Lung cancer is the leading cause of preventable death globally [1-3]. This preventable disease is strongly associated with tobacco smoking [3]. However, with increased awareness and advancements in research, it has become evident that lung cancer is also found in individuals who have never smoked. This recognition has led to the identification of distinct subtypes of lung cancer. The prevalence of lung cancer among never smokers is approximately 10% to 15% worldwide, but it varies geographically and by sex [3-5]. The prevalence of never smokers in Asian countries is higher than that in non-Asian countries [4].

Small cell lung cancer (SCLC) is aggressive, has a high response rate to first-line chemotherapy, and has an overall poor prognosis [6]. SCLC is called ‘smoker’s disease’ because it is strongly associated with smoking and the majority of cases occur in individuals with a history of tobacco use [7,8]. However, it can also occur in individuals without a history of smoking [9]. In non-Asian countries, the proportion of SCLC cases among never smokers was reported to be only 1.8% to 7% [10-12]. However, in Asian countries, the prevalence ranged from 13% to 22.8% [13-15]. Previous studies have provided conflicting results regarding prognosis; some showed better survival among patients with SCLC who were never smokers, but others have reported no differences in survival [10,13]. One study showed a poorer prognosis in never smokers than in smokers [14]. Therefore, we investigated the clinical features of never smokers with SCLC and compared their treatment outcomes with those of smokers with SCLC.

Tobacco smoking is a well-established risk factor for SCLC. Smoking increases mutational burden, cell-to-cell heterogeneity, and the several distinct mutational signatures of substitutions of insertion or deletions [16]. However, the cause of never smokers’ SCLC is not clear. The risk factors other than active tobacco smoking include exposure to second-hand smoke, radiation, occupational exposures (such as asbestos), domestic radon, previous lung disease, organ transplantation, and genetic factors [9,10,17]. One study found bi-allelic inactivation of tumor protein p53 (TP53) and RB transcriptional corepressor 1 (RB1), sometimes by complex genomic rearrangements in SCLC [18]. And another study analyzed the genomic difference of never smoker SCLC. They found a lower tumor mutation burden, a lower frequency of TP53 mutations, and absence of mutational signature in never smoker [10].

In our study, never smokers accounted for 11.4% of patients with SCLC. This was higher than that reported in non-Asian countries. In non-Asian countries, never smokers accounted for 1.8% to 7% of patients with SCLC [10-12], while in Asian countries, a prevalence of 13% to 22.8% has been reported [13-15]. Our study showed slightly lower prevalence than those reported in other studies conducted in Asian countries. This finding reputes the belief that SCLC is a smoker’s disease. This variation suggests that the prevalence of SCLC among never smokers is influenced by many factors such as geographic variation, cultural differences, tobacco control policies, or environmental factors. It may also be affected by demographic factors and second-hand smoke exposure, occupational exposures, family history, or lifestyle factors [19]. In addition, there were 15 patients with COPD (9.3%) among the never smokers. This suggests that COPD and SCLC may share several risk factors other than smoking. There are well known risk factors for COPD including air pollution, occupational exposures, poorly controlled asthma, environmental tobacco smoke, infectious diseases, and low socioeconomic status [20].

In never smokers with SCLC, females were more prevalent. Never smokers with SCLC were also shorter, weighed less, and had a higher BMI than smokers with SCLC. Never smokers had less ischemic heart disease and chronic obstructive lung disease than smokers. Never smokers had less symptoms at diagnosis than smokers but more toxicity after first-line chemotherapy than smokers. This seems to due to greater proportion of female patients in the never smoker group. Never smokers showed better ORR than smokers. In multivariate analysis, never smoking was an independent factor for better ORR. Second-line treatment was also associated with better ORR. This probably means that those who responded better to the first-line treatment were more likely to get second-line treatment. However, there was no significant difference in PFS and OS probably due to a small sample size of this single-center study. It is speculated that high recurrence after a temporary response and rapidly progressing characteristics of SCLC may also be the reason for no difference in survival.

Several previous studies have found clinical and genetic characteristics of SCLC in never smokers. Thomas et al. [10] evaluated 5,632 patients with SCLC and found that 100 of these patients (1.8%) had no smoking history. In this study, never smokers were more likely to be female and had a higher rate of ED than smokers. No statically significant difference in OS was found between never smokers and smokers [10]. Sun et al. [13] also examined clinical and genetic characteristics. Of 412 patients with SCLC, 50 (13%) were never smokers. Most patients were female. In terms of other characteristics, there were no differences between never smokers and smokers. The OS of never smokers was longer than that of smokers. In the multivariate analysis, never smoking was an independent good prognostic factor [13]. Liu et al. [15] studied the characteristics of never smokers and associations with clinical outcomes. Of 303 patients with SCLC, 69 (22.8%) patients were never smokers. Both the median PFS and OS were significantly longer in never smokers than in smokers. In the multivariate analysis, never smoking was a significant good prognostic factor for PFS. In terms of the ORR, there was no significant difference between the two groups [15]. Kang et al. [14] evaluated the characteristics and clinical outcomes of non-smoking SCLC. They registered 1,043 patients with SCLC, and 154 (14.8%) were never smokers. Unlike previous studies, the OS of never smokers was shorter than that of smokers. Kang et al.’s [14] study included untreated patients with an ED rate of 66.2%, whereas our study only included treated patients with ED rate of 49.4%. The high rate of ED may have contributed to the shorter OS in never smokers. In the multivariate analysis, never smoking was not associated with a shorter OS [14].

There are several limitations in this study. First, this was a retrospective study conducted at a single institution, and we could not perform comprehensive genetic analysis such as next-generation sequencing. Second, there might have been selection bias in our study because we only included the patients who had received chemotherapy and excluded those with insufficient medical records. Third, only 3% of patients in this study received the atezolizumab/carboplatin/etoposide regimen, indicating that most of our results were obtained before the advent of immunotherapy which is the current standard in SCLC-ED. Fourth, we did not include the histologic transformed SCLC from particularly epidermal growth factor receptor mutant-adenocarcinoma which occurs occasionally in never smoker.

In conclusion, never smokers with SCLC accounted for quite a small proportion of patients with SCLC. They had distinct clinical characteristics (including sex, ischemic heart disease, symptoms at diagnosis, and toxicity after chemotherapy). Moreover, never smoking was a good response parameter. Our study suggests that more prospective studies need to examine the clinical characteristics and survival rates between never smokers and smokers with SCLC.