Sex differences in lung cancer susceptibility: A review

doi:10.1016/j.genm.2010.10.002

Gender Medicine

Volume 7, Issue 5, October 2010, Pages 381-401

https://doi.org/10.1016/j.genm.2010.10.002 Get rights and content

Abstract

Background: Several epidemiologic and molecular epidemiologic studies have indicated that, for a given number of cigarettes smoked, women may be at higher risk of lung cancer compared with men.

Objective: The objective of this article was to address sex differences in lung cancer susceptibility, with special emphasis on genetic, biological, and sex-related hormonal factors.

Methods: Using the search terms gender or sex difference in combination with lung cancer, susceptibility, survival, polymorphism, biomarker, and smoking, we conducted a review of the available literature in the MEDLINE, Current Contents, and Web of Science biomedical databases. Relevant English-language publications (January 1966–December 2009) on sex differences in lung cancer were identified.

Results: Higher levels of polycyclic aromatic hydrocarbon DNA adducts were observed in female lung cancer patients compared with their male counterparts, even though the level of tobacco carcinogens was lower among women than among men. DNA repair capacity was found to be lower in female lung cancer patients than in their male counterparts. A higher frequency of G-to-T transversion mutations in the tumor suppressor protein p53 gene has been observed in women compared with men. Non-small cell lung tumors in women appeared to be more likely than those in men to harbor K-ras, c-erbB-2, or epidermal growth factor receptor mutations. Sex differences have been identified in the expression of the cytochrome P4501A1 gene and gastrin-releasing peptide receptor gene, with women exhibiting higher gene expression than men for both of these genes. Evidence supporting a possible association between estrogen and lung cancer risk based on epidemiologic studies has not been consistent, but sex hormones may influence susceptibility to lung carcinogenesis.

Conclusions: Women may be more susceptible to tobacco smoke and potentially more vulnerable to lung cancer development. If additional studies yield supporting evidence, researchers, the public, and policy makers should focus on ways to reduce the risk of lung cancer for women.

References (133)

S Payne
‘Smoke like a man, die like a man’?: A review of the relationship between gender, sex and lung cancer
Soc Sci Med.
(2001)
P Boyle et al.
Cancer incidence and mortality in Europe, 2004
Ann Oncol.
(2005)
HH McDuffie et al.
Determinants of cell type in patients with cancer of the lungs
Chest.
(1990)
AJ Alberg et al.
Epidemiology of lung cancer
Chest.
(2003)
JB Fu et al.
Lung cancer in women: Analysis of the national Surveillance, Epidemiology, and End Results database
Chest.
(2005)
BE Johnson et al.
Female patients with small cell lung cancer live longer than male patients
Am J Med.
(1988)
D Ouellette et al.
Lung cancer in women compared with men: Stage, treatment, and survival
Ann Thorac Surg.
(1998)
D Ouellette et al.
Lung cancer in women compared with men: Stage, treatment, and survival
Ann Thorac Surg.
(1998)
H Minami et al.
Lung cancer in women: Sex-associated differences in survival of patients undergoing resection for lung cancer
Chest.
(2000)
R Moore et al.
Sex differences in survival in non-small cell lung cancer patients 1974–1998
Acta Oncol.
(2004)
NE Caporaso et al.
New malignancies following cancer of the respiratory tract

CP Belani et al.

Women and lung cancer: Epidemiology, tumor biology, and emerging trends in clinical research

Lung Cancer.

(2007)

LT Nordquist et al.

Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung

Chest.

(2004)

JH Lubin et al.

Assessment of lung cancer risk factors by histologic category

J Natl Cancer Inst.

(1984)

H Tulinius et al.

Risk factors for malignant diseases: A cohort study on a population of 22,946 Icelanders

Cancer Epidemiol Biomarkers Prev.

(1997)

JE Castelao et al.

Genderand smoking-related bladder cancer risk

J Natl Cancer Inst.

(2001)

P Hartge et al.

Unexplained excess risk of bladder cancer in men

J Natl Cancer Inst.

(1990)

G Kellermann et al.

Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma

N Engl J Med.

(1973)

AK Alexandrie et al.

Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: A study on host factors in relation to age at onset, gender and histological cancer types

Carcinogenesis.

(1994)

D Ryberg et al.

Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients

Cancer Res.

(1994)

EH Kure et al.

p53 Mutations in lung tumours: Relationship to gender and lung DNA adduct levels

Carcinogenesis.

(1996)

DM Parkin et al.

Global cancer statistics, 2002

CA Cancer J Clin.

(2005)

C Kiyohara et al.

Genetic polymorphisms and environmental risk of lung cancer: A review

Rev Environ Health.

(2004)

E Taioli et al.

Re: Endocrine factors and adenocarcinoma of the lung in women

J Natl Cancer Inst.

(1994)

S Zheng et al.

A genetic mouse model for metastatic lung cancer with gender differences in survival

Oncogene.

(2007)

SA Belinsky et al.

The A/J mouse lung as a model for developing new chemointervention strategies

Cancer Res.

(1993)

AD Lopez

The Lung Cancer Epidemic in Developed Countries

US Department of Health and Human Services, Office of the Surgeon General. Women and Smoking: A Report of the Surgeon...

Lung cancer

T Marugame et al.

Lung cancer death rates by smoking status: Comparison of the Three-Prefecture Cohort study in Japan to the Cancer Prevention Study II in the USA

Cancer Sci.

(2005)

US Department of Health and Human Services, Public Health Service, Office on Smoking and Health. The health...

JH Lubin et al.

Patterns of lung cancer risk according to type of cigarette smoked

Int J Cancer.

(1984)

D Hoffmann et al.

Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines: Chemistry, biochemistry, carcinogenicity, and relevance to humans

J Toxicol Environ Health.

(1994)

BR Davis et al.

Response of rat lung to inhaled tobacco smoke with or without prior exposure to 3,4-benzpyrene (BP) given by intratracheal instillation

Br J Cancer.

(1975)

SS Devesa et al.

Changing patterns of lung cancer incidence by histological type

Cancer Epidemiol Biomarkers Prev.

(1991)

AR Patel et al.

Adenocarcinoma of the lung

Cancer Epidemiol Biomarkers Prev.

(1995)

F Levi et al.

Lung carcinoma trends by histologic type in Vaud and Neuchâtel, Switzerland, 1974–1994

Cancer.

(1997)

MK Ferguson et al.

Sex-associated differences in presentation and survival in patients with lung cancer

J Clin Oncol.

(1990)

MK Ferguson et al.

Sexassociated differences in survival of patients undergoing resection for lung cancer

Ann Thorac Surg.

(2000)

MK Ferguson et al.

Sexassociated differences in survival of patients undergoing resection for lung cancer

Ann Thorac Surg.

(2000)

C Alexiou et al.

Do women live longer following lung resection for carcinoma?

Eur J Cardiothorac Surg.

(2002)

R Bátevik et al.

The female gender has a positive effect on survival independent of background life expectancy following surgical resection of primary non-small cell lung cancer: A study of absolute and relative survival over 15 years

Lung Cancer.

(2005)

H Asamura et al.

A Japanese Lung Cancer Registry study: Prognosis of 13,010 resected lung cancers

J Thorac Oncol.

(2008)

E Radzikowska et al.

Lung cancer in women: Age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20,561 cases

Ann Oncol.

(2002)

HH McDuffie et al.

Femalemale differences in patients with primary lung cancer

Cancer.

(1987)

JB Schoenberg et al.

Variation in smoking-related lung cancer risk among New Jersey women

Am J Epidemiol.

(1989)

KE Osann et al.

Sex differences in lung-cancer risk associated with cigarette smoking

Int J Cancer.

(1993)

RC Brownson et al.

Gender and histologic type variations in smoking-related risk of lung cancer

Epidemiology.

(1992)

HA Risch et al.

Are female smokers at higher risk for lung cancer than male smokers? A case-control analysis by histologic type

Am J Epidemiol.

(1993)

RE Harris et al.

Race and sex differences in lung cancer risk associated with cigarette smoking

Int J Epidemiol.

(1993)

Cited by (155)

Sex gaps in perception of tobacco conversations between adult patients who now smoke cigarettes and oral health care providers: National Health and Nutrition Examination Survey 2017-March 2020 prepandemic
2023, Journal of the American Dental Association
Smoking cessation is difficult. A potential gap based on sex exists in the tobacco cessation aid that dental care professionals provide to patients. The purpose of this research was to examine whether there is a sex difference in dental patients' reports of having a direct conversation about the benefits of giving up cigarettes or other types of tobacco products with their oral health care provider.
National Health and Nutrition Examination Survey 2017-March 2020 prepandemic data were used in this cross-sectional study for participants 18 years and older who reported that they “now smoke cigarettes,” had a dental visit within the previous year, self-reported their sex, and responded whether their oral health care provider had a direct conversation about the benefits of giving up cigarettes or other types of tobacco products to improve dental health at their last visit (n = 582). Multivariable logistic regression analysis was conducted to compare data according to sex.
Overall, 50.7% of patients (59.2% of men, 42.9% of women; P = .0037) reported having a conversation about tobacco cessation at their dental visit. The odds of women reporting having no such discussion were twice those of men (odds ratio, 2.17; 95% CI, 1.10 to 4.28; P = .0270).
One-half of the participants reported having no tobacco cessation conversation about the benefits of giving up cigarettes or other types of tobacco with their dental care provider. Women were twice as likely to report no such discussion.
Oral health care providers need to ensure that primary and secondary prevention information and intervention programs about the benefits of giving up cigarettes or other types of tobacco products are provided equitably to all patients.
Role of geographic characteristics in the spatial cluster detection of cancer: Evidence in South Korea, 1999–2013
2023, Environmental Research
Identification of high-risk areas of cancer, referred to as spatial clusters, can inform targeted policies for cancer control. Although cancer cluster detection could be affected by various geographic characteristics including sociodemographic and environmental factors which impacts could also vary over time, studies accounting for such influence remain limited. This study aims to assess the role of geographic characteristics in the spatial cluster detection for lung and stomach cancer over an extended period.
We obtained sex-specific age-standardized incidence and mortality rates of lung and stomach cancer as well as geographic characteristics across 233 districts in South Korea for three five-year periods between 1999 and 2013. We classified geographic characteristics of each district into four categories: demography, socioeconomic status, behaviors, and physical environments. Specifically, we quantified physical environments using measures of greenness, concentrations of particulate matter and nitrogen dioxide, and air pollution emissions. Finally, we conducted cluster detection analyses using weighted normal spatial scan statistics with the residuals from multiple regression analyses performed with the four progressive sets of geographic attributes.
We found that the size of clusters reduced as we progressively adjusted for geographic covariates. Among the four categories, physical environments had the greatest impact on the reduction or disappearance of clusters particularly for lung cancer consistently over time. Whereas older population affected a decrease of lung cancer clusters in the early period, the contribution of education was large in the recent period. The impact was less clear in stomach cancer than lung cancer.
Our findings highlight the importance of geographic characteristics in explaining the existing cancer clusters and identifying new clusters, which jointly provides practical guidance to cancer control.
Calcium Intake and Lung Cancer Risk: A Pooled Analysis of 12 Prospective Cohort Studies
2023, Journal of Nutrition
Previous studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to the differences in intake amounts and contributing sources of calcium and smoking prevalence.
We investigated the associations of lung cancer risk with intake of calcium from foods and/or supplements and major calcium-rich foods in 12 studies.
Data from 12 prospective cohort studies conducted in the United States, Europe, and Asia were pooled and harmonized. We applied the DRI to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intake. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall HR (95% CI).
Among 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 y. Overall, the dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98–1.18) for higher (>1.5 RDA) and 1.01 (0.95–1.07) for lower intake (<0.5 RDA) comparing with recommended intake (EAR to RDA). Milk and soy food intake were positively or inversely associated with lung cancer risk [HR (95% CI) = 1.07 (1.02–1.12) and 0.92 (0.84–1.00)], respectively. The positive association with milk intake was significant only in European and North American studies (P-interaction for region = 0.04). No significant association was observed for calcium supplements.
In this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.
Daily adherence to nicotine replacement therapy in low-income smokers: The role of gender, negative mood, motivation, and self-efficacy
2023, Addictive Behaviors
Low-income smokers may benefit from interventions promoting nicotine replacement therapies (NRTs), particularly for women, as women have worse smoking cessation outcomes than men. Little is known about factors that affect daily NRT adherence, such as negative mood, motivation, and self-efficacy, and whether gender moderates these associations.
Secondary analysis of a randomized controlled trial comparing a novel, in session sampling of short-acting combination NRT intervention (In Vivo) to standard care smoking cessation behavioral counseling was performed. Low-income smokers (n = 62; M_age = 47.4; 42 % female; 61 % non-White) completed daily surveys using the Insight™ mHealth platform for 55 consecutive days. Three types of NRT adherence were examined: dose amount of short-acting NRT, nicotine patch wear time, and combination NRT (cNRT) (combined nicotine patch and short-acting NRT).
Generalized multilevel models report same-day negative mood was associated with greater likelihood of nicotine patch adherence in men, but unrelated to women’s nicotine patch adherence. Same-day negative mood was associated with greater likelihood of cNRT adherence in men, but less likelihood in women. The relationship between same-day motivation and use of short-acting NRT varied by gender, but simple slope analyses revealed that motivation was unrelated to short-acting NRT use within either group. Same-day self-efficacy was related to an increased likelihood of nicotine patch adherence and cNRT adherence in women but unrelated to men’s adherence of either type.
Future research should focus on gender differences in low-income smokers’ same-day negative mood, motivation, and self-efficacy processes on NRT adherence during smoking cessation interventions.
The prognostic impact of KRAS, TP53, STK11 and KEAP1 mutations and their influence on the NLR in NSCLC patients treated with immunotherapy
2023, Cancer Treatment and Research Communications
PD-L1 expression is used to predict NSCLC response to ICIs, but its performance is suboptimal. The impact of KRAS mutations in these patients is unclear. Studies evaluating co-mutations in TP53, STK11 and KEAP1 as well as the NLR showed that they may predict the benefit of ICIs.
This is a retrospective study of patients with NSCLC treated with ICIs at the CHUM between July 2015 and June 2020. OS and PFS were compared using Kaplan-Meier and logrank methods. Co-mutations in TP53, STK11 and KEAP1 as well as the NLR were accounted for. ORR and safety were compared using Wald method.
From 100 patients with known KRAS status, 50 were mutated (KRAS^Mut). Mutation in TP53, STK11 and KEAP1 were present, and their status known in, respectively, 19/40 (47.5 %), 8/39 (20.5 %) and 4/38 (10.5 %) patients. STK11^Mut and KEAP1^Mut were associated with shorter overall survival when compared with wild type tumors (respectively median OS of 3.3 vs 20.4, p = 0.0001 and 10.1 vs 17.7, p = 0.24). When KRAS status was compounded with STK11/KEAP1, KRAS^Mut trended to a better prognosis in STK11+KEAP1^WT tumors (median OS 21.1 vs 15.8 for KRAS^WT, p = 0.15), but not for STK11+/-KEAP1^Mut tumors. The NLR was strongly impacted by STK11 (6.0^Mut vs 3.6^WT, p = 0.014) and TP53 (3.2^Mut vs 4.8^WT, p = 0.048), but not by KEAP1 or KRAS mutations.
STK11^Mut and KEAP1^Mut are adverse predictors of ICI therapy benefit. The NLR is strongly impacted by STK11^Mut but not by KEAP1^Mut, suggesting differences in their resistance mechanism. In STK11-KEAP1^WT tumors, KRAS^Mut seem associated with improved survival in NSCLC patients treated with ICIs.
Response of NSCLC to immunotherapy is not easily predictable. We conducted a retrospective study in 100 patients with NSCLC and a known KRAS status. By accounting for different co-mutations, KRAS mutation was found to be associated with a better median overall survival in STK11 and KEAP1 wild-type tumors (21.1 vs 15.8, p = 0.15). NLR was impacted by STK11, but not KEAP1 mutation, suggesting a difference in their resistance mechanism.
Lung Cancer in Women
2022, Annals of Thoracic Surgery
Citation Excerpt :
Several large case-control studies have shown that women are at higher risk of lung cancer than men at all smoking levels, with an odds ratio (OR) almost 3 times greater.4,9,10 Additionally women are often diagnosed with lung cancer at a younger age than men despite lower cigarette consumption.4 These differences are hypothesized to be caused by a greater susceptibility of women to the damaging effects of tobacco carcinogens.
Lung cancer is the leading cause of cancer-related death for women in the United States. Clinical characteristics, histology, epidemiology, and treatment responses are unique for women with lung cancer.
A literature search of Medline publications from 1989 to 2021 was conducted for lung cancer in women. Subsequent narrative review focused on identified differences in risk factors, diagnosis, and treatment of importance to the surgical care of these patients.
Studies investigating lung cancer in which sex differences were explored demonstrated differences in risk factors, histology, and treatment response among women, with a significant postsurgical survival advantage over men (41.8 months vs 26.8 months, P = .007) and greater clinical benefit from anti-PD-1 combined with chemotherapy (hazard ratio, 0.44; 95% confidence interval, 0.25-0.76) compared with men (hazard ratio, 0.76; 95% confidence interval, 0.64-0.91). Smoking remains a dominant risk factor, and multiple clinical trials suggest lung cancer screening provides greater benefit for women. However young nonsmoking patients with lung cancer are 2-fold more likely to be female, advocating for broader sex-based screening criteria. Potential roles of genetic mutations, estrogen signaling, and infectious elements in sex-based differences in presentation, histology, prognosis, and treatment response are explored.
Overall much remains unknown regarding how sex influences lung cancer risk, treatment decisions, and outcomes. However evidence of specific differences in presentation, environmental risk, molecular drivers, and mutational burden support the need to better leverage these sex-associated differences to further improve detection, diagnosis, surgical outcomes, and systemic regimens to advance the overall care strategy for women with lung cancer.

View all citing articles on Scopus

View full text

Sex differences in lung cancer susceptibility: A review

Abstract

Soc Sci Med.

Ann Oncol.

Chest.

Chest.

Chest.

Am J Med.

Ann Thorac Surg.

Ann Thorac Surg.

Chest.

Acta Oncol.

Lung Cancer.

Chest.

J Natl Cancer Inst.

Cancer Epidemiol Biomarkers Prev.

J Natl Cancer Inst.

J Natl Cancer Inst.

N Engl J Med.

Carcinogenesis.

Cancer Res.

Carcinogenesis.

Global cancer statistics, 2002

CA Cancer J Clin.

Genetic polymorphisms and environmental risk of lung cancer: A review

Rev Environ Health.

Re: Endocrine factors and adenocarcinoma of the lung in women

J Natl Cancer Inst.

A genetic mouse model for metastatic lung cancer with gender differences in survival

Oncogene.

The A/J mouse lung as a model for developing new chemointervention strategies

Cancer Res.

The Lung Cancer Epidemic in Developed Countries

Lung cancer

Lung cancer death rates by smoking status: Comparison of the Three-Prefecture Cohort study in Japan to the Cancer Prevention Study II in the USA

Cancer Sci.

Patterns of lung cancer risk according to type of cigarette smoked

Int J Cancer.

Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines: Chemistry, biochemistry, carcinogenicity, and relevance to humans

J Toxicol Environ Health.

Response of rat lung to inhaled tobacco smoke with or without prior exposure to 3,4-benzpyrene (BP) given by intratracheal instillation

Br J Cancer.

Changing patterns of lung cancer incidence by histological type

Cancer Epidemiol Biomarkers Prev.

Adenocarcinoma of the lung

Cancer Epidemiol Biomarkers Prev.

Lung carcinoma trends by histologic type in Vaud and Neuchâtel, Switzerland, 1974–1994

Cancer.

Sex-associated differences in presentation and survival in patients with lung cancer

J Clin Oncol.

Sexassociated differences in survival of patients undergoing resection for lung cancer

Ann Thorac Surg.

Sexassociated differences in survival of patients undergoing resection for lung cancer

Ann Thorac Surg.

Do women live longer following lung resection for carcinoma?

Eur J Cardiothorac Surg.

The female gender has a positive effect on survival independent of background life expectancy following surgical resection of primary non-small cell lung cancer: A study of absolute and relative survival over 15 years

Lung Cancer.

A Japanese Lung Cancer Registry study: Prognosis of 13,010 resected lung cancers

J Thorac Oncol.

Lung cancer in women: Age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20,561 cases

Ann Oncol.

Femalemale differences in patients with primary lung cancer

Cancer.

Variation in smoking-related lung cancer risk among New Jersey women

Am J Epidemiol.

Sex differences in lung-cancer risk associated with cigarette smoking

Int J Cancer.

Gender and histologic type variations in smoking-related risk of lung cancer

Epidemiology.

Are female smokers at higher risk for lung cancer than male smokers? A case-control analysis by histologic type

Am J Epidemiol.

Race and sex differences in lung cancer risk associated with cigarette smoking

Int J Epidemiol.