzed using FoundationOne genomic testing including tumor mutational burden (TMB).Results386 CRC pts were analysed between 2012 and 2018 (208 with atypical RAS or BRAF mutation, 119 with classical RAS or BRAF mutation, 59 RAS/BRAF wild type): 11 edPOLE mutated tumors were identified, most frequently in young male pts (Sex ratio 4,5, mean age: 54 years), pMMR (91%, 10/11), with left-sided tumors (73%, 8/11). The prevalence of edPOLE mt in atypical KRAS/BRAF mutated tumor was 5.3% (11/208) vs 0% (0/178) in other cases (p  = 0.02). Among the 11 edPOLE mt cases, 2 had a low TMB (
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research

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CONCLUSION: A significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy. IMPLICATIONS FOR PRACTICE: Microsatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical...
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Oncologist Source Type: research
This study provides strong evidence that following a healthy lifestyle can substantially extend the years a person lives disease-free." Commentary on Recent Evidence for Cognitive Decline to Precede Amyloid Aggregation in Alzheimer's Disease https://www.fightaging.org/archives/2020/01/commentary-on-recent-evidence-for-cognitive-decline-to-precede-amyloid-aggregation-in-alzheimers-disease/ I can't say that I think the data presented in the research noted here merits quite the degree of the attention that it has been given in the popular science press. It is interesting, but not compelling if its role...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Publication date: Available online 3 January 2020Source: Seminars in Cancer BiologyAuthor(s): Kelly Olino, Tristen Park, Ntia AhujaAbstractAdvances in immunotherapy, most notably antibodies targeting the inhibitory immune receptors cytotoxic T-lymphocyte associated protein 4 (CTLA-4/CD152), programmed death protein 1 (PD-1/CD279) and programmed death-ligand 1 (PD-L1/B7H1/CD274) have become effective standard therapies in advanced malignancies including melanoma,1–4 merkel cell carcinoma5, urological cancers6–8, non-small cell lung cancer9–11, mis-match repair (MMR) deficient tumors12, and Hodgkin lymphoma...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
ConclusionsWe have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF- β pathway to reinforce T cell reactivity in this patient group.
Source: Genome Medicine - Category: Genetics & Stem Cells Source Type: research
ConclusionsGVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
Publication date: Available online 23 December 2019Source: Seminars in Cancer BiologyAuthor(s): Sara K. Daniel, Y. Dave Seo, Venu G. PillarisettyAbstractSingle agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to ...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
Authors: Parmar A, Chan KKW, Ko YJ Abstract Therapeutic options for chemorefractory metastatic colorectal cancer (mcrc) have significantly expanded since 2009. The oral targeted therapies regorafenib and trifluridine/tipiracil have been established to be efficacious and safe in patients with mcrc who have progressed beyond 2 or more lines of chemotherapy. Evidence for the use of immunotherapy in a subgroup of this patient population is also encouraging, particularly in patients with mcrc that exhibits high microsatellite instability or deficient mismatch repair. Those significant advances have led to Health Canada ...
Source: Current Oncology - Category: Cancer & Oncology Tags: Curr Oncol Source Type: research
A subset of patients with MSS/MSI-low-colorectal cancer showed increased CD8(+) TILs together with up-regulated IFN-γ. Oncol Lett. 2019 Dec;18(6):5977-5985 Authors: Kikuchi T, Mimura K, Okayama H, Nakayama Y, Saito K, Yamada L, Endo E, Sakamoto W, Fujita S, Endo H, Saito M, Momma T, Saze Z, Ohki S, Kono K Abstract A small subset of patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS)-colorectal cancer (CRC) benefit from immunotherapy with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade. Therefore, the aim of the current study was to evaluate t...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
AbstractImmune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/...
Source: Targeted Oncology - Category: Cancer & Oncology Source Type: research
ConclusionsThe present case supports the efficacy of immune checkpoint inhibition in mCRC with heterogeneity in MMR/microsatellite instability status. Clinical issues that may arise in these rare patients are discussed in detail.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
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