Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients

Gene expression; Immunotherapy; Malignant pleural mesotheliomaExpresión génica; Inmunoterapia; Mesotelioma pleural malignoExpressió gènica; Immunoteràpia; Mesotelioma pleural maligneMPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.The study was partially funded by Project PREDICT-Meso (GEACC19003CED), funded by Fundación AECC

The Role of <i>TP53</i> Mutations in <i>EGFR</i>-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including NSCLC. TP53 mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. TP53 mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different TP53 mutations and responses to Epidermal Growth Factor Receptor (EGFR) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of TP53 mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) EGFR-directed, investigating the possible mechanisms of TP53 mutants within the cellular compartments. We also discuss the role of the TP53 mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment

Real-World Outcomes and Treatments Patterns Prior and after the Introduction of First-Line Immunotherapy for the Treatment of Metastatic Non-Small Cell Lung Cancer

This study provides insights into the treatment use and outcomes of metastatic non-small cell lung cancer (NSCLC) patients in a real-world setting prior to and after the availability of immuno-oncology (IO) regimens in the first line (1L)

Wide Next-Generation Sequencing Characterization of Young Adults Non-Small-Cell Lung Cancer Patients

Simple Summary Molecular characterization of advanced non-small-cell lung cancer (NSCLC) is mandatory before any treatment decision making. Next-generation sequencing (NGS) approaches represent the best strategy in this context. In our study, we analyzed a case series of young (under 65 years old) NSCLC patients with a wide NGS gene panel assay. The most frequent altered genes were TP53 (64.55%), followed by KRAS (44.1%), STK11 (26.9%), CDKN2A (21.5%), CDKN2B (14.0%), EGFR (16.1%), and RB1 (10.8%). Tumor mutational burden (TMB) was also evaluated considering different cut-offs, and we found a significant association between TMB and STK11 and KRAS mutations. Conversely, EGFR and EML4-ALK alterations were more frequently found in tumors with low TMB. We compared results obtained from this approach with those obtained from a single or few genes approach, observing perfect concordance of the results. Molecular characterization of advanced non-small-cell lung cancer (NSCLC) is mandatory before any treatment decision making. Next-generation sequencing (NGS) approaches represent the best strategy in this context. The turnaround time for NGS methodologies and the related costs are becoming more and more adaptable for their use in clinical practice. In our study, we analyzed a case series of young (under 65 years old) NSCLC patients with a wide NGS gene panel assay. The most frequent altered genes were TP53 (64.55%), followed by KRAS (44.1%), STK11 (26.9%), CDKN2A (21.5%), CDKN2B (14.0%), EGFR (16.1%), and RB1 (10.8%). Tumor mutational burden (TMB) was also evaluated. Considering the cut-off of 10 mut/Mb, 62 (68.9%) patients showed a TMB = 10 mut/Mb. STK11 and KRAS mutations were significantly associated with a higher TMB (p = 0.019 and p = 0.004, respectively). Conversely, EGFR and EML4-ALK alterations were more frequently found in tumors with low TMB (p = 0.019 and p < 0.001, respectively). We compared results obtained from this approach with those obtained from a single or few genes approach, observing perfect concordance of the results

Wide Next-Generation Sequencing Characterization of Young Adults Non-Small-Cell Lung Cancer Patients

Molecular characterization of advanced non-small-cell lung cancer (NSCLC) is mandatory before any treatment decision making. Next-generation sequencing (NGS) approaches represent the best strategy in this context. The turnaround time for NGS methodologies and the related costs are becoming more and more adaptable for their use in clinical practice. In our study, we analyzed a case series of young (under 65 years old) NSCLC patients with a wide NGS gene panel assay. The most frequent altered genes were TP53 (64.55%), followed by KRAS (44.1%), STK11 (26.9%), CDKN2A (21.5%), CDKN2B (14.0%), EGFR (16.1%), and RB1 (10.8%). Tumor mutational burden (TMB) was also evaluated. Considering the cut-off of 10 mut/Mb, 62 (68.9%) patients showed a TMB &lt; 10 mut/Mb, whereas 28 (31.1%) showed a TMB &ge; 10 mut/Mb. STK11 and KRAS mutations were significantly associated with a higher TMB (p = 0.019 and p = 0.004, respectively). Conversely, EGFR and EML4-ALK alterations were more frequently found in tumors with low TMB (p = 0.019 and p &lt; 0.001, respectively). We compared results obtained from this approach with those obtained from a single or few genes approach, observing perfect concordance of the results

Dynamic changes in circulating tumor DNA assessed by shallow whole‐genome sequencing associate with clinical efficacy of checkpoint inhibitors in NSCLC

Immune checkpoint inhibitors (ICIs) targeting the PD‐1/PD‐L1 axis are the main therapeutic option for patients with advanced non‐small cell lung cancer (NSCLC) without a druggable oncogenic alteration. Nevertheless, only a portion of patients benefit from this type of treatment. Here, we assessed the value of shallow whole‐genome sequencing (sWGS) on plasma samples to monitor ICI benefit. We applied sWGS on cell‐free DNA (cfDNA) extracted from plasma samples of 45 patients with metastatic NSCLC treated with ICIs. Over 150 samples were obtained before ICI treatment initiation and at several time points throughout treatment. From sWGS data, we computed the tumor fraction (TFx) and somatic copy number alteration (SCNA) burden and associated them with ICI benefit and clinical features. TFx at baseline correlated with metastatic lesions at the bone and the liver, and high TFx (≥ 10%) associated with ICI benefit. Moreover, its assessment in on‐treatment samples was able to better predict clinical efficacy, regardless of the TFx levels at baseline. Finally, for a subset of patients for whom SCNA burden could be computed, increased burden correlated with diminished benefit following ICI treatment. Thus, our data indicate that the analysis of cfDNA by sWGS enables the monitoring of two potential biomarkers—TFx and SCNA burden—of ICI benefit in a cost‐effective manner, facilitating multiple serial‐sample analyses. Larger cohorts will be needed to establish its clinical potential