scholarly journals A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice

Open Medicine ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. 53-60
Author(s):  
Hanfei Guo ◽  
Lei Qian ◽  
Xiao Chen ◽  
Yuguang Zhao ◽  
Wei Song ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Lung Adenocarcinoma ◽  
Driver Genes ◽  
Cancer Driver ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Clinical Benefits ◽  
Hyperprogressive Disease ◽  
Low Expression

Abstract Clinical treatment is challenging for elderly patients with lung cancer who cannot tolerate chemotherapy, do not have cancer driver genes, and have low expression of PD-L1. Since these patients are usually excluded from clinical studies, evidence-based medicine supporting the use of immunotherapy is lacking. Considering the potentially limited clinical benefits and high associated risk of hyperprogressive disease, determining an appropriate treatment is an urgent clinical challenge. We report a 71 year-old male patient diagnosed with advanced lung adenocarcinoma lacking key driving genes (EGFR, ALK, and ROS-1), and low expression of PD-L1 on tumor cells (10–15%). The tumor tissue showed a low level of microsatellite instability, low tumor mutational burden, and no DNA mismatch repair deficiency on whole-exome sequencing (WES). However, a high blood tumor mutational burden was detected. After considering the biomarkers of therapeutic effect and ruling out the risk of hyperprogressive disease, pembrolizumab 200 mg was administered every 3 weeks for a year (17 cycles). The disease remained stable for >39 months, and adverse effects were mild and well-tolerated. Therefore, a comprehensive biomarker evaluation, especially in elderly patients lacking driving genes, is essential. Liquid biopsy technology and WES may be useful for overcoming the limitations of tissue biopsy.

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

scholarly journals 71 Tumors with higher heterogeneity were associated with superior survival outcome amongst stage I lung cancer patients with low tumor mutational burden (TMB)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A79-A79
Author(s):  
Stanislav Fridland ◽  
Young Kwang Chae
Keyword(s):  
Tumor Heterogeneity ◽  
Immune Cell ◽  
Cancer Genomics ◽  
Stage I ◽  
P Value ◽  
Driver Genes ◽  
Mutational Burden ◽  
Cell Enrichment ◽  
Tumor Mutational Burden ◽  
Adults And Children

BackgroundTumor mutational burden (TMB) has been shown to predict response to immune checkpoint inhibitors.1 Furthermore, the FDA has approved the use of TMB as a biomarker for response to pembrolizumab in solid tumors.2 Simultaneously, the relationship between tumor heterogeneity and outcome has been studied across a range of cancer indications and has shown predictive value.3 For Lung Squamous Cell Carcinoma (LUSC) the utility of heterogeneity metrics has not been established. To study this relationship we used both TMB and tumor heterogeneity to stratify patients, compare outcomes, explore differences in immune cell enrichment, and predict driver genes.MethodsWe obtained Tumor Cancer Genome Atlas (TCGA) LUSC SNP, CNV, and RNASeq data from the GDC Data Portal4 and clinical data from the PanCancer Atlas dataset through cBioPortal.5 TMB was calculated by dividing the number of mutations by 38 to yield a mut/Mb value. To estimate tumor heterogeneity we ran PyClone, an algorithm that estimates the number of tumor clones.6 PyClone uses a random seed and output for the same sample may differ. We ran each sample in triplicate on three separate days yielding 9 runs per sample, yielding an average PyClone clone number. Clones with >2 mutations were counted. Using p-value minimization we chose 5 for the TMB cutoff and 4.6 for the PyClone cutoff. This yielded 4 groups: HTHP, HTLP, LTHP, and LTLP, where H - high, L- low, T-TMB, and P-Pyclone. Immune cell enrichment analysis was accomplished with ssGSEA via the GenePattern platform.7 Driver gene prediction was performed with OncoDriveClust8 via the R package maftools.9ResultsA statistically significant difference was found in progression free survival (PFS) between stage I LTHP (LTHPI, N = 15) and stage I LTLP (LTLPI, N = 77) patients (51.27 months vs. 25.4 months, p-value = 0.0059). Intriguingly, highly heterogeneous tumors revealed superior survival outcomes compared to less heterogeneous tumors in this subgroup. LTLPI patients were enriched for immature B cells, regulatory T cells, and myeloid derived suppressor cells (figure 1). Three driver genes were predicted for the LTLPI cohort (NFE2L2, PIK3CA, and TP53), while none were predicted for the LTHPI cohort.Abstract 71 Figure 1Immune Cell Gene Set EnrichmentConclusionsContrary to previous literature, superior survival outcomes were observed in high tumor heterogeneity, low TMB Stage I LUSC patients. Early stage patients can be stratified using heterogeneity metrics like PyClone. Given the presence of specific driver genes and an immunosuppressive tumor microenvironment, this population warrants further investigation for therapeutic implications.AcknowledgementsThis research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University’s high performance computing facility, with the purpose to advance research in genomics.Trial RegistrationN/AReferencesSamstein RM, Lee C-H, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nature Genetics 2019;51(2):202–6.Center for Drug Evaluation and Research. FDA approves pembrolizumab for adults and children With TMB-H solid tu [Internet]. U.S. Food and Drug Administration. FDA; [cited 2021 Jul 28]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumorsMorris LGT, Riaz N, Desrichard A, Şenbabaoğlu Y, Hakimi AA, Makarov V, et al. Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival. Oncotarget 2016;7(9):10051–63.GDC. [cited 2021Jul28]. Available from: https://portal.gdc.cancer.gov/cBioPortal for cancer genomics [Internet]. cBioPortal for Cancer Genomics. [cited 2021Jul28]. Available from: https://www.cbioportal.org/Roth A, Khattra J, Yap D, Wan A, Laks E, Biele J, et al. PyClone: Statistical inference of CLONAL population structure in cancer. Nature Methods 2014;11(4):396–8.GenePattern [Internet]. GenePattern sign in. [cited 2021Jul28]. Available from: https://cloud.genepattern.org/gp/pages/index.jsfTamborero D, Gonzalez-Perez A, Lopez-Bigas N. OncodriveCLUST: Exploiting the Positional clustering of somatic mutations to identify CANCER GENES. Bioinformatics. 2013;29(18):2238–44.Mayakonda A, Lin D-C, Assenov Y, Plass C, Koeffler HP. Maftools: Efficient and comprehensive analysis of somatic variants in cancer. Genome Research 2018;28(11):1747–56.Ethics ApprovalN/AConsentN/A

scholarly journals MA19.05 Difference of Tumor Mutational Burden Is Associated with Distinct Immune Microenviroment in the T Cell-Inflamed Lung Adenocarcinoma

2018 ◽  
Vol 13 (10) ◽  
pp. S423
Author(s):  
T. Karasaki ◽  
K. Kitano ◽  
K. Nagayama ◽  
J. Nitadori ◽  
M. Sato ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Adenocarcinoma ◽  
Mutational Burden ◽  
Tumor Mutational Burden

scholarly journals MiRNA expression patterns are associated with tumor mutational burden in lung adenocarcinoma

2019 ◽  
Vol 8 (10) ◽  
pp. e1629260
Author(s):  
Yufeng Lv ◽  
Zhong Huang ◽  
Yan Lin ◽  
Yuan Fang ◽  
Zhichao Chen ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mirna Expression ◽  
Expression Patterns ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma

Gut ◽  
2020 ◽  
pp. gutjnl-2020-320730 ◽  
Author(s):  
Robert C Grant ◽  
Robert Denroche ◽  
Gun Ho Jang ◽  
Klaudia M Nowak ◽  
Amy Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mismatch Repair ◽  
Exact Matching ◽  
Driver Genes ◽  
Cancer Driver ◽  
Dna Mismatch ◽  
Clinical Cohort ◽  
Pancreatic Cancers ◽  
Repair Deficiency ◽  
Basket Trials

ObjectiveTo describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).DesignWe identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)).Results12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity.ConclusionsMMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.

scholarly journals A novel NCOR2-NTRK1 fusion detected in a patient of lung adenocarcinoma and response to larotrectinib: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lei Zhang ◽  
Huanhuan Liu ◽  
Ye Tian ◽  
Huina Wang ◽  
Xueying Yang
Keyword(s):  
Targeted Therapy ◽  
Lung Adenocarcinoma ◽  
Ct Scan ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Molecular Profiling ◽  
Case Presentation ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Breakpoint Location

Abstract Background The identification of NTRK fusions in tumours has become critically important due to the actionable events predictive of response to TRK inhibitor. It is not clear whether the NTRK breakpoint location is different for response to targeted therapy and NTRK fusions affects the efficacy of immunotherapy. Case presentation Here we reported a 60-year-old female diagnosed with advanced lung adenocarcinoma. NGS-based molecular profiling identified a novel NCOR2-NTRK1 fusion and high tumor mutational burden (TMB) (58.58 mutations/Mb) in this case. Additionally, program death-ligand 1 (PD-L1) expression was detected in 20–30% of the tumor cells by immunohistochemical (IHC) staining. The patient received treatment with anti-PD-1 immune checkpoint inhibitor of camrelizumab. After two cycles of treatment, the CT scan showed some tumor nodules were still enlarged, indicating disease progression. She was then changed to TRK inhibitor larotrectinib. One month later, the CT scan showed the volume of some lesions started to decrease, and no metastasis lesions were found. The patient then continued the administration of larotrectinib, and some lesion sizes were significantly reduced or even disappeared in the next few months. Currently, this patient is still alive. Conclusions Altogether, this report provided a new driver of lung adenocarcinoma expanded the mutational spectrum of NTRK1 fusion variants and suggested using larotrectinib as the targeted therapy is more effective than anti-PD-1 inhibitor in lung adenocarcinoma harboring with NTRK fusion, positive PD-L1 expression, and high TMB simultaneously.

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