Dataset Information

Higher Tumor Mutation Burden and Higher PD-L1 Activity Predicts the Efficacy of Immune Checkpoint Inhibitor Treatment in a Patient With Four Lung Cancers. A Case Report.

ABSTRACT: We experienced a patient who had four lung cancers with different pathological features, with the most advanced being diagnosed as pStage IIA. A month after the resection, the original lung cancer had metastasized to the lung and to the liver. Of the original lung cancers that were resected, the biggest adenocarcinoma of S3 showed 50 × 31 × 17 mm (invasion 50 mm) and pT2bN0M0 (pStage IIA) with epidermal growth factor receptor (EGFR) mutation (-) and anaplastic lymphoma kinase (ALK) translocation (-), but expression of programmed death ligand 1 (PD-L1) (+) tumor proportion score (TPS) 80%. The pleomorphic carcinoma showed 23 × 20 × 17 mm (invasion 23 mm) and pT1cN0M0 (pStage Ic) with EGFR (-), ALK (-), PD-L1 (+), TPS 95%. Tumor mutation burden (TMB), microsatellite instability (MSI), and structural chromosome aberration analysis by DNA microarray were performed. One hundred somatic mutations in the adenocarcinoma and 75 somatic mutations in the pleomorphic carcinoma were identified, which showed an extremely high mutation rate, although only 16 somatic mutations were common between the two cancers. Chromosomal structural aberrations differed greatly between the two cancers, but common aberrations were found in chromosomes 8 and 10 and partially common aberration in chromosomes 4, 14, 17, and X. These results indicated that each lung cancer originated from a common ancestor clone and developed on an individual molecular evolution. The patient received a single injection of pembrolizumab and 13 injections of atezolizumab. Immune checkpoint inhibitor treatment made metastatic pulmonary and liver lesions reduce in size and show as Partial response (PR). Multiple lung cancers with high PD-L1 activity tend to be TMB-high, reflecting rapid molecular evolution and relevance to the patient's response to immune checkpoint inhibitors. Genomic examination could help determine what had happened in multiple cancers on progression and provide useful data to patient treatment. Each lung cancer originated from a common ancestor clone and developed on an individual molecular evolution.

SUBMITTER: Usuda K

PROVIDER: S-EPMC7280536 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Higher Tumor Mutation Burden and Higher PD-L1 Activity Predicts the Efficacy of Immune Checkpoint Inhibitor Treatment in a Patient With Four Lung Cancers. A Case Report.

Usuda Katsuo K Niida Yo Y Iwai Shun S Funasaki Aika A Sekimura Atsushi A Motono Nozomu N Yamada Sohsuke S Uramoto Hidetaka H

Frontiers in oncology 20200602

We experienced a patient who had four lung cancers with different pathological features, with the most advanced being diagnosed as pStage IIA. A month after the resection, the original lung cancer had metastasized to the lung and to the liver. Of the original lung cancers that were resected, the biggest adenocarcinoma of S3 showed 50 × 31 × 17 mm (invasion 50 mm) and pT2bN0M0 (pStage IIA) with epidermal growth factor receptor (EGFR) mutation (-) and anaplastic lymphoma kinase (ALK) translocation ...[more]

PMID: 32582526

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Project description:ImportanceAlthough tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC).ObjectivesTo determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC.Design, setting, and participantsThis multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022.ExposuresTreatment with PD-1/PD-L1 inhibition without chemotherapy.Main outcomes and measuresAssociation of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsIn the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1-positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures.Conclusions and relevanceThese findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell-mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.

Project description:BackgroundThe prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies.ObjectivesThis study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies.DesignThis real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014-2018).MethodsTMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1-49%), and negative (<1%)). Data was curated from the electronic medical records.ResultsIn 388 evaluable patients, the most common diagnoses were B-cell non-Hodgkin lymphoma (NHL) (35%) and Philadelphia chromosome-negative myeloproliferative disorders (16%). Median TMB was 1.6 mutations/Mb (range, 0-46.83). Forty-eight patients (12%) had TMB ⩾10 mutations/Mb, 90% of which were B-cell or T-cell NHL. In 85 samples with available PD-L1 scores, 11 were high; 26, low; and 48, no tumor cell expression. PD-L1 TPS positive (⩾1%) was most common in T-cell NHL (7/9 (77%) cases) followed by B-cell NHL (21/51 (41%) cases). TMB ⩾4 mutations/Mb and PD-L1 score ⩾1% were significantly associated with shorter overall survival (OS) from diagnosis, with hazard ratio (HR) = 1.46 (p = 0.02, 95% confidence interval (CI) 1.05-2.03) and HR = 2.11 (p = 0.04, 95% CI 1.04-4.30), respectively; the relationship was more pronounced when PD-L1 ⩾50% versus <50% was used (HR = 2.80, p = 0.02, 95% CI 1.19-6.59). Higher TMB and higher PD-L1 positivity correlation were significant but weak (Pearson correlation coefficient R 2 = 0.04, p = 0.04).ConclusionTMB ⩾4 mutations/Mb and positive PD-L1 TPS are poor prognostic factors, correlating with shorter OS across hematologic malignancies.Trial registrationClinicalTrials.gov NCT02478931.

Project description:BACKGROUND:Immune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC. METHODS:Tumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria. RESULTS:Patients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03). CONCLUSIONS:Overall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.

Dataset Information

Higher Tumor Mutation Burden and Higher PD-L1 Activity Predicts the Efficacy of Immune Checkpoint Inhibitor Treatment in a Patient With Four Lung Cancers. A Case Report.

Publications

Higher Tumor Mutation Burden and Higher PD-L1 Activity Predicts the Efficacy of Immune Checkpoint Inhibitor Treatment in a Patient With Four Lung Cancers. A Case Report.

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