A sharp increase over recent decades in the number of female patients diagnosed with SCLC has been reported in several countries [3, 4]. Over the past two decades, the female-to-male incidence rate ratios among 40 to 54 years of age non-hispanic whites of SCLC had generally increased [5]. A research from China showed the proportion of women with SCLC increased from 17.95–24.75%, compared to all patients diagnosed with SCLC from West China Hospital between 1995 and 2015 [10]. Our study identified 18234 patients from SEER database, more than half of whom were females (50.2%), and the reasons for such ratio need to be further investigated. Generally, smoking is closely related to the mortality and morbidity of SCLC [11], and smoking is often associated with worse prognosis [12, 13]. Malvezzi et al. demonstrated mortality rates of lung cancer in males were declining, which were rising in females, and this fact was strongly linked to smoking status in Europe [14]. Moreover, a meta-analysis of 27 studies, and concluded that smoking cessation could reduce the incidence of SCLC, especially in female patients [15]. Paradoxically, Lorraine et al.’s study indicated an increased incidence of SCLC in non-smokers [16]. In a 2016 study of SCLC, María et al. published a result that the prognosis of non-smokers was as poor as that of smokers [17]. A previous work reported that the tobacco-attributed proportion was increasing in men, but low, and decreasing in women in Chinese population [18].
The prognosis of SCLC in female patients is controversial. Several previous works reported that sex had no prognostic significance in SCLC [12, 19], nevertheless, a French study included 967 patients diagnosed with SCLC showed that median survival was better among males in patients older than 70 years old [20]. However, various other studies reported that females had significantly better survival than males with SCLC [1, 21–24]. Singh et al. demonstrated that females were more susceptible to chemotherapy and its associated toxicity, which probably due to pharmacokinetic difference and higher baseline BMI of females, and this result was confirmed by Wheatley et al. in 2018 [25, 26]. In our study, sex was an independent prognostic factor in patients with SCLC, females had preferable OS and CSS in comparison to males. After drawing a conclusion that female sex predicts better survival in SCLC, we stratified these patients for further analysis. Our results showed that females significantly associated with better survival both in elderly cohort and younger cohort. Similar results were obtained when stratifying these patients by race and stage.
Sex-related differences in SCLC patients have not been reported previously. Our study found that females were more likely to carry with smaller tumors. Tumor size is also closely related to prognosis of SCLC patients. A prospective study reported that gross tumor volume significantly influenced survival of stage I to III SCLC patients treated with concurrent chemoradiation therapy [27]. In our study, females tended to have more favorable TNM stage compared with males with SCLC. We have already known that stage groupings using the TNM category clearly identified SCLC patient subgroups with different prognoses [28], and the survival of advanced stage was significantly worse than that of earlier stages for SCLC patients from IASLC database [29]. A previous study reported that N-stage (OR = 4.94; P < 0.01) was associated with survival of SCLC patients according to AJCC TNM category, seventh edition [30]. Our results showed that females had earlier N stage than males with SCLC. In Herndon et al’ s study, liver metastasis and bone metastasis were significantly associated with poor prognosis of SCLC [24]. These patterns were also seen in our results. Our study demonstrated that all of lung metastasis, liver metastasis, brain metastasis and bone metastasis were less common in females than in males with SCLC. These results may serve as evidence that females have better outcomes than males with SCLC.
From the analysis of two GEO datasets, a total of 7 genes were found to be more expressed in male patients than in female patients. RPS4Y1, KDM5D, DDX3Y and PRKY are male-specific region of Y chromosome (MSY) genes [31]. Amphiphysin is thought to encode a protein peripherally associated with synaptic vesicles, expressed in many neurons and certain endocrine cell types, and may be related to heritable disorders of the nervous system and endocrine tissues [32]. GRIN2C encodes a subunit of the N-methyl-D-aspartate (NMDA) receptor, which also presents in the nervous system and is associated with pathophysiological conditions such as Parkinson’s disease, Alzheimer’s disease, depression and schizophrenia [33]. WNT4 gene is the first signaling molecule shown to influence the sex-determination cascade, and it encodes a protein played a pro-carcinogenic role in numerous cancer types [34].
HOXA5 is a gene more expressed in female patients than in male patients with SCLC which was reported by Teo et al. that could prevent the occurrence and development of breast cancer [35]. RB1 is one of the most frequently mutated genes in SCLC and is closely related to the pathogenesis of SCLC [36]. Our results showed that the mutation frequency of RB1 in female SCLC patients is higher than that in male patients, which may be related to the mechanism of different characteristics of female and male SCLC.
Whether the sex differences of SCLC patients are related to hazardous living habits such as exposure to tobacco or real gender difference like genetic predisposition and influences of sex steroid hormones is remain unclear. Further studies are required to address these questions.
This population-based study has many virtues. First, SEER, TCGA and GEO databases are authoritative source for cancer statistics in the United States, which ensures the reliability of cases in our research. Second, the sources of case data from SEER database have a wide range of regions and a long span of time, which guarantees the representativeness of the outcomes in this study. Third, we contained 18234 patients with SCLC in our study, including the largest number of cases of any homogeneous studies. This research adds to current knowledge by answering more in-depth research questions about gender and prognosis through analysis of population-based data from the large SEER database. Nonetheless, this study has some potential limitations. First, like all retrospective studies, this study was not capable of avoiding selective bias. Second, there was no mRNA expression data of SCLC in TCGA database, so we can only use the microarray data from GEO datasets for gene differential expression analysis, which may affect the results on account of the heterogeneity. Third, the sample size was limited in GEO database, and a larger sample size is necessary to replicate the study results in the future.