Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non-Small Cell Lung Cancer.

The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non-small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC. SIGNIFICANCE: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599.

Clinical and genomic features of Chinese lung cancer patients with germline mutations.

The germline mutation landscape in Chinese lung cancer patients has not been well defined. In this study, sequencing data of 1,021 cancer genes of 1,794 Chinese lung cancer patients was analyzed. A total of 111 pathogenic or likely pathogenic germline mutations were identified, significantly higher than non-cancer individuals (111/1794 vs. 84/10,588, p < 2.2e-16). BRCA1/2 germline mutations are associated with earlier onset age (median 52.5 vs 60 years-old, p = 0.008). Among 29 cancer disposition genes with germline mutations detected in Chinese cohort and/or TCGA lung cancer cohort, Only 11 from 29 genes are identified in both cohorts and BRCA2 mutations are significantly more common in Chinese cohort (p = 0.015). Chinese patients with germline mutations have different prevalence of somatic KRAS, MET exon 14 skipping and TP53 mutations compared to those without. Our findings suggest potential ethnic and etiologic differences between Western and Asian lung cancer patients.

Comprehensive evaluation of BRCA1/2 variant interpretation ability among laboratories in China.

High-quality interpretation of BRCA1/2 variants plays a critical role in the clinical practice of precision medicine. However, a comprehensive system to evaluate the quality and accuracy of variant interpretation has yet to be established. This study investigates the performance of an interpretation system in evaluating the capacities of BRCA1/2 interpretation among distinct laboratories in China. The evaluation system is based on a reference database that contains 750 different variants in BRCA1/2 Evaluation was performed among 41 laboratories in China. We classified their performance into five levels. Only level A was considered qualified. This level allows for a 0.3% error rate for clinical decision-related misinterpretation; 26 of 41 laboratories (63%) met the qualified standard, while 7 laboratories were at levels D and E, which indicated egregious mistakes and systemic problems in variant interpretation. Due to strict quality demands, the interpretation of several variants was amended, which largely influenced the quality rate. The number of qualified laboratories would decrease from 26 to 17 if those incorrect recommended interpretations were not corrected. This evaluation system provides a potential approach for standardisation of variant interpretation and lowers the discordance of variant interpretation between different laboratories. A well-designed interpretation ability evaluation is essential to evaluate the interpretation level of laboratories before they provide service in real-world clinical settings.

Evolutionary Overview of Consumer Health Informatics: Bibliometric Study on the Web of Science from 1999 to 2019.

BACKGROUND: Consumer health informatics (CHI) originated in the 1990s. With the rapid development of computer and information technology for health decision making, an increasing number of consumers have obtained health-related information through the internet, and CHI has also attracted the attention of an increasing number of scholars. OBJECTIVE: The aim of this study was to analyze the research themes and evolution characteristics of different study periods and to discuss the dynamic evolution path and research theme rules in a time-series framework from the perspective of a strategy map and a data flow in CHI. METHODS: The Web of Science core collection database of the Institute for Scientific Information was used as the data source to retrieve relevant articles in the field of CHI. SciMAT was used to preprocess the literature data and construct the overlapping map, evolution map, strategic diagram, and cluster network characterized by keywords. Besides, a bibliometric analysis of the general characteristics, the evolutionary characteristics of the theme, and the evolutionary path of the theme was conducted. RESULTS: A total of 986 articles were obtained after the retrieval, and 931 articles met the document-type requirement. In the past 21 years, the number of articles increased every year, with a remarkable growth after 2015. The research content in 4 different study periods formed the following 38 themes: patient education, medicine, needs, and bibliographic database in the 1999-2003 study period; world wide web, patient education, eHealth, patients, medication, terminology, behavior, technology, and disease in the 2004-2008 study period; websites, information seeking, physicians, attitudes, technology, risk, food labeling, patient, strategies, patient education, and eHealth in the 2009-2014 study period; and electronic medical records, health information seeking, attitudes, health communication, breast cancer, health literacy, technology, natural language processing, user-centered design, pharmacy, academic libraries, costs, internet utilization, and online health information in the 2015-2019 study period. Besides, these themes formed 10 evolution paths in 3 research directions: patient education and intervention, consumer demand attitude and behavior, and internet information technology application. CONCLUSIONS: Averaging 93 publications every year since 2015, CHI research is in a rapid growth period. The research themes mainly focus on patient education, health information needs, health information search behavior, health behavior intervention, health literacy, health information technology, eHealth, and other aspects. Patient education and intervention research, consumer demand, attitude, and behavior research comprise the main theme evolution path, whose evolution process has been relatively stable. This evolution path will continue to become the research hotspot in this field. Research on the internet and information technology application is a secondary theme evolution path with development potential.

Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma.

BACKGROUND: Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported. METHODS: An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway. FINDINGS: The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy. INTERPRETATION: Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs. FUNDING: The study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).

Oncogenic mutations within the ß3-αC loop of EGFR/ERBB2/BRAF/MAP2K1 predict response to therapies.

BACKGROUND: ß3-αC loop is a highly conserved structural domain across oncogene families, which is a switch for kinase activity. There have been numerous researches on mutations within ß3-αC loop in EGFR, but relatively less in ERBB2, BRAF, and MAP2K1. In addition, previous studies mainly focus on ß3-αC deletion in EGFR, which is the most common type affecting kinase activity and driving lung cancer. Other mutation types are not well studied. METHODS: Here we analyzed the profile of ß3-αC loop mutations in a total of 10,000 tumor biopsy and/or ctDNA patient samples using hybridization capture-based next-generation sequencing. RESULTS: We identified 1616 mutations within ß3-αC loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAF, and MAP2K1. EGFR ß3-αC deletions occurred at a high percentage of 96.7% and were all drug-relevant. We also detected rare EGFR ß3-αC insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 ß3-αC deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAF and MAP2K1 mutations within ß3-αC loop also demonstrated drugs relevance. CONCLUSION: Our study showed that oncogenic mutations within the ß3-αC loop of ERBB2, MAP2K1, and BRAF are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the ß3-αC loop is critical for targeted therapies.

Genotyping of Circulating Tumor DNA Reveals the Clinically Actionable Mutation Landscape of Advanced Colorectal Cancer.

Circulating tumor DNA (ctDNA) enables genomic profiling of colorectal cancer. We investigated therapeutic targets by performing ctDNA panel-captured sequencing of 152 blood samples from advanced stage patients, from which somatic mutations and potentially actionable targets were evaluated. An additional 11 matched tissue samples were retrospectively obtained to verify target validity. The mutation frequencies of 1,127 collective genetic variants identified in our study strongly correlated with those of multiple public databases (Pearson R 2 = 0.92, P < 0.0001). The clonal fraction of driver genes was 90.3%, which was significantly higher than that of potential passenger genes (58.12%). Totally, 90 drug-sensitive genes from 56 patients (36.84%) were identified, including recurring targets PIK3CA, FBXW7, EGFR, BRAF, and NRAS Various resistance mechanisms of anti-EGFR antibodies were revealed via ctDNA profiling, with 29 patients individually exhibiting multiple mechanisms, suggesting considerable resistance heterogeneity in our study population. Of the matched tissue/blood pairs, 88.14% of tissue-derived mutations were detected in ctDNA, and 88.9% of actionable targets were validated. The mutational landscape of ctDNA was highly consistent with tissue databases, and ctDNA profiling showed favorable concordance with tumor tissues in our matched analysis. Thus, comprehensive ctDNA genotyping is a promising noninvasive alternative to biopsy-derived analysis for determining targeted therapy in advanced colorectal cancer.

Diagnosis related group grouping study of senile cataract patients based on E-CHAID algorithm.

AIM: To figure out the contributed factors of the hospitalization expenses of senile cataract patients (HECP) and build up an area-specified senile cataract diagnosis related group (DRG) of Shanghai thereby formulating the reference range of HECP and providing scientific basis for the fair use and supervision of the health care insurance fund. METHODS: The data was collected from the first page of the medical records of 22 097 hospitalized patients from tertiary hospitals in Shanghai from 2010 to 2012 whose major diagnosis were senile cataract. Firstly, we analyzed the influence factors of HECP using univariate and multivariate analysis. DRG grouping was conducted according to the exhaustive Chi-squared automatic interaction detector (E-CHAID) model, using HECP as target variable. Finally we evaluated the grouping results using non-parametric test such as Kruskal-Wallis H test, RIV, CV, etc. RESULTS: The 6 DRGs were established as well as criterion of HECP, using age, sex, type of surgery and whether complications/comorbidities occurred as the key variables of classification node of senile cataract cases. CONCLUSION: The grouping of senile cataract cases based on E-CHAID algorithm is reasonable. And the criterion of HECP based on DRG can provide a feasible way of management in the fair use and supervision of medical insurance fund.

Detection of inherited mutations for hereditary cancer using target enrichment and next generation sequencing.

Hereditary cancers occur because of inherited gene mutations. Genetic testing has been approved to provide information for risk assessment and rationale for appropriate intervention. Testing methods currently available for clinical use have some limitations, including sensitivity and testing throughput, etc. Next generation sequencing (NGS) has been rapidly evolving to increase testing sensitivity and throughput. It can be potentially used to identify inherited mutation in clinical diagnostic setting. Here we develop an effective method employing target enrichment and NGS platform to detect common as well as rare mutations for all common hereditary cancers in a single assay. Single base substitution across 115 hereditary cancer related genes using YH (the first Asian genome) was characterized to validate our method. Sensitivity, specificity and accuracy of 93.66, 99.98 and 99.97 %, were achieved, respectively. In addition, we correctly identified 53 SNVs and indels of BRCA1 and BRCA2 in two breast cancer specimens, all confirmed by Sanger sequencing. Accuracy in detecting copy number variation (CNV) was corroborated in 4 breast cancer specimens with known CNVs in BRAC1. Application of the method to 85 clinical cases revealed 22 deleterious mutations, 11 of which were novel. In summary, our studies demonstrate that the target enrichment combined with NGS method provides the accuracy, sensitivity, and high throughput for genetic testing for patients with high risk of hereditary or familial cancer.