Immune checkpoint blockade improves survival in a subset of patients with non-small-cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. ...Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited.
We performed comprehensive flow cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next-generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC).
Cytometric profiling identified an immunologically "hot" cluster with abundant CD8
T cells expressing high levels of PD-1 and TIM-3 and an immunologically "cold" cluster with lower relative abundance of CD8
T cells and expression of inhibitory markers. The "hot" cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the "hot" cluster. Additionally, approximately 20% of cases had high B cell infiltrates with a subset producing IL-10.
Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer.
The Robert A. and Renée E. Belfer Family Foundation, Expect Miracles Foundation, Starr Cancer Consortium, Stand Up to Cancer Foundation, Conquer Cancer Foundation, International Association for the Study of Lung Cancer, National Cancer Institute (R01 CA205150), and the Damon Runyon Cancer Research Foundation.
Plasma cell-free DNA (cfDNA) analysis is increasingly used clinically for cancer genotyping, but may lead to incidental identification of germline-risk alleles. We studied
T790M mutations in ...non-small cell lung cancer (NSCLC) toward the aim of discriminating germline and cancer-derived variants within cfDNA.
Patients with
-mutant NSCLC, some with known germline
T790M, underwent plasma genotyping. Separately, deidentified genomic data and buffy coat specimens from a clinical plasma next-generation sequencing (NGS) laboratory were reviewed and tested.
In patients with germline T790M mutations, the T790M allelic fraction (AF) in cfDNA approximates 50%, higher than that of
driver mutations. Review of plasma NGS results reveals three groups of variants: a low-AF tumor group, a heterozygous group (∼50% AF), and a homozygous group (∼100% AF). As the
driver mutation AF increases, the distribution of the heterozygous group changes, suggesting increased copy number variation from increased tumor content. Excluding cases with high copy number variation, mutations can be differentiated into somatic variants and incidentally identified germline variants. We then developed a bioinformatic algorithm to distinguish germline and somatic mutations; blinded validation in 21 cases confirmed a 100% positive predictive value for predicting germline T790M. Querying a database of 31,414 patients with plasma NGS, we identified 48 with germline T790M, 43 with nonsquamous NSCLC (
< 0.0001).
With appropriate bioinformatics, plasma genotyping can accurately predict the presence of incidentally detected germline risk alleles. This finding in patients indicates a need for genetic counseling and confirmatory germline testing.
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Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to ...osimertinib is a growing clinical challenge that is poorly understood.
To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.
Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.
Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.
Of the 143 patients evaluated, 41 (28 68% women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).
Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
We present a survey of the early evolution of 12 Type IIn supernovae (SNe IIn) at ultraviolet and visible light wavelengths. We use this survey to constrain the geometry of the circumstellar material ...(CSM) surrounding SN IIn explosions, which may shed light on their progenitor diversity. In order to distinguish between aspherical and spherical CSM, we estimate the blackbody radius temporal evolution of the SNe IIn of our sample, following the method introduced by Soumagnac et al. We find that higher-luminosity objects tend to show evidence for aspherical CSM. Depending on whether this correlation is due to physical reasons or to some selection bias, we derive a lower limit between 35% and 66% for the fraction of SNe IIn showing evidence for aspherical CSM. This result suggests that asphericity of the CSM surrounding SNe IIn is common-consistent with data from resolved images of stars undergoing considerable mass loss. It should be taken into account for more realistic modeling of these events.
We present a survey of the early evolution of 12 Type IIn supernovae (SNe IIn) in the Ultra-Violet (UV) and visible light. We use this survey to constrain the geometry of the circumstellar material ...(CSM) surrounding SN IIn explosions, which may shed light on their progenitor diversity. In order to distinguish between aspherical and spherical circumstellar material (CSM), we estimate the blackbody radius temporal evolution of the SNe IIn of our sample, following the method introduced by Soumagnac et al. We find that higher luminosity objects tend to show evidence for aspherical CSM. Depending on whether this correlation is due to physical reasons or to some selection bias, we derive a lower limit between 35% and 66% on the fraction of SNe IIn showing evidence for aspherical CSM. This result suggests that asphericity of the CSM surrounding SNe IIn is common - consistent with data from resolved images of stars undergoing considerable mass loss. It should be taken into account for more realistic modelling of these events.
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