scholarly journals ctDNA Clearance and Radiographic Resolution of Disease in Response to Dual Checkpoint Inhibition in Metastatic Microsatellite Stable Colorectal Cancer with a High Tumor Mutation Burden

2021 ◽  
pp. 849-853
Author(s):  
Charles J. Schneider ◽  
Michael Krainock ◽  
Allyson Koyen Malashevich ◽  
Meenakshi Malhotra ◽  
Perry Olshan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lymph Node ◽  
Ct Scan ◽  
Circulating Tumor Dna ◽  
Therapeutic Benefit ◽  
Tumor Mutation Burden ◽  
Early Treatment Response ◽  
Mutation Burden ◽  
Disease Present

Immunotherapy (IO) has increasingly been demonstrated to provide therapeutic benefit to patients with metastatic colorectal cancer (mCRC). However, only a subset of mCRC tumors respond to IO. Monitoring response with tumor biomarkers like carcinoembryonic antigen (CEA) has been challenging in patients with microsatellite stable (MSS) mCRC due to low expression of CEA (CEA/lo). Noninvasive blood-based biomarkers such as circulating tumor DNA (ctDNA) can inform early treatment response and augment radiographic monitoring. We describe a case study of a patient with chemotherapy-refractory CEA/lo MSS mCRC, with metastatic disease present in a cardiophrenic lymph node. The patient was given 2 cycles of combination IO (ipilimumab/nivolumab). Response was monitored by ctDNA using a multiplex PCR next-generation sequencing assay, CEA, and CT scan. After IO administration, ctDNA levels rapidly declined, becoming undetectable. This was concurrent with radiographic resolution of the lymph node metastasis. Serial monitoring of CEA during this same period was uninformative, with no significant changes observed. Significant decline in ctDNA identified metastatic response to IO in a patient with CEA/lo, MSS mCRC and was concurrently validated by CT scan. This case study provides evidence that ctDNA can be used as a prospective surrogate for radiographic tumor response.

Efficacy of PD-1 Blockade in Refractory Microsatellite-Stable Colorectal Cancer With High Tumor Mutation Burden

2019 ◽  
Vol 18 (4) ◽  
pp. 307-309
Author(s):  
Jun Gong ◽  
Mandy D. Robertson ◽  
Edward Kim ◽  
Marwan Fakih ◽  
Alexa B. Schrock ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden

Correlation of negative PD-L1 expression with TMB-H and MSI-H rates.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13162-e13162
Author(s):  
Jun Dong ◽  
Xiaoni Zhang ◽  
Hongyue Qu ◽  
Shifu Chen ◽  
Ziyang Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Cancer Colorectal ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Sequencing Library ◽  
Expression Evaluation ◽  
L1 Protein ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e13162 Background: PD-L1 protein expression, tumor mutation burden (TMB) and microsatellite instability (MSI) are majorbiomarkers for PD-1/PD-L1 blockade therapy for solid tumors. We designed a study to evaluate the relevance of these biomarkers. Methods: From April 2018 to December 2018, 197 patients with lung cancer, colorectal cancer, andgastric cancer wereprospectivelyenrolled.Foreachpatient, afreshfrozentissuesampleor FFPE sample wascollected. Each sample was dividedinto3parts for next-generation sequencing (NGS), PD-L1 protein expression evaluation and MSI evaluation. The sequencing library was captured using a 605-gene panel and sequenced at~5,000×coverage.Mutationsinthe NGS datawereidentified,andTMB was then calculated. The PD-L1 protein expression was analyzedby immunohistochemistry, and the MSI was evaluated using a multiplex PCR comprising 5 loci(NR27, NR21, NR24, BAT25, and BAT26). Results: 18.78% (37/197) were detected with high PD-L1 expression (positive tumor cells ≥50%); 5.08% (10/197) ofpatientswere diagnosed as MSI-H; 4.06% (8/197) of patients had a TMB-H (TMB > 20 mutations/Mb). Among the 37 PD-L1 positive patients, only one patientwith TMB-Hwas detected, and 3patients were MSI-H. In contrast, among the 14 patients with PD-L1 expression less than 1%, 8patients (57.14%) were detected with TMB-H or MSI-H (3 with TMB-H only, 3 with MSI-H only, and 2 with both). In addition, among all the 10patients with MSI-H, 4patients had TMB-H, indicating that MSI-H may be partly associatedwith high TMB. Conclusions: From our preliminary result, PD-L1 protein expression negative patients tend to have higher rates of TMB-H and MSI-H. For patients with negative PD-L1 expression, it issuggested to evaluate its TMB level and MSI status. This study is ongoing, and more data will be collected to verify these findings.

scholarly journals MUC4 mutation correlates with tumor mutation burden and the immune microenvironment in colorectal cancer

2020 ◽  
Author(s):  
Ting Li ◽  
Wenjia Hui ◽  
Halina Halike ◽  
Feng Gao
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Gene Mutations ◽  
Cancer Genome ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Mutant Genes

Abstract Background: Immunotherapy is a new strategy for Colorectal cancer (CRC) treatment. Tumor mutation burden (TMB) may act as an emerging biomarker for predicting responses to immunotherapy. Nevertheless, no studies investigate if these gene mutations correlate to TMB and tumor-infiltrating immune cells. Methods: Somatic mutation data for CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Then, we investigated the relationship between these mutant genes, TMB and overall survival outcomes. GSEA analysis was performed to explore the underlying mechanism of mutant gene. Finally, we further verified the connection between gene mutations and immune response.Results: We identified 17 common mutant genes shared by both two cohorts. Further analysis found that MUC4 mutation was strongly related to higher TMB and predicted a poorer prognosis. Moreover, functional enrichment analysis of samples with MUC4 mutation revealed that they were involved in regulating the natural killer cell mediated cytotoxicity signaling pathway. Significant changes in the proportion of the immune cells of CD8 T cells, activated NK cells, M1 macrophages and resting memory CD4 T cells were observed using the CIBERSORT algorithm. Conclusions: Our research revealed that MUC4 mutation significantly correlated with increased TMB, a worse prognosis and modulating the immune microenvironment, which may be considered a biomarker to predict the outcome of the immune response in colorectal cancer.

PD-1 antibody combined with COX inhibitor in MSI-h/dMMR or high TMB colorectal cancer: A single arm phase II study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS729-TPS729
Author(s):  
Zehua Wu ◽  
Yanhong Deng ◽  
Jianwei Zhang ◽  
Huabin Hu ◽  
Yue Cai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Objective Response ◽  
Progression Free Survival ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cox Inhibitor ◽  
Duration Of Response ◽  
Colorectal Cancer Patients ◽  
To Receive

TPS729 Background: Programmed death protein 1 (PD-1) antibody has been to approved in patients with MSI-H/dMMR colorectal cancer and has achieved significant efficacy. It's also reported that tumor mutation burden (TMB) may be another biomarker of response to PD-1 therapy. But there were about 50-60% of patients with MSI-H/dMMR were insensitive to PD-1 antibody. Cyclooxygenase (COX) inhibitor has been proved to prevent adenomas in colorectal and it is safe for most of the patients. Preclinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors. Methods: This single arm, phase II trial will assess the efficacy and safety of combination of PD-1 antibody and COX inhibitor in patients with MSI-H/dMMR or high tumor mutation burden colorectal cancer. Patients diagnosed with MSI-H/dMMR or high tumor mutation burden colorectal cancer which was unresectable and had at least one lines of chemotherapy fail or refuse to receive chemotherapy were eligible. Eligible patients were assigned to receive BAT1306 (100 mg once every three weeks) plus COX inhibitor (aspirin 200 mg every day or Celebrex 400 mg every day). Chest/abdomen/pelvic CT with IV contrast will be performed to assess clinical response. The primary endpoint is objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety and duration of response. Adverse events are graded per NCI CTCAE v4.03 and will be monitored for 30 days after treatment. Patients will be followed for survival. Planned enrollment is 54 patients. Clinical trial information: NCT03638297.

NTRK fusion positive colorectal cancer as a unique subset of CRC with high tumor mutation burden and microsatellite instability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3544-3544
Author(s):  
Hui WANG ◽  
Qiuxiang Ou ◽  
Xue Wu ◽  
Misako Nagasaka ◽  
Sai-Hong Ignatius Ou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Neurotrophin Receptor ◽  
Driver Mutations ◽  
Fusion Partner ◽  
Tumor Mutation Burden ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Genetic Features ◽  
Colorectal Cancer Patients

3544 Background: Neurotrophin receptor tyrosine kinase ( NTRK) gene fusions are rare but actionable oncogenic drivers that are present in a wide variety of solid tumors. This study aims to identify the frequency and the clinicopathologic and genetic features of NTRK-driven colorectal cancers (CRC). Methods: Colonic and rectal tumor DNA specimen from colorectal cancer patients submitted for molecular profiling at a CLIA-certified genomics laboratory in China that performed NTRK1/2/3 fusion detection by hybridization-based targeted next generation sequencing (NGS) were retrospectively reviewed. Patients’ demographic, clinical characteristics, and treatment history were retrieved from the database for further evaluation. Results: A total of 2,519 unique Chinese colorectal cancer cases were profiled from April 2016 to May 2020, and 17 NTRK+ fusion events were identified (0.7%, 17/2,519) consisting of 14 cases of NTRK1+ and 3 cases of NTRK3+ fusions. Furthermore, thirteen out of 17 NTRK+ CRC tumors (76%) were microsatellite instability-high (MSI-H) tumors, a much higher rate than that of the molecularly unselected CRC population (8%) or NTRK+ non-CRC tumors ( < 1%). NTRK+ CRC patients also had increased tumor mutation burden (median TMB = 65 mut/MB) compared to that of non- NTRK+ CRC (median TMB = 7.7 mut/MB) or NTRK+ non-CRC tumors (median TMB = 4 mut/MB). POLE/POLD1 mutations were also enriched in NTRK+ CRC (8/17, 47%) relative to molecularly unstratified CRC patients (8%) with over half carrying concurrent POLE and POLD1 mutations. TPM3 was the most common fusion partner of NTRK1 (78%, N = 14), followed by LMNA and TRP. Three NTRK3+ CRC were identified (ETV6-NTRK3, RUNX1-NTRK3, CSNK1G1-NTRK3). RNF43 (71%) was the most frequently mutated gene and the aberrations of RNF43 and ARID1 were significantly enriched in MSI-positive NTRK+ tumors as compared to the MSS NTRK+ subgroup. TP53 (53%) and APC (35%) aberrations frequently co-occurred with NTRK fusions, whereas the majority of the NTRK+ cohort were RAS/BRAF wildtype, except in one case that an oncogenic KRAS Q61R variant co-occurred with RUNX1-NTRK3. Conclusions: NTRK+ colorectal cancer is rare. In addition to the absence of canonical driver mutations, NTRK+ tumors demonstrated increased tumor mutation burden, higher frequency of microsatellite instability, and an enrichment of POLE/POLD1 mutations relative to molecularly unselected CRC population.

Abstract 3975: Tumor mutation burden and microsatellite instability in colorectal cancer

2019 ◽  
Author(s):  
Francesca Fenizia ◽  
Raffaella Pasquale ◽  
Cristin Roma ◽  
Francesca Bergantino ◽  
Anna Maria Rachiglio ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Tumor Mutation Burden ◽  
Mutation Burden

scholarly journals P1.04-47 Tumor Mutation Burden Through Hybrid Capture – Circulating Tumor DNA May Predict Response to Immunotherapy in NSCLC

2019 ◽  
Vol 14 (10) ◽  
pp. S459 ◽  
Author(s):  
R. Grinberg ◽  
L. Roisman ◽  
S. Geva ◽  
M. Lefterova ◽  
K. Quinn ◽  
...  
Keyword(s):  
Circulating Tumor Dna ◽  
Tumor Mutation Burden ◽  
Hybrid Capture ◽  
Mutation Burden ◽  
Tumor Dna

scholarly journals Tumor Mutation Burden and Prognosis in Patients with Colorectal Cancer Treated with Adjuvant Fluoropyrimidine and Oxaliplatin

2019 ◽  
Vol 25 (20) ◽  
pp. 6141-6147 ◽  
Author(s):  
Dae-Won Lee ◽  
Sae-Won Han ◽  
Jeong Mo Bae ◽  
Hoon Jang ◽  
Hyojun Han ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden

scholarly journals A six-gene signature related with tumor mutation burden for predicting lymph node metastasis in breast cancer

2021 ◽  
Vol 10 (5) ◽  
pp. 2229-2246
Author(s):  
Cenzhu Wang ◽  
Kun Xu ◽  
Fei Deng ◽  
Yiqiu Liu ◽  
Jinyi Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Gene Signature ◽  
Tumor Mutation Burden ◽  
Node Metastasis ◽  
Mutation Burden
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