Lung cancer has been of great concern as the malignancy with the highest incidence and mortality rate worldwide, and the rapid increase in the incidence of lung cancer in women, as well as the clinicopathological and molecular features that distinguish it from male lung cancer and its exceptional response to certain treatments and good prognosis, have triggered a fervent interest in its research and exploration. In order to understand and treat female lung cancer more comprehensively and effectively, we will review the above aspects. I. Epidemiology Since the 1930s, with global industrialization, the incidence of lung cancer began to rise and reached a peak in the mid-20th century, becoming the leading cause of cancer-related deaths in men. With smoking cessation and changes in lifestyle habits, the incidence of lung cancer in men has leveled off or even begun to decline in developed countries such as Europe and the United States; in contrast, the incidence of lung cancer in women has seen a rapid increase, with its peak incidence expected to occur in 2020. The age-standardized incidence rate of lung cancer is 35.5/100,000 person-years for men (42.4/100,000 person-years in China) and 12.1/100,000 person-years for women (19.0/100,000 person-years in China); however, among non-smokers aged 40 to 79 years, the incidence rate of lung cancer is higher for women than for men (14.4-20.8/100,000 person-years vs. 4.8-13.7/100,000 person-years). . Mortality from lung cancer in men has reached a “plateau”, while mortality from lung cancer in women has increased rapidly over the last 30 years, quadrupling since 1970. The age-standardized mortality rates for male and female lung cancer are 31.2/100,000 person-years and 10.3/100,000 person-years, respectively; in China, they are 28.60/100,000 person-years and 12.18/100,000 person-years, respectively. Similar to male lung cancer, the occurrence of female lung cancer is the result of a combination of factors. All factors that may lead to lung cancer, such as radiation, environmental pollution, exposure to asbestos, heredity, previous lung diseases, etc. are involved in the occurrence of lung cancer in women, but the following factors deserve more attention. Smoking is the primary causative factor of lung cancer. Since the peak of smoking in women is later than in men and the percentage of smoking cessation is lower, the incidence and mortality rate of lung cancer in women continues to rise unlike lung cancer in men. Compared to men, passive smoking is a predisposing factor for lung cancer in women, with a complex component called environmental tobacco smoke (ETS), a class A carcinogen, being inhaled. Some studies have initially shown that ETS raises the risk of lung cancer in non-smoking women. However, it is inconclusive whether there is a quantitative-effect relationship between passive smoking and lung cancer in women. The factor of lung cancer due to cooking fumes has also received more attention in Chinese women than in Europe and the United States. In addition, human papillomavirus infection, hormonal information pathways, family history, and genetic susceptibility have attracted increasing attention. Clinicopathological and molecular biology characteristics The proportion of nonsmokers among female lung cancer patients is higher than that of males (53% vs. 15%). Among nonsmokers, the incidence of lung cancer was 14.4-20.8/100,000 person-years in women and 4.8-13.7/100,000 person-years in men. Patients included in NSCLC-related clinical studies were classified into all-stage, early-stage, and late-stage conditions, and it was found that in the all-stage NSCLC patient group, women were younger than men, had earlier stages, and adenocarcinoma was more common; in the early-stage NSCLC patient group, women also had earlier stages than men, and adenocarcinoma or large-cell carcinoma was more common; and in the late-stage NSCLC patient group, adenocarcinoma was more common in women. Overweight or obese and anemia are less common. With the advancement of molecular biology technology and the deepening of basic tumor-related research, more and more studies suggest that female lung cancer may be more prone to molecular mutations. Mollerup et al. reported that the level of DNA adducts in the lungs of female smokers was higher than that of males (P = 0.0004). toyooka et al. found that the mutation rate in female patients who smoked was significantly higher than that in non-smoking females and smoking males. 2. K-ras gene mutations The rate of K-ras mutations in the smoking population is higher in women than in men and may suggest a poor prognosis. However, in non-smoking women with lung cancer, there are almost no mutations in K-ras. 3. Growth factor receptor mutations EGFR mutations are more common in Oriental races, women, bronchoalveolar carcinoma or adenocarcinoma containing bronchoalveolar carcinoma, and nonsmokers, and are predictive of effectiveness for EGFR-TKI therapy. In the IDEAL and INTACT studies, the EGFR mutation rate was higher in female patients than in men (19% vs. 9%, p=0.006). A meta-analysis of EGFR mutations in the mainland Chinese lung cancer population by Professor Yilong Wu showed an overall national mutation rate of 30.04%, with a higher rate in female patients than in men (42.9% vs. 23.1%, p < 0.0001). Even in the Spanish population, the EGFR mutation rate was significantly higher in female than in male patients with advanced NSCLC (72.8% vs. 27.2%). HER-2/neu mutation rate in NSCLC was about 1.6%, was seen only in adenocarcinoma, and was higher in Oriental, female, and nonsmokers. IV. Prognosis and treatment Without stage stratification of NSCLC, women have a relatively better prognosis, regardless of pathological type, stage and treatment received. Hsu et al. in Taiwan, China, analyzed 738 patients with NSCLC and showed that the survival advantage of female patients may be related to their younger age and fewer number of smokers, while Ries concluded that among several factors affecting prognosis, stage is the most important, and the earlier the stage the better the prognosis. Because the studies analyzed for NSCLC prognosis included patients with different NSCLC stages, received diverse treatments, had uneven comorbidities, and contained other prognostic factors, the conclusions obtained need to be further validated. In view of the above, we stratified the stages of NSCLC affecting prognosis as much as possible to understand the role of gender in their prognosis. 1, early NSCLC (1), early NSCLC postoperative Currently, it is mostly believed that women are an independent prognostic factor after early NSCLC and are not affected by stage; some studies have also concluded that the survival advantage of female NSCLC patients from stage I to stage III gradually decreases with stage and disappears by stage III; other studies have found that female patients do not have a survival advantage after early NSCLC. Chang et al. in Korea retrospectively analyzed the survival of 2770 NSCLC patients (1689 men and 1081 women) who underwent surgery from 1995 to 2005 at the National Cancer Center in Tokyo, Japan, and found that the 5-year survival rate was higher in women than in men (81% vs. 70%, P < 0.001); among patients with adenocarcinoma, the 5-year survival rates for women and men with pTNM stage I Among adenocarcinoma patients, the 5-year survival rates were 95% and 87% for women and men with pTNM stage I, respectively (P < 0.001), and 58% and 51% for patients with stage II or later (P = 0.017). In contrast, among non-adenocarcinoma patients, there was no gender difference in 5-year survival rates for patients with stage I (p = 0.313) and stage II or more advanced (p = 0.770). minami et al. followed up 1242 patients with postoperative lung cancer and showed that only women in the age group over 60 years had a survival advantage over men (p < 0.05). Therefore, the prognostic impact of women on postoperative early-stage NSCLC is interfered by factors such as pathological type, age (2), inoperable, radiotherapy-treated early-stage NSCLC The prognosis of inoperable, radiotherapy-treated early-stage NSCLC patients is also concerned whether it is influenced by gender.McGovern et al. retrospectively analyzed 831 patients with stage I to III NSCLC treated with radiotherapy and found that the 5-year survival rate of women (16.1% vs. 28.6%, p < 0.001), 5-year progression-free progression-free survival (20.1% vs. 31.2%, P = 0.02), and 5-year distant metastasis-free survival (37.6% vs. 48.8%, P < 0.02) were higher in women than in men; multifactorial analysis also showed that male patients had a poor prognosis (P < 0.02).Matsuo et al. looked at the effects of age, maximum tumor diameter, gender, general status score, and histological type on The role of prognosis determination in stage I NSCLC patients receiving stereotactic radiation therapy revealed that the 3-year survival rate was higher in female patients than in males (80.3% vs. 51.3%, p=0.008). It can be seen that women have more survival advantage in this group of patients. (3), adjuvant chemotherapy for early-stage NSCLC Several studies have shown that adjuvant chemotherapy after stage II NSCLC can increase 5-8% of 5-year survival; multifactorial analysis showed that women may benefit more. the IALT study compared the prognosis of stage I-III NSCLC receiving 3/4 cycles of cisplatin-based chemotherapy after surgery and the observation group, and found that the risk of death was lower in women than men in the adjuvant chemotherapy group. In the ANITA study, women receiving adjuvant chemotherapy with vincristine combined with cisplatin (NP) regimen after stage IB-IIIA NSCLC had a 13% higher 5-year survival rate than men. the JBR.10 study compared the prognosis of women receiving adjuvant chemotherapy with NP regimen after stage IB-II NSCLC with the observation group and showed that 35% of female patients had a prolonged survival (p=0.03). However, Jean-Pierre Pignon et al. pooled and analyzed five large clinical studies of cisplatin-based adjuvant chemotherapy after NSCLC surgery and did not find a survival advantage for women over men after receiving adjuvant chemotherapy. similar data were reported by the NSCLC Meta-Analysis Collaboration. Therefore, whether there is a gender difference in the survival advantage of adjuvant chemotherapy after surgery for early stage NSCLC needs to be further verified. 2. Locally advanced NSCLC Combination radiotherapy is the best choice for patients with locally advanced NSCLC. Some studies have concluded that women have a survival advantage over men in this group of patients; meanwhile, some studies have shown that there is no survival difference between the two groups. However, the reliability of the conclusion may be affected by the inclusion of stage I/II patients who were inoperable due to poor general condition in all of the above studies, as well as by the fact that some patients received only radiotherapy, and by the presence of multiple potential confounding factors. 3. Advanced NSCLC (1), molecular targeted therapy The emergence of molecular targeted drugs has provided new options for the treatment of advanced NSCLC. As clinical experience continues to accumulate, female patients have been found to benefit more from them. ISEL, a global multicenter, randomized clinical study of gefitinib versus placebo for relapsed advanced NSCLC, showed a higher ORR in female patients than in men (14.7% vs. 5.1%), although there was no survival advantage in the overall population in the gefitinib group. the INTEREST study compared gefitinib and docetaxel in the treatment of relapsed advanced NSCLC and found that female patients in both groups had a longer OS than men (gefitinib group: 11.2 months vs. 6.1 months; docetaxel group: 10.0 months vs. 7.0 months). BR.21 compared the value of erlotinib with placebo in patients with advanced NSCLC after failure of standard chemotherapy and found that the MST was 8.4 months and 6.2 months in the erlotinib and placebo groups, respectively, in female patients and 5.7 months and 4.5 months in male patients, respectively, with no statistical difference between the four groups (p=0.76), and therefore gender was not considered a predictor of efficacy of erlotinib. However, since MST was prolonged in female patients compared to men in both the erlotinib group (8.4 months vs. 5.7 months) and the placebo group (6.2 months vs. 4.5 months), the authors concluded that female patients had a better prognosis. (2), chemotherapy Many studies have shown that female patients with advanced NSCLC benefit more from chemotherapy but tolerate treatment less than men. the ECOG 1594 study compared the effects of paclitaxel combined with cisplatin, gemcitabine combined with cisplatin, docetaxel combined with cisplatin and paclitaxel combined with carboplatin regimens for the first-line treatment of advanced NSCLC and found that although there was no difference in ORR and MST between the four groups of patients. However, MST (9.1 months vs. 7.4 months), 1-year survival rate (38% vs. 30%), and 2-year survival rate (30% vs. 10%) were better in women than in men. Yamamoto et al. observed gender differences in 227 patients with stage IIIB/IV NSCLC treated with paclitaxel in combination with carboplatin and found that ORR was 39% in both female and male groups; however, PFS in women (5.3 months vs. 4.4 months, p = 0.0081) and MST were longer in women (22.2 months vs . 11.9 months, p < 0.001). The incidence of grade 3/4 neutropenia was higher in women than in men (39% vs. 15%, p < 0.001). Wheatley-Price et al. also reported that grade 3/4 vomiting, delayed chemotherapy, and lower drug doses were more common in women than in men with advanced NSCLC receiving platinum-based chemotherapy, but there were no differences in hematologic toxicity between the two groups. It has also been shown that female patients do not have a survival advantage over males when receiving chemotherapy. Further analysis found that whether female patients with advanced NSCLC benefit from chemotherapy is influenced by factors such as pathology type and age.Albain et al. reported at the 2007 ASCO meeting that MST (11 months vs. 8 months), 1-year survival (46% vs. 35%), and 2-year survival (19% vs. 13%) were better in women than in men with advanced NSCLC receiving chemotherapy. ) were all better than men, and the risk of death was reduced by 14% (p=0.02); however, further analysis found a survival advantage for women only in patients over 60 years of age. Wheatley-Price et al. found that female patients with advanced NSCLC had higher ORR (42% vs. 40%, p = 0.01) and longer OS (9.6 months vs. 8.6 months, p = 0.002) than males, and differences in survival time by standard age, stage, general condition score, and histologic type (p = 0.0005); however, further analysis showed that survival was longer in women than in men only in patients with adenocarcinoma (P = 0.006). In the phase III clinical study (JMDB) comparing pemetrexed combined with cisplatin (PC) to gemcitabine combined with cisplatin (GC) regimens for the first-line treatment of advanced NSCLC, women had longer MST than men in both the PC group (13.3 months vs. 9.6 months) and the GC group (11.4 months vs. 9.9 months), and women had more survival benefit from PC chemotherapy. An analysis by Syrigos et al. based on baseline characteristics of patients in the JMDB study showed that female patients did not have a better outcome than men and that patients with non-squamous cancer had a better prognosis; while in patients with non-squamous cancer, women had a better prognosis than men (P < 0.001; MST was 13.80 and 9.82 months for women and men in the PC group and 11.79 and 9.40 months in the GC group, respectively). In conclusion, the value of gender in treatment selection, efficacy prediction and prognosis determination of NSCLC has been increasingly appreciated. It is now mostly believed that female patients may benefit more from treatment and have a better prognosis, but it will be influenced by various factors such as stage, pathological type, general condition score, and molecular biological changes. V. Conclusion In conclusion, with the deepening of lung cancer research, our understanding of female lung cancer has changed from superficial to deep, from emotional to rational, and we hope that this understanding can gradually transform and guide our clinical practice of female lung cancer, improve the overall treatment level of female lung cancer, and prolong the survival of female lung cancer.