Lung cancer is the leading cause of cancer death worldwide, accounting for nearly 20% of all cancer deaths.¹ Previously, low-dose computerized tomography (LDCT) was shown to detect asymptomatic lung cancer cases better than chest radiography, and many countries in the West have initiated small randomized studies of LDCT for lung cancer screening.¹ However, many studies in North America and Europe only involved high-risk smokers and may not be able to capture the actual risk of lung cancer among the general population.¹ In East Asia, screening studies are often extended to low-risk or never smokers and it was found that a high proportion of lung cancer patients in East Asia are typically young, never smokers and carry epidermal growth factor receptor (EGFR) mutations.² In fact, the incidence of lung cancer among never smokers is increasing, particularly for the adenocarcinoma subtype.^3,4

In Taiwan, over 50% of all lung cancer patients and over 90% of female lung cancer patients are never smokers.⁵ This female gender bias of lung cancer cases among never smokers can be attributed to passive smoking.⁵ To evaluate the effectiveness of LDCT screening among never smokers, the Taiwan Lung Cancer Screening in Never Smoker Trial (TALENT) recruited 12,011 individuals aged 55 to 75 years with negative chest x-rays who had never smoked or had done so more than 15 years previously, had risk factors such as a family history of lung cancer within third-degree relatives, passive smoke exposure, a history of tuberculosis or chronic obstructive pulmonary disease, or had regularly been exposed to frying food. Participants were recruited from February 2015 to July 2019 and followed for 3 years.

Participants underwent LDCT after chest radiography, followed by biopsy if necessary.6 Participants were designated positive on LDCT with solid or part-solid nodules >6mm in diameter or pure ground-glass nodules >5mm in diameter.⁶ LDCT was performed annually for 3 consecutive years.⁶ If LDCT was positive, short-term follow-up or tissue diagnosis would be arranged.⁸ DNAs were also extracted from peripheral blood mononuclear cells for single nucleotide polymorphism (SNP) typing.⁶ Additionally, a risk score that integrated family history and SNPs was calculated for each participant.⁶

From TALENT, LDCT detected largely invasive lung cancer in 2.6% of participants. Tumors were of stage 0–I in 95% of cases, with more than half of the cases (58.5%) being invasive adenocarcinomas. Interestingly, the lung cancer detection rate of 2.6% in TALENT among never smokers was higher than that of other LDCT lung cancer screening studies which only enrolled smokers, including the 1.1% from the United States National Lung Screening Trial study (NLST) and the 0.9% from the Dutch-Belgian NELSON study. Compared to other LDCT lung cancer screening studies, TALENT also had the highest T0 and stage 0-1 detection rate with the highest positive predictive value.

In terms of risk factors, 4 SNPs (TERT, TP63, HLA-DRB1/HLA-DQA1 and HLA-DRB9/HLA-DRB5) were significantly associated with risk of lung cancer in never smokers.⁶ Having a first-degree family history of lung cancer significantly increased an individual’s lung cancer risk. Furthermore, this risk increased with an increasing number of first degree relatives with lung cancer. Notably, having a sister with lung cancer increased the risk of the disease by 78%, and an affected brother would further double the risk. Based on the results of the TALENT study, LDCT lung cancer screening among high-risk never smokers is feasible and particularly relevant to Asian females.

In Europe, validated risk models that include age, smoking status, family history of lung cancer and history of respiratory diseases have been used to select high-risk individuals for screening.⁷ The National Institutes of Health in the United States has also incorporated genetic susceptibility pathways and circulating biomarkers in the risk-prediction models.⁷ On the other hand, risk-factor based eligibility criteria were only used for recruitment in the TALENT study and individual risk scores were computed after the study enrolment. As this individual risk score-based selection was suggested to be more efficient and cost-effective than the subgroup-based selection, a wider adoption of individual risk scores can help accord differential weightages to varying risk factors and improve future screening recruitment strategies.⁸ However, a longer follow-up with mortality outcomes will be required to comprehensively assess the benefits of this emerging lung cancer screening modality.

Dr. Pan-Chyr Yang, National Taiwan University Institute of Biomedical Sciences, Center of Genomics, Academia Sinica, Taiwan, concluded, “LDCT screening for lung cancer in never smokers with high risk may be feasible, which is very important to all who are fighting against lung cancer, [considering] the increasing global threat for lung cancer in never smokers. Most importantly, the study showed that family history of lung cancer may increase the risk of lung cancer.”