Sex and Gender in LUNG CANCER
How Big is the Problem?
Historically, lung cancer has mostly affected men and was considered rare in women. Although lung cancer mortality is still high in men accounting for 36 in 100,000 deaths, it is now also becoming a much more important cause of cancer death in women, accounting for about 13 in 100,000 deaths. The incidence rate across Europe is just over 290 per 1000,000 for men and 119 per 100,000 for women.1 It is predicted that lung cancer will cause nearly 187,000 male deaths and 93,000 female deaths in 2015, accounting for over 20% of cancer deaths in Europe.2,3
Over the last decades there has been a decline in men’s lung cancer dropping by 8% across Europe from 2000-2004 to 2005-2009. Despite this drop, lung cancer remains the principle cause of cancer death in men. There are marked country by country variation with the eastern European countries showing the highest mortality rates at over 50 per 100,000 in much of Eastern Europe as compared to 35-40 per 100,000 in western Europe.3
The rate of new cases of lung cancer in men is leveling off or decreasing in nearly all countries across Europe with an overall decline in smoking, but there are exceptions to this trend, with Belgium, Bulgaria, Iceland and Romania all seeing increases between 2000-2004 and 2005- 2009.3 The fall in lung cancer is greatest in younger men; it is now estimated that only about 25% of young European men ages 20 to 25 years smoke as compared to 60% in the 1980s.
For women, there has been an overall increase in female lung cancer of 50% between the mid 1960s and the early 2000s across Europe.3,4 While there are indications that in some countries rates of lung cancer in women have started to fall in recent years, the overall rates continue to climb across the EU, rising to 14 in 100,000 deaths by 2015. Female lung cancer rates in the 35 to 64 age range are now greater than male rates in Denmark, Iceland and Sweden.5 The female lung cancer epidemic is expanding in countries of western and southern Europe, particularly in France, Portugal and Spain due to a recent uptake of smoking by women.4
Cancer of the lung/bronchus is the third most common cancer among women (7.4%) and second for men (15.9%).q In women, lung cancer death has overtaken that of breast in many European Countries including Denmark, Hungary, Iceland, Ireland, Poland, Sweden and the UK.1 A recent study estimates that in the UK, for example, lung cancer death is expected to quadruple in women in the next 30 years.6 However, while women fear breast cancer, they seem to be unaware of their lung cancer risk. The poor prognosis for lung cancer leads to similar incidence and mortality patterns throughout the world.
Relatively low survival rates mean that despite high incidence rates there are fewer patients surviving. Lung cancer is one of the most lethal cancers with only 13% average relative survival at 5 years in Europe with better survival for women than for men at 16% and 12% respectively.7 Although this has long been recognised,8 the reasons are still not fully understood. However, the effect seems to be mostly limited to early stage adenocarcinoma; sex does not affect survival of patients with squamous carcinoma.9
Prevention of Lung Cancer
Although lung cancer is deadly, it is highly preventable. The most important cause of lung cancer is smoking, accounting for 85% of lung cancer cases in men and 80% of cases in women in the UK.10 Across Europe, men still are heavier smokers than women, but the gap has been narrowing due to a decrease in male smokers and increase in female smokers in some countries. Women stopping smoking well before the age of 30 avoids more than 97% of the excess mortality caused by continuing smoking, but those who have smoked at some point in their life retain a 1.2 greater risk of death than those who have never smoked.11
The most effective approach is to persuade young women not to start smoking, but if they are smoking, the earlier they stop the better. A high percentage of lung cancer in both men and women is smoking-related, though not all.12 Despite lung cancer’s strong association with tobacco use, one in five people who develops the disease has never smoked. Non-smoking women appear to be at two to three times greater risk for developing lung cancer than men, suggesting that other factors such as passive or environmental smoke play a role.13
The Tobacco industry has long targeted young people in the promotion of their products.28 Their aggressive marketing strategies are increasingly aimed at women who are considered to be a lucrative, unexplored market. Creating women-only brands, their packaging plays on the appeal of glamorous images such as cigarettes as party accessories, sponsored events, like women’s tennis games and dances. Female-targeted branding includes light or slim cigarettes, low prices, easy availability and free samples.29 Despite the industry aggressively targeting women with their promotional activities, few anti-smoking initiatives have taken a gender-based approach. 33
Smoking is more common in lower socio-economic groups. Women on average are poorer than men, have a lower employment status, and often are economically dependent. Increasingly, they are heading single parent and low-income households. Their lower-paid work may expose them to a smoking environment through parttime house or hospitality work. Maternal smoking has a devastating effect on their offspring, causing miscarriages, birth defects, premature births etc. Smoking cessation programmes for vulnerable women must offer a way out of breaking the cycle of deprivation and tobacco dependency.
There is a strong link between socio-economic factors and smoking for men too, which brings a higher burden of cancer and further negative impact on struggling families.26 With men being numerically much more at risk of lung cancer in these settings and smoking-attributed mortality accounting for nearly half of total male mortality in the lowest social stratum of each country continued action must be taken to target socially disadvantaged men with smoking cessation programmes.34
Why Gender Matters: Biological Differences
Researchers are just beginning to understand the differences in lung cancer between women and men. Lung cancer results from the interactions between genetic, hormonal, behavioural and environmental factors. For example, the odds of lung cancer in women who have ever smoked heavily compared with those who had never smoked were increased 19-fold, which is more than men for the same number.15
The gender difference in cancer susceptibility is one of the most consistent findings in cancer epidemiology, although findings are often questioned. .14,16,17 Additional research into the gender and biological differences needs to be urgently encouraged and funded.
Studies suggest that lung cancer differs biologically between men and women1:6, 18-22
- Women’s genes may make them more vulnerable to the harmful effects of smoking.
- Women’s bodies may metabolise the chemicals in tobacco differently.
- Various genetic associations with lung cancer are specific to either males or females, which either increase their risk of developing the disease or being protected from it.
- Elderly women with early lung cancer have better risk adjusted survival than men, both when treated and untreated.
- A lowered ability to repair DNA damage may aid in cancer development.
- Women’s hormones, such as estrogen, may directly or indirectly influence cancer progression.
- Some treatments may work better in women than men.
Why Gender Matters: Biological Differences
Though men are more likely to develop and die from lung cancer, many are still unaware of the risk and the signs and symptoms they should be reporting. In part, this is due to an overall lower understanding of health and being less likely to seek health information in men compared to women.24 This view of men being unlikely to present with what they consider ‘trivial’ conditions is reinforced by the negative response from health professionals some men receive on self referral.25 More men die of lung cancer because they are more likely to smoke, so more effort needs to be made in getting smoking prevention programmes in place.26
Few studies have explored the differences between women and men in the procedures and outcomes of lung cancer screening. Studies have found that women were less likely to undergo surgery to treat lung cancer than men. Radiation therapy is more frequently administered to men than women.
Women have better survival rates than men following surgery even when adjusting for confounders for both non-small cell and small cell lung cancers as well as various types of treatments (surgery, chemotherapy, radiation therapy, no treatment)—although the reasons for the difference are unknown. Targeted therapies, adjusting for tumor characteristics, are improving lung cancer treatment. One of the most promising molecular targets to-date in lung cancer treatment focuses on the epidural growth factor receptor gene (EGFR). Mutations in this gene are more common in women who have never smoked and in those with adenocarcinoma of the lung than in other populations.22
Special thanks to expert-contributor
Alan White, PhD, Leeds Beckett University
Special thanks to expert-reviewers
Ramón y Cajal, Madrid, Spain
Norma Cronin, International Network of Women Against Tobacco (INWAT)
Pilar Garrido MD PhD, Hospital Universitario
Christian Grohé, PGD International GmbH
- Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374–403. doi:10.1016/j.ejca.2012.12.027
- Malvezzi M, Bertuccio P, Rosso T, et al. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann Oncol 2015;:1–8. doi:10.1093/annonc/mdv001
- Malvezzi M, Bosetti C, Rosso T, et al. Lung cancer mortality in European men: trends and predictions. Lung Cancer 2013;80:138–45. doi:10.1016/j.lungcan.2013.01.020
- Bosetti C, Malvezzi M, Rosso T, et al. Lung cancer mortality in European women: trends and predictions. Lung Cancer 2012;78:171–8. doi:10.1016/j.lungcan.2012.08.008
- Lortet-Tieulent J, Renteria E, Sharp L, et al. Convergence of decreasing male and increasing female incidence rates in major tobacco-related cancers in Europe in 1988-2010. Eur J Cancer 2013;33. doi:10.1016/j.ejca.2013.10.014
- Maddams J, Utley M, Møller H. Projections of cancer prevalence in the United Kingdom, 2010-2040. Br J Cancer 2012;107:1195–202. doi:10.1038/bjc.2012.366
- De Angelis R, Sant M, Coleman MP, et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE-5-a population-based study. Lancet Oncol 2013;2045:1–12. doi:10.1016/S1470-2045(13)70546-1
- Ederer F, Mersheimer WL. Sex differences in the survival of lung cancer patients. Cancer 1962;15:425–32
- Warwick R, Shackcloth M, Mediratta N, et al. Female sex and long-term survival post curative resection for non-small-cell lung cancer. Eur J Cardiothorac Surg 2013;44:624–30. doi:10.1093/ejcts/ezt139
- Parkin DM. 2. Tobacco-attributable cancer burden in the UK in 2010. Br J Cancer 2011;105 Suppl :S6–13. doi:10.1038/bjc.2011.475
- Pirie K, Peto R, Reeves GK, et al. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet 2013;381:133–41. doi:10.1016/S0140-6736(12)61720-6
- McCartney G, Mahmood L, Leyland AH, et al. Contribution of smoking-related and alcohol-related deaths to the gender gap in mortality: evidence from 30 European countries. Tob Control 2011;20:166–8. doi:10.1136/tc.2010.037929
- Wakelee H a, Chang ET, Gomez SL, et al. Lung cancer incidence in never-smokers. J Clin Oncol 2009;25:472–8. doi:10.1200/JCO.2006.07.2983.Lung
- IARC. Tobacco smoking. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs, Volume 100 (E) 2012. 43– 211
http://monographs.iarc.fr/ENG/Monographs/vol100E/mono100E-6.pdf (accessed 11 May2013)
- Powell HA, Iyen-Omofoman B, Hubbard RB, et al. The association between smoking quantity and lung cancer in men and women. Chest 2013;143:123–9. doi:10.1378/chest.12-1068
- Dorak MT, Karpuzoglu E. Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet 2012;3. doi:10.3389/fgene.2012.00268
- De Matteis S, Consonni D, Pesatori AC, et al. Are women who smoke at higher risk for lung cancer than men who smoke? Am J Epidemiol 2013;177:601–12. doi:10.1093/aje/kws445
- Micheli A, Ciampichini R, Oberaigner W, et al. The advantage of women in cancer survival: An analysis of EUROCARE-4 data. Eur J Cancer 2009;45:1017– 27
- Carey M a, Card JW, Voltz JW, et al. It’s all about sex: gender, lung development and lung disease. Trends Endocrinol Metab 2007;18:308–13. doi:10.1016/j.tem.2007.08.003
- Kiyohara C, Ohno Y. Sex differences in lung cancer susceptibility: a review. Gend Med 2010;7:381–401. doi:10.1016/j.genm.2010.10.002
- Yang Y, Li T, Nielsen ME. Aging and cancer mortality: Dynamics of change and sex differences. Exp Gerontol 2012;47:695–705. doi
- Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: Higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 2012;18:6169–77. doi:10.1158/1078-0432.CCR-11-3265
- Micheli A, Ciampichini R, Oberaigner W, et al. The advantage of women in cancer survival: an analysis of EUROCARE-4 data. Eur J Cancer 2009;45:1017–27. doi:10.1016/j.ejca.2008.11.008
- Manierre MJ. Gaps in knowledge: Tracking and explaining gender differences in health information seeking. Soc Sci Med 2015;128:151–8. doi:10.1016/j.socscimed.2015.01.028
- Hale S, Grogan S, Willott S. Male GPs’ views on men seeking medical help: A qualitative study. Br J Health Psychol 2010;15:697–713. doi:10.1348/135910709×479113
- EC. The State of Men’s Health in Europe: Extended Report. Luxembourg: : European Commission, http://ec.europa.eu/health/population_groups/docs/men_health_extended_en.pdf
(authors White, A, de Sousa, B, de Visser, R, Hogston, R, Madsen, SAa, Makara, P, Richardson, N, Zatoski, W) 2011. http://ec.europa.eu/health/population_groups/docs/men_health_extended_en.pdf
- European Commission. Data and Information on Women’s Health in the European Union. Luxembourg: 2009. http://ec.europa.eu/health/population_groups/docs/women_report_en.pdf
- Amos a., Greaves L, Nichter M, et al. Women and tobacco: a call for including gender in tobacco control research, policy and practice. Tob Control 2012;21:236–43. doi:10.1136/tobaccocontrol-2011-050280
- Borg T. Tobacco Products Directive: Making tobacco products and smoking less attractive. Brussels: 2012. http://europa.eu/rapid/press-release_SPEECH-12-968_en.htm
- BBC. Australia cigarette plain packaging law upheld by court. 2012.
- UN. Anti-tobacco ruling in Australia welcomed by UN health agency. 2012
- Cullen P. Irish plain packaging tobacco law can create ‘domino effect. Irish Times. 2014
- Hitchman S, Fong GT. Gender empowerment and female-to-male smoking prevalence ratios. Bull World Health Organ 2010;89:195–202. doi:10.2471/BLT.10.079905
- Jha P, Peto R, Zatonski W, et al. Social inequalities in male mortality, and in male mortality from smoking: indirect estimation from national death rates in England and Wales, Poland, and North America. Lancet 2006;368:367–70. doi:10.1016/S0140-6736(06)68975-7
About the EUGenMed Project
Research addressing sex and gender (S&G) in biomedical sciences and health research is emerging as a novel and highly promising field. This interaction between S&G leads to different manifestation of diseases—such as infarction, heart failure, diabetes, rheumatic disease—in women and men. Research in the area will lead to novel, better targeted and, therefore, to more efficient treatment strategies than the previous global approaches, creating additional opportunities for prevention and increased healthy life expectancy.
The EUGenMed Project is coordinated by Charité, Universitaetsmedizin Berlin in partnership with the European Institute of Women’s Health and the University Maastricht. The Project is funded by the European Commission under the Seventh Framework Programme and began on October 1st 2013. The Project aims to create a multi-sectorial source of knowledge based on consensus of experts.
The EUGenMed Project will produce an innovative roadmap for implementation of S&G in in biomedicine and health, based on the generation of material and results from four workshops and the final project conference. For more information, please visit the EUGenMed website: http://eugenmed.eu.
This project the European Gender Medicine Network (EUGenMed) has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 602050.