Associations Between Sex-Specific Reproductive Factors and Risk of New-Onset Lung Cancer Among Female Patients

Abstract

BackgroundSeveral characteristics distinguish lung cancer in female patients from that in male patients, with adenocarcinoma being more prevalent in female patients and occurring more frequently in female patients who do not smoke. Uncertainty surrounds the relationship between female-specific reproductive factors and lung cancer risk.Research QuestionAre sex-specific reproductive factors associated with risk of lung cancer in different genetic risk groups and histologic types?Study Design and MethodsA Cox proportional hazard model was used to evaluate the association between multiple reproductive factors and the risk of lung cancer developing in a prospective cohort study involving 273,190 female individuals from the UK Biobank. Subgroup analyses stratified by age, smoking status, BMI, genetic risk, and histologic subtype were conducted to emphasize the modification effects further.ResultsA total of 1,182 cases of lung cancer in female patients were recorded over a median follow-up period of 12.0 years in the cohort study. In multivariable-adjusted models, early menarche (age ≤ 11 years: hazard ratio [HR], 1.22; 95% CI, 1.03-1.46), early menopause (age ≤ 46 years: HR, 1.49; 95% CI, 1.19-1.86), a shorter reproductive span (≤ 32 years: HR, 1.42; 95% CI, 1.18-1.71; and 33-35 years: HR, 1.24; 95% CI, 1.00-1.53), and early age at first birth (age ≤ 20 years: HR, 1.63; 95% CI, 1.33-2.01) were associated with a higher risk of lung cancer. Stratified analysis revealed that several reproductive factors, including early age at menopause, shortened reproductive span, and early age at first birth, showed a substantially stronger relationship with an elevated risk of lung cancer, particularly of lung adenocarcinoma, in populations with high genetic risk and more detrimental behaviors.InterpretationEarly age at menopause, a shortened reproductive life span, and early age at first birth were associated with higher risks of lung cancer, particularly of lung adenocarcinoma, in a subpopulation with higher genetic susceptibility and detrimental behaviors. The evidence provided by this study emphasizes the significance of screening for multiple reproductive factors to prevent lung cancer among female individuals. Several characteristics distinguish lung cancer in female patients from that in male patients, with adenocarcinoma being more prevalent in female patients and occurring more frequently in female patients who do not smoke. Uncertainty surrounds the relationship between female-specific reproductive factors and lung cancer risk. Are sex-specific reproductive factors associated with risk of lung cancer in different genetic risk groups and histologic types? A Cox proportional hazard model was used to evaluate the association between multiple reproductive factors and the risk of lung cancer developing in a prospective cohort study involving 273,190 female individuals from the UK Biobank. Subgroup analyses stratified by age, smoking status, BMI, genetic risk, and histologic subtype were conducted to emphasize the modification effects further. A total of 1,182 cases of lung cancer in female patients were recorded over a median follow-up period of 12.0 years in the cohort study. In multivariable-adjusted models, early menarche (age ≤ 11 years: hazard ratio [HR], 1.22; 95% CI, 1.03-1.46), early menopause (age ≤ 46 years: HR, 1.49; 95% CI, 1.19-1.86), a shorter reproductive span (≤ 32 years: HR, 1.42; 95% CI, 1.18-1.71; and 33-35 years: HR, 1.24; 95% CI, 1.00-1.53), and early age at first birth (age ≤ 20 years: HR, 1.63; 95% CI, 1.33-2.01) were associated with a higher risk of lung cancer. Stratified analysis revealed that several reproductive factors, including early age at menopause, shortened reproductive span, and early age at first birth, showed a substantially stronger relationship with an elevated risk of lung cancer, particularly of lung adenocarcinoma, in populations with high genetic risk and more detrimental behaviors. Early age at menopause, a shortened reproductive life span, and early age at first birth were associated with higher risks of lung cancer, particularly of lung adenocarcinoma, in a subpopulation with higher genetic susceptibility and detrimental behaviors. The evidence provided by this study emphasizes the significance of screening for multiple reproductive factors to prevent lung cancer among female individuals. Take-home PointsStudy Question: Are sex-specific reproductive factors associated with the risk of lung cancer in different genetic risk groups and histologic types?Results: Early menopause, shortened reproductive span, and early age at first birth are associated with a higher risk of lung cancer, particularly of lung adenocarcinoma, in those populations with a high genetic risk and more detrimental behaviors.Interpretation: This study emphasizes the significance of screening for multiple reproductive factors for the prevention of lung cancer in female individuals. Study Question: Are sex-specific reproductive factors associated with the risk of lung cancer in different genetic risk groups and histologic types? Results: Early menopause, shortened reproductive span, and early age at first birth are associated with a higher risk of lung cancer, particularly of lung adenocarcinoma, in those populations with a high genetic risk and more detrimental behaviors. Interpretation: This study emphasizes the significance of screening for multiple reproductive factors for the prevention of lung cancer in female individuals. Lung cancer is the second most common cancer and the leading cause of cancer-related mortality in the world.1Ferlay J. Colombet M. Soerjomataram I. et al.Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.Eur J Cancer. 2018; 103: 356-387Abstract Full Text Full Text PDF PubMed Scopus (1669) Google Scholar,2Dyba T. Randi G. Bray F. et al.The European cancer burden in 2020: incidence and mortality estimates for 40 countries and 25 major cancers.Eur J Cancer. 2021; 157: 308-347Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar In 2020, 2.21 million new cases of lung cancer (11.4% of all cancer cases) and 1.80 million deaths (18.0% of all deaths resulting from cancer) were estimated by the Global cancer statistics 2020,3Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (48824) Google Scholar thus causing a tremendous burden on socioeconomic and medical resources. Compared with lung cancer in male patients with a history of smoking, a subtype of adenocarcinoma occurs more frequently in female patients who have never smoked.4Zang E.A. Wynder E.L. Differences in lung cancer risk between men and women: examination of the evidence.J Natl Cancer Inst. 1996; 88: 183-192Crossref PubMed Scopus (629) Google Scholar Although smoking exhibits a dose-response relationship with all major subtypes of lung cancer, this relationship is attenuated in adenocarcinoma, indicating that other risk factors may play a significant role in this cell type.5Kabat G.C. Aspects of the epidemiology of lung cancer in smokers and nonsmokers in the United States.Lung Cancer. 1996; 15: 1-20Abstract Full Text PDF PubMed Scopus (69) Google Scholar Female individuals who do not smoke are approximately three times more susceptible to lung cancer than male individuals who do not smoke. Although the incidence of lung cancer in females has increased substantially in recent decades worldwide, particularly lung adenocarcinoma (LUAD),6Gabrielson E. Worldwide trends in lung cancer pathology.Respirology. 2006; 11: 533-538Crossref PubMed Scopus (112) Google Scholar the risk factors, with the exception of smoking and pollution, have not been identified fully. Hormonal and reproductive factors are thought to be involved in the occurrence of lung cancer in female patients5Kabat G.C. Aspects of the epidemiology of lung cancer in smokers and nonsmokers in the United States.Lung Cancer. 1996; 15: 1-20Abstract Full Text PDF PubMed Scopus (69) Google Scholar,7Schabath M.B. Wu X. Vassilopoulou-Sellin R. Vaporciyan A.A. Spitz M.R. Hormone replacement therapy and lung cancer risk: a case-control analysis.Clin Cancer Res. 2004; 10: 113-123Crossref PubMed Scopus (172) Google Scholar; however, these findings are far from consistent across studies. Numerous studies have attempted to investigate sex discrepancies by examining the relationship between reproductive factors and multiple cancers.8Lambertini M. Santoro L. Del Mastro L. et al.Reproductive behaviors and risk of developing breast cancer according to tumor subtype: a systematic review and meta-analysis of epidemiological studies.Cancer Treat Rev. 2016; 49: 65-76Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 9Kvale G. Heuch I. Ursin G. Reproductive factors and risk of cancer of the uterine corpus: a prospective study.Cancer Res. 1988; 48: 6217-6221PubMed Google Scholar, 10Chiaffarino F. Pelucchi C. Parazzini F. et al.Reproductive and hormonal factors and ovarian cancer.Ann Oncol. 2001; 12: 337-341Abstract Full Text PDF PubMed Scopus (88) Google Scholar In addition to reproductive tumors, these reproductive factors and fluctuations in sex hormones have been linked to tumors stemming from nonreproductive organs and tissues, such as the colorectum, bladder, and lung.11Xu X. Mo Q. Shen H. Wang S. Liu B. Reproductive and hormonal factors and bladder cancer risk: a prospective study and meta-analysis.Aging (Albany NY). 2020; 12: 14691-14698Crossref PubMed Scopus (8) Google Scholar, 12Murphy N. Xu L. Zervoudakis A. et al.Reproductive and menstrual factors and colorectal cancer incidence in the Women’s Health Initiative Observational Study.Br J Cancer. 2017; 116: 117-125Crossref PubMed Scopus (29) Google Scholar, 13Ben Khedher S. Neri M. Papadopoulos A. et al.Menstrual and reproductive factors and lung cancer risk: a pooled analysis from the international lung cancer consortium.Int J Cancer. 2017; 141: 309-323Crossref PubMed Scopus (28) Google Scholar The International Lung Cancer Consortium conducted a case-control study involving 2,064 patients with lung cancer and 5,342 control and that of menarche at years of age of menopause at years of age and menopause were linked to an elevated risk of lung S. et factors in association with lung cancer among women: a pooled analysis from the International Lung Cancer J Cancer. 2021; PubMed Scopus Google Scholar case-control study in of female with lung cancer and female control association between lung cancer and reproductive factors age at menarche and menopause, of menstrual and of and a in risk with the of replacement therapy and M. M. J. L. Hormonal factors and risk of lung cancer among J PubMed Scopus Google Scholar case-control and studies conducted with to the between multiple reproductive factors and lung cancer, the have been conducted a prospective cohort study on the of female individuals from the UK to investigate an association between sex-specific multiple reproductive factors and the incidence of lung cancer. This study was on females from the UK The UK medical and genetic from more than a million UK between and was by the for Health and and the the from UK provided for In this multiple reproductive factors, including age at menarche and reproductive life age at first of and history of as as to hormones such as and Early menarche was as the of the age of Early menopause was as the of years of The age between menarche and menopause was to the reproductive life Lung cancer incidence was according to the International of and from the UK Biobank. the of lung cancer the used from in and as as with lung cancer were from the of the of follow-up to J. M. M. et between and lung cancer risk: a prospective cohort study in UK 2021; Scopus Google Scholar In stratified lung cancer was histologic cell lung cancer and cell lung cancer. cell lung cancer was by International of for and and was by cell and and and other E. M. et al.The of cancers of on international in for cell and cell lung cancer J Cancer. 2021; PubMed Scopus (8) Google Health of for Health Scholar of characteristics with are as and are as these were and the Cox proportional with and were used to the between sex-specific reproductive factors and lung cancer incidence hazard and 95% in the model age, BMI, smoking status, status, and The proportional was in with and the was not by reproductive factors and of in the for In multiple J. M. Reproductive factors and the risk of a cohort study of UK Scopus (29) Google Scholar were to the of between the risk of lung cancer and multiple reproductive of the and with the median of these was as the risk were used to the between groups of reproductive to evaluate the of reproductive factors not a model to the of factors the of and the of multiple factors to sex including age at menopause, history of and of and Stratified analyses according to age, smoking status, BMI, genetic risk et association analysis new lung cancer susceptibility and in genetic susceptibility across 2017; 49: PubMed Scopus Google Scholar and histologic subtypes were conducted to the effects of the of the analyses were with the of with of and multiple with such as age, BMI, smoking status, status, and who lung cancer the second of follow-up were the effects of risk factors on reproductive factors, was conducted to the with and lung cancer. This was by for reproductive consistent with those in the Cox and to individuals on the of a ratio of to with analyses were conducted for the the was for multiple and a of was significant in male patients were with with lung cancer at 273,190 female were in the study and 1,182 cases of lung cancer were recorded a median follow-up period of 12.0 The characteristics of the female in the study were in that the with a lung cancer were and were more to smoke. In of reproductive factors, lung cancer was with an age at menarche and menopause, shorter reproductive span, age at first birth, of and to for reproductive factors of was provided in of 273,190 UK Lung Cancer Cancer A of the not to smoking smoking smoking not to not to at of at first birth, of of of of reproductive at menopause, of of used used are as of replacement in a new are as of replacement of reproductive showed a association with risk of lung cancer Early menarche (age at ≤ 11 was linked to an increased incidence of lung cancer 1.22; 95% CI, with female who menarche at age In with who menopause at a of to years of age, early menopause was associated with a and increased risks of lung cancer in female who menopause 46 years of age 1.49; 95% CI, and between and years of age 1.42; 95% CI, In the relationship between reproductive life span and risk of lung cancer and that female with reproductive years (≤ 32 years: HR, 1.42; 95% CI, 1.18-1.71; 33-35 years: HR, 1.24; 95% CI, showed higher risks of lung cancer than those with a reproductive life span from 36 to The of factors between the risk of lung cancer and reproductive factors, such as age at menarche age at menopause and reproductive years a history of was to an elevated risk of lung cancer 95% CI, a history of was not associated with risk of lung cancer with those who never Reproductive and Lung Cancer in Female for age and for smoking status, and of at ≤ at menopause, ≤ years ≤ at first birth, ≤ of of of used hazard replacement for age and for smoking status, and in a new hazard replacement In of factors, age at of first birth was identified as being associated with an increased risk of lung cancer in a relationship with female who were at the of first birth being at a risk of lung cancer developing (≤ 20 years: HR, 1.63; 95% CI, years: HR, 95% CI, than female first birth between and years of were identified as risk factors for lung cancer was the of In the a relationship was between and the risk of lung cancer 95% CI, identified a significant association between and risk of lung cancer in the model 95% CI, however, this association in the model for age, BMI, smoking status, status, and in the was with a higher risk of lung cancer in with a age of years in the stratified analysis 95% CI, In stratified analysis was according to age at smoking status, status, genetic and histologic subtypes of lung cancer. that the of the findings with multiple reproductive factors a of significant in with age of years with a smoking history and of 25 studies have the of genetic risks on the relationship between risk of lung cancer and histologic and identified a stronger association between the findings in a subpopulation with a higher genetic In of histologic several reproductive factors, such as early menopause, shortened reproductive span, and early age at first birth, showed a stronger association with the incidence of not of cell lung cancer a more of including cell and other of lung cancer, and that the association between reproductive factors and lung cancer risk was more significant in and other of lung cancer, particularly in the stratified analyses of populations with smoking the of the and the of on menopause, a analysis was conducted by who The of reproductive factors, such as age at menopause, reproductive and age at first birth, were to the thus indicating the of in female individuals. In a analysis with multiple and for a to the to the effects of multiple reproductive factors, the between and reproductive and lung cancer risk were The showed between the of multiple reproductive factors in the model and those that factors not the estimated to the of analyses were by female with the second of ratio of with was to The were with the thus a relationship between multiple reproductive factors and the occurrence of lung cancer In the prospective cohort study of to of European to provided evidence that multiple reproductive factors, including age at menopause, shorter reproductive span, and age at the of first birth, were associated with elevated risks of lung cancer developing in particularly a subtype of Numerous studies have between reproductive factors, such as age at the of menarche menopause and lung cancer, the across and cohort studies have been C. et of the age at menarche with cancer risks in pooled from Res. 2021; PubMed Scopus Google Shen L. B. factors, reproductive factors and lung cancer risk: a 15: Google Scholar and study lung cancer and factors, such as may be to this In a cohort study from Wang F. F. et al.Menstrual factors, reproductive and risk of lung a cohort study in Lung Cancer Res. 2021; 10: PubMed Scopus Google Scholar menarche years of was linked to a higher risk of adenocarcinoma in a cohort study in with female to years of age with years of menarche was linked to a incidence of lung cancer, with the being for the histologic subtype of A. et al.Reproductive and hormonal factors and lung cancer risk in the and Health Study PubMed Scopus Google Scholar In this with early menarche (≤ 11 years of showed a higher risk of lung cancer association was identified in those with menarche years of between age at menopause and risk of lung cancer were in A. J. of and and the risk of lung cancer in J Cancer. PubMed Scopus Google M. et al.Reproductive and hormonal factors and the risk of lung the J Cancer. PubMed Scopus Google Scholar that a studies used the of menarche and menopause as used of age, such as early of menarche and menopause, may have in different findings of the of the prospective cohort study of female including female patients with lung cancer, to an association between lung cancer and multiple reproductive factors, such as age at the of menarche and menopause, of and history of et reproductive factors and the risk of lung cancer in women: a cohort J Cancer. 2020; PubMed Scopus Google Scholar findings showed an elevated risk of lung cancer in female who early menarche 11 years of early menopause (≤ years of and reproductive life span Although were prospective cohort studies with in several these populations from different may have to the to populations with a status, such as an age of years for menarche and to years of age for menopause, were as the in more and In reproductive span of ≤ years has been linked to a substantially elevated incidence of lung cancer. the of this was the prospective cohort study to a association between reproductive span and lung cancer, to studies. the of the findings the analysis showed that female who menopause of The of these findings to menarche and menopause a in with a age of years and those with a history of This is the first to the of genetic susceptibility on risk of lung cancer and histologic identified a stronger association in a subpopulation with higher genetic susceptibility that not been identified In of histologic several reproductive factors, such as early menopause, shortened reproductive span, and early age at first birth, showed a association with an elevated risk of and other of lung cancer, was consistent with A. et al.Reproductive and hormonal factors and lung cancer risk in the and Health Study PubMed Scopus Google M. et al.Reproductive and hormonal factors and the risk of lung the J Cancer. PubMed Scopus Google et effects on and of with cell lung cancer.Ann Full Text Full Text PDF PubMed Scopus Google A. et al.Reproductive and hormonal factors and the risk of cell lung J Cancer. PubMed Scopus Google Scholar et revealed that in female patients showed higher for and than in female patients, tumor and and was to in lung E. R. et and by sex and hormonal in lung Res. PubMed Scopus Google Scholar tumors, including tumors, and for of other histologic lung cancer and were of such as and reproductive factors in female G. N. et of and in PubMed Google Wu Wang tumor of the with and 10: PubMed Scopus (8) Google Scholar cases of cell were among other of lung cancer. In cell elevated of increased the of and J. X. N. S. the and of cell lung cancer 2018; PubMed Scopus Google Scholar, et of on and of lung cancer PubMed Scopus Google Scholar, L. J. R. of by and in cell PubMed Scopus Google Scholar on the that early menarche and menopause, as as a shortened reproductive span, are associated with a higher incidence of particularly in populations with higher genetic susceptibility more detrimental factors, such as of hormones has been of the major G.C. Aspects of the epidemiology of lung cancer in smokers and nonsmokers in the United States.Lung Cancer. 1996; 15: 1-20Abstract Full Text PDF PubMed Scopus (69) Google Scholar to significant female reproductive for the of between menarche and J. A. Wang hormones and lung 2021; PubMed Scopus Google Scholar A role of is in the and of M. et al.Reproductive and hormonal factors and the risk of lung the J Cancer. PubMed Scopus Google et al.Menstrual and reproductive factors in association with lung cancer in female J PubMed Scopus Google Scholar in the detrimental effects of early menopause and shorter reproductive that female patients who a history of not were susceptible to a risk of lung cancer, and this was in who were than who not who a of who showed genetic risk, and particularly in those with The elevated risk of lung cancer may be the of the early of on lung at a T. B. et menopause is associated with lung and increased mortality among female J Full Text Full Text PDF PubMed Scopus Google Scholar Although be that early age at menarche was to an elevated risk of lung cancer. early age at menarche may more menstrual over the of a and to Lung tumor be by hormonal such as and in lung Oncol. PubMed Scopus Google Scholar and may of lung tumor G. Liu X. et in lung cancer PubMed Scopus Google Scholar that in this cohort with early menarche showed higher of early menopause not and that this may be by these findings the of that was a risk for lung cancer in female than years with a of and the increased risk to years of In a significant of female may have been the of ovarian has been to distinguish between the effects of and with a history of from the the of detrimental effects of and thus In these findings may have been by such as the in total of hormones used between female patients in and reproductive particularly the and of were higher in the M. T. S. Reproductive factors, and the risk of lung cancer among women: a cohort J Cancer. PubMed Scopus Google Scholar to the in factors, a of surrounds the association between and risk of lung cancer, the that has been linked to risk in most M. M. J. L. Hormonal factors and risk of lung cancer among J PubMed Scopus Google G. Liu X. et in lung cancer PubMed Scopus Google C. H. A. et therapy and lung cancer risk in the cancer prevention study PubMed Scopus Google Scholar not all including the Women’s Health Initiative et cancer among with in the Natl Cancer Inst. PubMed Scopus Google H. et and lung cancer in Health Initiative a analysis of a Full Text Full Text PDF PubMed Scopus Google Scholar have the more studies with are to the relationship and in the prospective studies in the have the between factors and incidence of lung cancer. In the the of association with lung cancer, age than 20 years at the of first birth was linked to an elevated incidence of lung cancer with female first birth between and years of age, in with several M. et al.Reproductive and hormonal factors and the risk of lung the J Cancer. PubMed Scopus Google G.C. Reproductive and hormonal factors and risk of lung cancer in women: a prospective cohort J Cancer. PubMed Scopus Google Scholar in to most studies that to a A. et al.Reproductive and hormonal factors and the risk of cell lung J Cancer. PubMed Scopus Google et al.Menstrual and reproductive factors in association with lung cancer in female J PubMed Scopus Google M. T. S. Reproductive factors, and the risk of lung cancer among women: a cohort J Cancer. PubMed Scopus Google Scholar association was between and lung cancer risk, thus to The of the study are that a and this prospective cohort study years of In are the first to to genetic risk to the relationship between reproductive factors and lung cancer, on different genetic an with of not as a the study has this study may be on and to the of of multiple reproductive female in the study were and individuals of European the and of the findings for other most who was to the on lung cancer to not the multiple were to the of factors, other factors to that were not such as and of the A. C. et of and characteristics of UK with those of the J 2017; PubMed Scopus Google Scholar In this identified that reproductive factors, including early age at menopause, shorter reproductive life span, and age at first birth, were associated with a risk of lung cancer, particularly in a subpopulation with higher genetic susceptibility and more detrimental behaviors. The evidence provided by this study the of screening for multiple reproductive factors to prevent lung cancer among populations of This was by the of the for of and the the of the of the the of the of the of the of the on and of and the and from

Topics & Concepts