Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer

Background The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC). Research Question How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC? Methods We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution. Results A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], \u3c 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P \u3c .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples. Interpretation Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC

Predicting Survival of NSCLC Patients Treated with Immune Checkpoint Inhibitors: Impact and Timing of Immune-related Adverse Events and Prior Tyrosine Kinase Inhibitor Therapy

Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. Objective: To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. Methods: A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Results: Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value \u3c0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value \u3c0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value \u3c 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. Conclusion: The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs

Differentiating Peripherally-Located Small Cell Lung Cancer From Non-small Cell Lung Cancer Using a CT Radiomic Approach

Lung cancer can be classified into two main categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are different in treatment strategy and survival probability. The lung CT images of SCLC and NSCLC are similar such that their subtle differences are hardly visually discernible by the human eye through conventional imaging evaluation. We hypothesize that SCLC/NSCLC differentiation could be achieved via computerized image feature analysis and classification in feature space, as termed a radiomic model. The purpose of this study was to use CT radiomics to differentiate SCLC from NSCLC adenocarcinoma. Patients with primary lung cancer, either SCLC or NSCLC adenocarcinoma, were retrospectively identified. The post-diagnosis pre-treatment lung CT images were used to segment the lung cancers. Radiomic features were extracted from histogram-based statistics, textural analysis of tumor images and their wavelet transforms. A minimal-redundancy-maximal-relevance method was used for feature selection. The predictive model was constructed with a multilayer artificial neural network. The performance of the SCLC/NSCLC adenocarcinoma classifier was evaluated by the area under the receiver operating characteristic curve (AUC). Our study cohort consisted of 69 primary lung cancer patients with SCLC (n = 35; age mean ± SD = 66.91± 9.75 years), and NSCLC adenocarcinoma (n = 34; age mean ± SD = 58.55 ± 11.94 years). The SCLC group had more male patients and smokers than the NSCLC group (P \u3c 0.05). Our SCLC/NSCLC classifier achieved an overall performance of AUC of 0.93 (95% confidence interval = [0.85, 0.97]), sensitivity = 0.85, and specificity = 0.85). Adding clinical data such as smoking history could improve the performance slightly. The top ranking radiomic features were mostly textural features. Our results showed that CT radiomics could quantitatively represent tumor heterogeneity and therefore could be used to differentiate primary lung cancer subtypes with satisfying results. CT image processing with the wavelet transformation technique enhanced the radiomic features for SCLC/NSCLC classification. Our pilot study should motivate further investigation of radiomics as a non-invasive approach for early diagnosis and treatment of lung cancer

Precision Medicine and Actionable Alterations in Lung Cancer: A Single Institution Experience

OBJECTIVES: Oncology has become more reliant on new testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians and researchers. However, to take advantage of vital clinical and research data for precision medicine, we must initially make an effort to create an infrastructure for the collection, storage, and utilization of this information with uniquely designed disease-specific registries that could support the collection of a large number of patients. MATERIALS AND METHODS: In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry. RESULTS: Of the 415 patients with lung adenocarcinoma, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The most common actionable alterations were identified in EGFR (n = 177/415 [42.7%]), ALK (n = 28/377 [7.4%]), and BRAF V600E (n = 7/288 [2.4%]). There was also a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 wild-type patients with a median OS of 26.0 months (P CONCLUSION: The use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes

Evaluation of Somatic Mutations in Solid Metastatic Pan-Cancer Patients

Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations in the mutually exclusive gene pair APC and CDKN2A showed an opposite effect on the overall survival. However, patients with CDKN2A mutations showed significantly shorter OS (HR: 1.72, 95% CI: 1.34–2.21, p \u3c 0.001) after adjusting for cancer type, age at diagnosis, and sex. Five-year post metastatic diagnosis survival analysis showed a significant improvement in OS (median survival 28 and 43 months in pre-2015 and post-2015 metastatic diagnosis, respectively, p = 0.00021) based on the year of metastatic diagnosis. Although the use of targeted therapies after metastatic diagnosis prolonged OS, the benefit was not statistically significant. However, longer five-year progression-free survival (PFS) was significantly associated with targeted therapy use (median 10.9 months (CI: 9.7–11.9 months) compared to 9.1 months (CI: 8.1–10.1 months) for non-targeted therapy, respectively, p = 0.0029). Our results provide a clinically relevant overview of the complex molecular landscape and survival mechanisms in metastatic solid cancers

Advancing an interdisciplinary framework to study seed dispersal ecology

Although dispersal is generally viewed as a crucial determinant for the fitness of any organism, our understanding of its role in the persistence and spread of plant populations remains incomplete. Generalizing and predicting dispersal processes are challenging due to context dependence of seed dispersal, environmental heterogeneity and interdependent processes occurring over multiple spatial and temporal scales. Current population models often use simple phenomenological descriptions of dispersal processes, limiting their ability to examine the role of population persistence and spread, especially under global change. To move seed dispersal ecology forward, we need to evaluate the impact of any single seed dispersal event within the full spatial and temporal context of a plant’s life history and environmental variability that ultimately influences a population’s ability to persist and spread. In this perspective, we provide guidance on integrating empirical and theoretical approaches that account for the context dependency of seed dispersal to improve our ability to generalize and predict the consequences of dispersal, and its anthropogenic alteration, across systems. We synthesize suitable theoretical frameworks for this work and discuss concepts, approaches and available data from diverse subdisciplines to help operationalize concepts, highlight recent breakthroughs across research areas and discuss ongoing challenges and open questions. We address knowledge gaps in the movement ecology of seeds and the integration of dispersal and demography that could benefit from such a synthesis. With an interdisciplinary perspective, we will be able to better understand how global change will impact seed dispersal processes, and potential cascading effects on plant population persistence, spread and biodiversity

The Sudden Dominance of blaCTX–M Harbouring Plasmids in Shigella spp. Circulating in Southern Vietnam

Shigellosis is a disease caused by bacteria belonging to Shigella spp. and is a leading cause of bacterial gastrointestinal infections in infants in unindustrialized countries. The Shigellae are dynamic and capable of rapid change when placed under selective pressure in a human population. Extended spectrum beta lactamases (ESBLs) are enzymes capable of degrading cephalosporins (a group of antimicrobial agents) and the genes that encode them are common in pathogenic E. coli and other related organisms in industrialized countries. In southern Vietnam, we have isolated multiple cephalosporin-resistant Shigella that express ESBLs. Furthermore, over two years these strains have replaced strains isolated from patients with shigellosis that cannot express ESBLs. Our work describes the genes responsible for this characteristic and we investigate one of the elements carrying one of these genes. These finding have implications for treatment of shigellosis and support the growing necessity for vaccine development. Our findings also may be pertinent for other countries undergoing a similar economic transition to Vietnam's and the corresponding effect on bacterial populations

Employing plant functional groups to advance seed dispersal ecology and conservation

Seed dispersal enables plants to reach hospitable germination sites and escape natural enemies. Understanding when and how much seed dispersal matters to plant fitness is critical for understanding plant population and community dynamics. At the same time, the complexity of factors that determine if a seed will be successfully dispersed and subsequently develop into a reproductive plant is daunting. Quantifying all factors that may influence seed dispersal effectiveness for any potential seed-vector relationship would require an unrealistically large amount of time, materials and financial resources. On the other hand, being able to make dispersal predictions is critical for predicting whether single species and entire ecosystems will be resilient to global change. Building on current frameworks, we here posit that seed dispersal ecology should adopt plant functional groups as analytical units to reduce this complexity to manageable levels. Functional groups can be used to distinguish, for their constituent species, whether it matters (i) if seeds are dispersed, (ii) into what context they are dispersed and (iii) what vectors disperse them. To avoid overgeneralization, we propose that the utility of these functional groups may be assessed by generating predictions based on the groups and then testing those predictions against species-specific data. We suggest that data collection and analysis can then be guided by robust functional group definitions. Generalizing across similar species in this way could help us to better understand the population and community dynamics of plants and tackle the complexity of seed dispersal as well as its disruption