Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

Incidence of Lung Adenocarcinoma by Age, Sex, and Smoking Status in Taiwan.

Importance: Knowing whether the effects of smoking and other risk factors with lung adenocarcinoma (ADC) incidence varies by sex would provide information on lung cancer prevention strategies. Objective: To evaluate whether women in Taiwan have higher age- and tumor stage-specific lung ADC incidence rates than men irrespective of smoking status (ie, ever smoker or never smoker). Design, Setting, and Participants: This population-based cohort study used data sets synthesized from the Taiwan Cancer Registry (TCR) from 1979 to 2019; the TCR Long Form (TCRLF) from 2011 to 2019, which provides individual-level smoking and tumor stage information; the Taiwan Cause of Death Database (TCOD) from 1985 to 2019; the National Health Insurance Research Database (NHIRD) from 2000 to 2020; the Monthly Bulletin of Interior Statistics (MBIS) from 2011 to 2019; the National Health Interview Survey from 2001, 2005, 2009, 2013, and 2017; and Taiwan Biobank data from 2008 to 2021. Included patients were aged 40 to 84 years and had any invasive lung cancer from January 1, 2011, to December 31, 2019. Exposure: Smoking status. Main Outcomes and Measures: The main outcomes were age-specific female-to-male incidence rate ratios (IRRs) of lung ADC by smoking status and tumor stage. Linked data from the TCR, TCOD, NHIRD, Taiwan National Health Interview Survey, and MBIS were used to estimate the age- and sex-specific numbers of cancer-free individuals at midyears from 2011 to 2019 by smoking status. Using the TCR and TCRLF, age-, sex-, tumor stage-, and diagnosis year-specific numbers of patients with lung ADC from 2011 to 2019 by smoking status were estimated. Results: A total of 61 285 patients (32 599 women [53.2%]) aged 40 to 84 years (mean [SD] age, 64.66 [10.79] years) in the Taiwanese population of approximately 23 million were diagnosed with invasive lung ADC as their first lifetime cancer between 2011 and 2019. Among smokers, men had higher tobacco use by almost all examined metrics, including nearly twice the mean (SD) number of pack-years smoked (eg, 7.87 [8.30] for men aged 30-34 years vs 4.38 [5.27] for women aged 30-34 years). For 5-year age bands between 40 and 84 years, incidence of lung ADC was significantly higher among females than males for nearly all age groups irrespective of tumor stage and smoking status (eg, for the age group 70-74 years, the female-to-male IRR for late-stage lung ADC among never smokers was 1.38 [95% CI, 1.30-1.50]). Conclusions and Relevance: In this cohort study, women had higher age- and stage-specific lung ADC incidence rates than men in Taiwan for both never and ever smokers, suggesting the possibility of differential exposures between sexes to risk factors other than smoking and the potential modification of ADC risk factors by sex. Further work is needed to determine whether this pattern replicates in other populations, discover the causes of lung ADC, and put preventive measures in place.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

Prevalence of comorbidities and their impact on survival among older adults with the five most common cancers in Taiwan: a population study.

Because of the cancer incidence increase and population aging in Taiwan, we aimed to assess the cancer prevalence, to summarize the comorbidities of older patients with the five most common cancers (i.e., breast, colorectal, liver, lung, and oral), and to develop a Taiwan cancer comorbidity index (TCCI) for studying their actual prognosis. The linkage of the Taiwan Cancer Registry, Cause of Death Database, and National Health Insurance Research Database was used. We followed the standard statistical learning steps to obtain a survival model with good discriminatory accuracy in predicting death due to noncancer causes, from which we obtained the TCCI and defined comorbidity levels. We reported the actual prognosis by age, stage, and comorbidity level. In Taiwan, cancer prevalence nearly doubled in 2004-2014, and comorbidities were common among older patients. Stage was the major predictor of patients' actual prognoses. For localized and regional breast, colorectal, and oral cancers, comorbidities correlated with noncancer-related deaths. Compared with the US, the chances of dying from comorbidities in Taiwan were lower and the chances of dying from cancer were higher for breast, colorectal, and male lung cancers. These actual prognoses could help clinicians and patients in treatment decision-making and help policymakers in resource planning.

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Recalibrating Risk Prediction Models by Synthesizing Data Sources: Adapting the Lung Cancer PLCO Model for Taiwan.

BACKGROUND: Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan. METHODS: Using Taiwanese multiple data sources, we formed an age-matched case-control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011-2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem. RESULTS: The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40+ pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%). CONCLUSIONS: The adapted PLCOT models had high predictive performance. IMPACT: The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Programmed Death Ligand 2 Gene Polymorphisms Are Associated With Lung Adenocarcinoma Risk in Female Never-Smokers.

OBJECTIVES: Lung cancer in never-smokers is a distinct disease associated with a different genomic landscape, pathogenesis, risk factors, and immune checkpoint inhibitor responses compared to those observed in smokers. This study aimed to identify novel single nucleotide polymorphisms (SNPs) of programmed death-1 (encoded by PDCD1) and its ligands, programmed death ligand 1 (CD274) and 2 (PDCD1LG2), associated with lung cancer risk in never-smoking women. MATERIALS AND METHODS: During September 2002 and July 2012, we enrolled never-smoking female patients with lung adenocarcinoma (LUAD) (n=1153) and healthy women (n=1022) from six tertiary hospitals in Taiwan. SNP data were obtained and analyzed from the genome-wide association study dataset and through an imputation method. The expression quantitative trait loci (eQTL) analysis was performed in both tumor and non-tumor tissues for the correlation between genetic expression and identified SNPs. RESULTS: A total of 12 PDCD1LG2 SNPs related to LUAD risk were identified in never-smoking women, including rs2381282, rs4742103, rs4237162, rs4742104, rs12237624, rs78096119, rs6476988, rs7857315, rs10975178, rs7854413, rs56001683, and rs7858319. Among them, six tagged PDCD1LG2 SNPs rs2381282, rs4742103, rs4237162, rs4742104, rs78096119, and rs56001683 were significantly associated with LUAD risk. Specifically, two PDCD1LG2 SNPs, rs12237624 and rs78096119, were associated with previous pulmonary tuberculosis infection in relation to LUAD susceptibility. Through an eQTL assay, we found that rs2381282 (p < 0.001), rs12237624 (p = 0.019), and rs78096119 (p = 0.019) were associated with the expression levels of programed death ligand 2. CONCLUSIONS: Novel SNPs of programed death ligand 2 associated with lung adenocarcinoma risk were identified. Among them, two SNPs were associated with pulmonary tuberculosis infection in relation to lung adenocarcinoma susceptibility. These SNPs may help to stratify high-risk populations of never-smokers during lung cancer screening.

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10-26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10-3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

Collateral Benefit of COVID-19 Control Measures on Influenza Activity, Taiwan.

Taiwan has strictly followed infection control measures to prevent spread of coronavirus disease. Meanwhile, nationwide surveillance data revealed drastic decreases in influenza diagnoses in outpatient departments, positivity rates of clinical specimens, and confirmed severe cases during the first 12 weeks of 2020 compared with the same period of 2019.

Predicting Lung Cancer Occurrence in Never-Smoking Females in Asia: TNSF-SQ, a Prediction Model.

BACKGROUND: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria. METHODS: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case-control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2). RESULTS: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660-0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95-5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04-36.28) had risk higher than 0.0151. CONCLUSIONS: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention. IMPACT: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.

Patterns of age-specific socioeconomic inequalities in net survival for common cancers in Taiwan, a country with universal health coverage.

INTRODUCTION: In high-income countries, advances in early diagnosis and treatment have improved cancer survival. However, socioeconomic inequalities in survival have persisted or increased for some adult cancers. MATERIALS AND METHODS: We assessed net survival for the 20 most common adult cancers in Taiwan. They were stratified into six age groups and three socioeconomic groups. RESULTS: Out of 120 cancer site and age group combinations, 49 showed improvements in 5-year net survival from 2000-2004 to 2005-2010. Only cervix uteri cancer in the 35-49-year age group showed a deterioration. During 2000-2010, 13 of the 20 cancer cases experienced socioeconomic inequalities for all age groups combined, and the deprivation gaps varied with cancer site and age at diagnosis. For the five most common cancers - liver, colon and rectum, lung, breast, and oral - there were socioeconomic inequalities, and 5-year net survival improved for most or all of the six age groups from 2000-2004 to 2005-2010. CONCLUSION: Reducing socioeconomic inequality in survival may lead to improvements in survival overall. We should focus on the age groups with large deprivation gaps. Our results are useful for prioritizing cancer sites and age groups for in-depth socioeconomic disparity studies and for proposing interventions for health disparity reductions and net cancer survival improvements.

Comparison of annual percentage change in breast cancer incidence rate between Taiwan and the United States-A smoothed Lexis diagram approach.

Recent studies compared the age effects and birth cohort effects on female invasive breast cancer (FIBC) incidence in Asian populations with those in the US white population. They were based on age-period-cohort model extrapolation and estimated annual percentage change (EAPC) in the age-standardized incidence rates (ASR). It is of interest to examine these results based on cohort-specific annual percentage change in rate (APCR) by age and without age-period-cohort model extrapolation. FIBC data (1991-2010) were obtained from the Taiwan Cancer Registry and the U.S. SEER 9 registries. APCR based on smoothed Lexis diagrams were constructed to study the age, period, and cohort effects on FIBC incidence. The patterns of age-specific rates by birth cohort are similar between Taiwan and the US. Given any age-at-diagnosis group, cohort-specific rates increased overtime in Taiwan but not in the US; cohort-specific APCR by age decreased with birth year in both Taiwan and the US but was always positive and large in Taiwan. Given a diagnosis year, APCR decreased as birth year increased in Taiwan but not in the US. In Taiwan, the proportion of APCR attributable to cohort effect was substantial and that due to case ascertainment was becoming smaller. Although our study shows that incidence rates of FIBC have increased rapidly in Taiwan, thereby confirming previous results, the rate of increase over time is slowing. Continued monitoring of APCR and further investigation of the cause of the APCR decrease in Taiwan are warranted.

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels.

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.

Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors.

RATIONALE: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patients with advanced NSCLC who have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS. OBJECTIVES: The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs. METHODS: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). MEASUREMENTS AND MAIN RESULTS: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P < 10-8) and with an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression of EGFR, which encodes the TKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene. CONCLUSIONS: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.

Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA).

We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30% increased risk of lung cancer (OR 1.3, 95% CI 1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.