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Purpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR -mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFR T790M -negative resistance., Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR -mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M + ) and -negative (T790M - ) disease., Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M - tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M - tumors. Almost half of resistant tumors were further classified as immune hot , with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M - and T790M + disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients., Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR -mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential., (©2021 The Authors; Published by the American Association for Cancer Research.)

We evaluate the immediate impact of a nutrition and gender behaviour change communication on dietary quality in rural communities in Myanmar and assess whether the communication helped mitigate the effect of the COVID-19 crisis on dietary quality. The intervention was designed and implemented as a cluster-randomised controlled trial in which 15 villages received the intervention and 15 control villages did not. The intervention was implemented from June to October 2020. This paper provides an assessment of the intervention's impact on dietary quality based on the results of two phone surveys conducted in August and October 2020. Immediate impacts of the intervention indicate an improvement in women's dietary diversity scores by half a food group out of 10. At baseline, 44% of women were likely to have consumed inadequately diverse diets; results indicate that 6% (p-value: 0.003, SE: 0.02) fewer sample women were likely to have consumed inadequately diverse diets. More women in treatment villages consumed pulses, nuts, eggs and Vitamin A-rich foods daily than in control villages. In response to economic shocks related to COVID-19, households in the treatment villages were less likely to reduce the quantity of meat and fish consumption than in control villages. The long-term impacts of the intervention need to be continuously evaluated., (© 2021 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

This article provides evidence of the immediate impacts of the first months of the COVID-19 crisis on farming communities in central Myanmar using baseline data from January 2020 and follow-up phone survey data from June 2020 with 1,072 women and men. Heterogeneous effects among households are observed. Fifty-one percent of the sample households experienced income loss from various livelihood activities, and landless households were more severely affected by the crisis, mainly because of lost farm and nonfarm employment and negative impacts on rural enterprises. Women and men in these landless households were equally engaged and affected by lower wages or more difficulties in finding farm work; fewer women were engaged in nonfarm work, but almost all of them lost such nonfarm wage employment. Women in landless households are also particularly vulnerable in terms of worsened workload and increased tension in the household during COVID-19. Landed households were also affected through lower prices, lower demand for crops, and difficulties in input access. Women and men differ in levels of stress, fear, and pessimism regarding the effects of COVID-19. In most households, there were no signs that household task-sharing and work balance improved, and no clear shift in intrahousehold relations was observed., (© 2021 The Authors. Agricultural Economics published by Wiley Periodicals LLC on behalf of International Association of Agricultural Economists.)

Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.

Objectives: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients., Materials and Methods: We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted., Results: A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time., Conclusions: This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy., (Copyright © 2019. Published by Elsevier B.V.)

Purpose: Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC., Patients and Methods: MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG., Results: Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154)., Conclusion: Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC.

EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.