The evolving landscape of sex-based differences in lung cancer: a distinct disease in women

In stark contrast to a few decades ago when lung cancer was predominantly a disease of men who smoke, incidence rates of lung cancer in women are now comparable to or higher than those in men and are rising alarmingly in many parts of the world. Women face a unique set of risk factors for lung cancer compared to men. These include exogenous exposures including radon, prior radiation, and fumes from indoor cooking materials such as coal, in addition to endogenous exposures such as oestrogen and distinct genetic polymorphisms. Current screening guidelines only address tobacco use and likely underrepresent lung cancer risk in women. Women were also not well represented in some of the landmark prospective studies that led to the development of current screening guidelines. Women diagnosed with lung cancer have a clear mortality benefit compared to men even when other clinical and demographic characteristics are accounted for. However, there may be sex-based differences in outcomes and side effects of systemic therapy, particularly with chemotherapy and immunotherapy. Ongoing research is needed to better investigate these differences to address the rapidly changing demographics of lung cancer worldwide.

Blood-Based Biomarker Panel for Personalized Lung Cancer Risk Assessment

PURPOSE To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics. METHODS A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCOm2012) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was assayed in 1,299 sera collected preceding lung cancer diagnosis and 8,709 noncase sera. RESULTS The 4MP alone yielded an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77 to 0.82) for case sera collected within 1-year preceding diagnosis and 0.74 (95% CI, 0.72 to 0.76) among the entire specimen set. The combined 4MP + PLCOm2012 model yielded an area under the receiver operating characteristic curve of 0.85 (95% CI, 0.82 to 0.88) for case sera collected within 1 year preceding diagnosis. The benefit of the 4MP in the combined model resulted from improvement in sensitivity at high specificity. Compared with the USPSTF2021 criteria, the combined 4MP + PLCOm2012 model exhibited statistically significant improvements in sensitivity and specificity. Among PLCO participants with ≥ 10 smoking pack-years, the 4MP + PLCOm2012 model would have identified for annual screening 9.2% more lung cancer cases and would have reduced referral by 13.7% among noncases compared with USPSTF2021 criteria. CONCLUSION A blood-based biomarker panel in combination with PLCOm2012 significantly improves lung cancer risk assessment for lung cancer screening.

Construction and Validation of a Lung Cancer Risk Prediction Model for Non-Smokers in China

BackgroundAbout 15% of lung cancers in men and 53% in women are not attributable to smoking worldwide. The aim was to develop and validate a simple and non-invasive model which could assess and stratify lung cancer risk in non-smokers in China.MethodsA large-sample size, population-based study was conducted under the framework of the Cancer Screening Program in Urban China (CanSPUC). Data on the lung cancer screening in Henan province, China, from October 2013 to October 2019 were used and randomly divided into the training and validation sets. Related risk factors were identified through multivariable Cox regression analysis, followed by establishment of risk prediction nomogram. Discrimination [area under the curve (AUC)] and calibration were further performed to assess the validation of risk prediction nomogram in the training set, and then validated by the validation set.ResultsA total of 214,764 eligible subjects were included, with a mean age of 55.19 years. Subjects were randomly divided into the training (107,382) and validation (107,382) sets. Elder age, being male, a low education level, family history of lung cancer, history of tuberculosis, and without a history of hyperlipidemia were the independent risk factors for lung cancer. Using these six variables, we plotted 1-year, 3-year, and 5-year lung cancer risk prediction nomogram. The AUC was 0.753, 0.752, and 0.755 for the 1-, 3- and 5-year lung cancer risk in the training set, respectively. In the validation set, the model showed a moderate predictive discrimination, with the AUC was 0.668, 0.678, and 0.685 for the 1-, 3- and 5-year lung cancer risk.ConclusionsWe developed and validated a simple and non-invasive lung cancer risk model in non-smokers. This model can be applied to identify and triage patients at high risk for developing lung cancers in non-smokers.

Influence of Psychological Factors in Breast and Lung Cancer Risk – A Systematic Review

Introduction: In 2020, according to the Global Cancer Observatory, nearly 10 million people died of cancer. Amongst all cancers, breast cancer had the highest number of new cases and lung cancer had the highest number of deaths. Even though the literatures suggest a possible connection between psychological factors and cancer risk, their association throughout studies remains inconclusive. The present systematic review studied the connection between psychological factors and the risk of breast and lung cancer, prior to a cancer diagnosis. The psychological factors of trauma, grief, and depression were studied.Methods: The current systematic review was carried out across multiple databases in two phases, an initial exploratory research in June 2020, refined with a second electronic research in December 2020. The inclusion criteria included studies describing the association between trauma, posttraumatic stress disorder (PTSD), grief, and depression with breast and lung cancer risk. The psychological data collection must have been carried out prior to a confirmed breast or lung cancer diagnosis, and accessed through self-report measures, questionnaires, clinical interviews, or clinical diagnoses. Study reports had to contain information about the incidence of cancer and effect size. The exclusion criteria were studies in which psychological factors were collected after cancer diagnosis.Results and Conclusion: A total of 26 studies were included. Although non-consensual, the findings from the present systematic review suggest that, in addition to the known risk factors, psychological factors may play an important role in the etiology of both breast and lung cancer. To include psychological factors as a variable that affects cancer development may be fundamental to opening new avenues for prevention and intervention.Systematic Review Registration: [www.ClinicalTrials.gov], identifier [CRD42020209161].

Identification of Genetic Variants Associated with Sex-Specific Lung-Cancer Risk

Background: The incidence of lung cancer differs between men and women, suggesting the potential role of sex-specific influences in susceptibility to this cancer. While behavioural differences may account for some of the risk, another possibility is that X chromosome susceptibility genes may have an effect. Little is known about genetic variants on the X chromosome that contribute to sex-specific lung-cancer risk, so we investigated this in a previously characterized cohort. Methods: We conducted a genetic association reanalysis of 518 lung cancer patients and 844 controls to test for lung cancer susceptibility variants on the X chromosome. Annotated gene expression, co-expression analysis, pathway, and immune infiltration analyses were also performed. Results: 24 SNPs were identified as significantly associated with male, but not female, lung cancer cases. These resided in blocks near the annotated genes DMD, PTCHD1-AS, and AL008633.1. Of these, DMD was differentially expressed in lung cancer cases curated in The Cancer Genome Atlas. A functional enrichment and a KEGG pathway analysis of co-expressed genes revealed that differences in immune function could play a role in sex-specific susceptibility. Conclusions: Our analyses identified potential genetic variants associated with sex-specific lung cancer risk. Integrating GWAS and RNA-sequencing data revealed potential targets for lung cancer prevention.

Genetic Polymorphism of Cyp2a6 and Cyp2a13 Genes and Environmental Tobacco Smoke Induced Lung Cancer Risk in Indonesian Female Never Smokers

BACKGROUND: The presence of nicotine metabolite in the urine of subjects exposed to tobacco smoke represents the nicotine metabolism activity in environmental tobacco smokers. CYP2A6 and CYP2A13 are known as the main enzymes responsible for nicotine metabolism and xenobiotic activity in tobacco smoke-related lung cancer. AIM: The aim of this study is to analyze the relationship between genetic polymorphism of CYP26 and CYP2A13 genes and environmental tobacco smoke-induced lung cancer risk in Indonesian females never smoker. METHODS: This is a case-control study with two-stage of distinguishing polymorphism detection. Restriction fragment length polymorphism polymerase chain reaction from venous blood extraction was performed to examine the CYP2A6 and CYP2A13 polymorphism. Logistic regression test in Epi Info-7 software was carried out to examine genetic polymorphism of CYP2A6 and CYP2A13 genes and environmental tobacco smoke-induced lung cancer risk in Indonesian female never smokers. RESULTS: A total of 203 participants enrolled in this study with the first stage of CYP2A6 polymorphism involved 101 subjects showed no significant correlation between the genotypes of CYP2A6 and the incidence of lung cancer. On the other hand, there was a significant correlation between genotypes of CYP2A13 and the incidence of lung cancer (p < 0.05). People with the genotype CT have a 2.7 higher risk for developing lung cancer compare with genotype CC. Allele *1B was the most common allele in CYP2A6. Allele C has more frequencies and has 0.62 times the risk for developing lung cancer compared with allele T with a wide range of confidence intervals (0.73–3.52). CONCLUSIONS: There was a significant correlation between polymorphism CYP213 with the incidence of lung cancer among female lung cancer never smoker. However, the results show no significant relationship between CYP2A6 genetic polymorphism and lung cancer incidence.

Toward Equity-oriented Cancer Care: a Strategy for Patient-oriented Research (SPOR) Protocol to Promote Equitable Access to Lung Cancer Screening.

Background: Screening for lung cancer with low dose CT can facilitate the detection of early-stage lung cancers that are amenable to treatment, reducing mortality related to lung cancer. Individuals are considered eligible for lung cancer screening if they meet specific high-risk criteria, such as age and smoking history. Population groups that are at highest risk of lung cancer, and therefore the target of lung cancer screening interventions, are also the least likely to participate in lung cancer screening, thus resulting in a widening of health inequities. Deliberate effort is needed to both reduce lung cancer risk (through upstream interventions that promote smoking cessation) as well as midstream interventions that promote equitable access to lung cancer screening. Methods: This protocol paper describes an equity-informed patient-oriented research study. Our study aims to promote equitable access to lung cancer screening by partnering with patients to co-design an e-learning module for healthcare providers. The learning module will describe the social context of lung cancer risk and promote access to lung cancer screening by increasing equity at the point of care. We have applied the Generative Co-Design Framework for Healthcare Innovation and detail our study processes in three phases and six steps: Pre-design (establishing a study governance structure); co-design (identifying research priorities, gathering and interpreting data, co-developing module content); and post-design (pilot testing the module and developing an implementation plan). Discussion: Patient engagement in research can promote the design and delivery of healthcare services that are accessible and acceptable to patients. This is particularly important for lung cancer screening as those at highest risk of developing lung cancer are also those who are least likely to participate in lung cancer screening. By detailing the steps of our participatory co-design journey, we are making visible the processes of our work so that they can be linked to future outcomes and related impact, and inform a wide range of patient co-led processes.