Gender-Related Differences in Lung Cancer

United States

In the United States, it is estimated that 118,080 men and 110,110 women were diagnosed with lung cancer in 2013, and 87,260 men and 72,220 women died of the disease. The age-adjusted death rate for the period from 2006 to 2010 was 63.5/100,000 and 39.2/100,000 for men and women per year, respectively.

The most common cancers expected to occur in men in 2013 included prostate, lung and bronchus, and colorectal, which account for about 50% of all newly diagnosed cancers (prostate cancer alone accounted for 28%, or 238,590 of all new cases). In women, the three most commonly diagnosed types of cancer in 2013 were breast, lung and bronchus, and colorectal, accounting for 52% of estimated cancer cases (breast cancer alone accounted for 29%, or 232,340 of all new cases). These cancers continue to be the most common causes of cancer death ( Fig. 5.2 ). In 2013, lung cancer was expected to account for 26% of all cancer-related deaths among women and 28% of all cancer-related deaths among men. Of the 2,437,163 deaths recorded in the United States in 2009, 567,628 were caused by cancer. Lung cancer is the leading cause of death among men aged 40 years and older and is the leading cause of cancer-related deaths among women aged 60 years and older.

The Hispanic/Latino population is the largest and fastest growing major demographic group in the United States, accounting for 16.3% (50.5 million/310 million) of the US population in 2010. In 2012, an estimated 112,800 new cases of cancer were diagnosed and 33,200 cancer-related deaths occurred among Hispanic individuals. The incidence and mortality rates for all cancers combined and for the four most common cancers (breast, prostate, lung and bronchus, and colorectal) are lower for the Hispanic population than for the non-Hispanic white population, but the incidence and mortality rates are higher for cancers of the stomach, liver, uterine cervix, and gallbladder. These differences in rates reflect greater exposure to cancer-related infectious agents, lower rates of screening for cervical cancer, differences in lifestyle and dietary patterns, and possibly genetic factors.

The considerable efforts in implementing tobacco-control strategies in the United States since the 1950s and the subsequent favorable changes in smoking behaviors in 1975 to 2000 have averted more than 240,000 lung cancer-related deaths in women. However, it is estimated that 20.6% of all American adults 18 years and older continue to smoke, a percentage that has changed slightly since approximately 1997. Smoking prevalence in the United States has decreased from a high of 53% for men and 32% for women in 1964 to rates of 21.6% for men and 16.5% for women in 2011.

Large geographic differences in public policies against tobacco use and socioeconomic factors affect the distribution of lung cancer mortality rates across states. California has been a leader in introducing public policies designed to reduce cigarette smoking. It was the first state to establish a comprehensive state-wide tobacco-control program in 1988 through increased excise taxes on cigarettes, and as early as the mid-1970s it had local government ordinances for smoke-free work places. As a result, progress in reducing smoking prevalence and mortality associated with smoking-related diseases, including lung cancer, has been much greater in California than in the rest of the United States. Jemal et al. evaluated state-specific lung cancer mortality rates among white women to assess regional differences in lung cancer trends. The decrease in age-specific lung cancer mortality rates among white women continued in younger age groups and birth cohorts in California, but the decline was slower or even reversed among women younger than 50 years of age and for women born after the 1950s in the remaining 22 states analyzed, especially in the South and Midwest.

Europe

Worldwide, the estimated incidence of lung cancer among women is 516,000, of which 100,000 are diagnosed in the United States and 70,000 in Europe. There are still differences when incidence rates from European cancer registries are compared with rates in the United States, suggesting that the lung cancer epidemic among women in Europe may not yet have reached the US rate from the 1990s (>25 lung cancers/100,000 women). Nevertheless, in the European Union (EU), the lung cancer mortality rate for women increased by 50% between the mid-1960s and the early 2000s and steady upward trends have been seen even in the youngest age groups in some southern European countries such as France and Spain up to the early 2000s.

In the EU, lung cancer mortality rates for women increased during the past decade, from 11.3/100,000 to 12.7/100,000 (2.3% per year) for all ages (a further increase is predicted to reach 14/100,000 women in 2015) and from 18.6/100,000 to 21.5/100,000 (3.0% per year) for middle-age women ( Fig. 5.3 ).

Despite the reduction in breast cancer mortality, this disease is still the leading cause of cancer-related deaths among women across the EU, as well as specifically in France, Germany, Italy, and Spain. Lung cancer is the leading cause of cancer-related deaths in several countries in Northern and Eastern Europe, including Denmark, Hungary, the Netherlands, Poland, Sweden, and the United Kingdom. The projected cancer mortality rate has increased among women in several European countries. In Serbia, colorectal cancer in men and lung cancer in women are estimated to have the most significant increase over time (2010 to 2014): 0.42/100,000 ( p = 0.036) and 0.626/100,000 ( p < 0.001) per year, respectively. From 1996 to 2001, the National Health Service Breast Screening Programme in the United Kingdom recruited 1.3 million women into the Million Women Study. The women signed consent forms and completed a questionnaire about lifestyle, medical history, and sociodemographic factors and were resurveyed by mail about 3 years and 8 years later. Twenty-three of the 30 most common causes of death occurred more frequently in smokers; the rate ratio for lung cancer was 21.4 (19.7–23.2). The increased mortality among smokers compared with never-smokers was mainly from diseases such as lung cancer that can be attributed to tobacco smoking. Among former smokers who stopped smoking permanently between the ages of 25 years and 34 years or between the ages of 35 years and 44 years, the respective relative risks were 1.05 (95% CI, 1.00–1.11) and 1.20 (95% CI, 1.14–1.26) for all-cause mortality and 1.84 (95% CI, 1.45–2.34) and 3.34 (95% CI, 2.76–4.03) for lung cancer–specific mortality.

In the EU in 2012, nearly 88,000 women died from breast cancer, corresponding to almost 16% of all cancer deaths among women. The projected lung cancer-related deaths for 2015 are 187,000 for men and 85,204 for women. In a pooled analysis of 13,169 lung cancer cases and 16,010 controls from Europe and Canada, the most common histologic subtype was squamous cell carcinoma among men (4747 of 8891; 53.4%) and adenocarcinoma among women (1013 of 2017; 50.2%). No clear-cut evidence for gender preference was found among the major subtypes of small cell lung cancer (SCLC): 19.8% in men and 21.9% in women. Never-smoking status was reported for 220 (2.1%) men and 609 (24.2%) women; the most common subtype was adenocarcinoma (57.6% in men and 70.1% in women).

Similar to US data, an epidemiologic study conducted in Poland showed that a higher proportion of women (23%) were diagnosed with lung cancer at a younger age (less than 50 years) compared with men (12%).

Asia

In Asia, the lung cancer mortality rates for women are lower than in the United States and Europe. However, these rates are increasing across several Asian countries, including China, South Korea, and Japan. Adenocarcinoma tends to be the most common histologic type in women in Asia, and this proportion continues to increase over time. Although tobacco smoke is the most common cause of lung cancer in women throughout the rest of the world, the cause of lung cancer in Asian woman is considered more complex ( Fig. 5.4 ). The proportion of women with lung cancer who are never-smokers ranges from 61% to 83%. In fact, the smoking rate is higher than 10% only for Filipino and Japanese women. Environmental tobacco smoke and indoor pollutants, including cooking oil fumes and burning coal, have been implicated in increasing the risk of lung cancer among nonsmoking Asian women.

In China, cancer incidence and mortality data for 2009, including demographic information from 104 population-based cancer registries, were reported to the National Central Cancer Registry, a government organization for cancer surveillance. After an evaluation procedure, data from 72 registries were deemed satisfactory and were then compiled for analysis. According to these data, lung cancer was the most common cancer in China overall and in its urban areas and the second most common cancer in its rural areas. There were 197,833 new cancer cases and 122,136 deaths. The crude cancer mortality was 184.67/100,000 overall, 228.14/100,000 for men and 140.48/100,000 for women. These findings indicate that lung cancer was the most common cancer for men in all areas, particularly urban areas, and second to breast cancer in women, especially in urban areas. Lung cancer was the leading cause of cancer-related deaths in all groups stratified by gender and area. Ages over 50 years were the high-risk age groups because of the increase in incidence and mortality rates that accompany increasing age.

In India, over a 2-year period, 130 trained physicians independently assigned causes to 122,429 deaths in 6671 randomly selected small areas from the 1991 census and monitored all births and deaths in 1.1 million homes representative of all of India. Among people 30 years to 69 years old, the three most common fatal cancers among men were oral (including lip and pharynx, 45,800 [22.9%]), gastric (25,200 [12.6%]), and lung (including trachea and larynx, 22,900 [11.4%]); among women, the three most common fatal cancers were cervical (33,400 [17.1%]), gastric (27,500 [14.1%]), and breast (19,900) [10.2%]). Tobacco-related cancers represented 42.0% (84,000) and 18.3% (35,700) of cancer-related deaths among men and women, respectively, and there were twice as many deaths caused by oral cancers compared with lung cancers.

Data from the Korean National Cancer Incidence Database on 599,288 adult patients diagnosed with solid cancers between 2005 and 2009 were analyzed to identify possible gender differences. For all solid cancer sites combined, the risk of death for women was 11% lower than that for men (relative excess risk 0.89; 95% CI, 0.88–0.90) after adjusting for year of follow-up, age, stage, and case mix. The relative excess risks for cancer of the lung, head/neck, esophagus, small intestine, liver, nasal cavities, bone/cartilage, soft tissue, brain and central nervous system, and thyroid and melanoma were significantly lower for women.

Never-Smokers

Never-smokers with lung cancer represent a unique subset of all people with lung cancer. Globally, an estimated 15% of lung cancer cases in men and 53% of cases in women are not attributable to tobacco smoking. The risk of lung cancer is 2.5 times more common among female lifetime nonsmokers than among male lifetime nonsmokers. One of the most relevant risk factors for nonsmoking women is environmental tobacco smoke exposure. A meta-analysis of 55 studies of spousal smoking on the risk of lung cancer for a nonsmoking spouse showed a pooled relative risk of 1.27 (95% CI, 1.17–1.37), with risk increasing monotonically with increasing exposure. This association has been replicated in different populations across Asia, Europe, and North America.

Nevertheless, there remains a large fraction of lung cancers among never-smokers that cannot be definitively associated with established environmental risk factors, and limited data are available on the epidemiologic risk factors for lung cancer in never-smokers according to gender. Although smoking prevalence has decreased, the incidence of lung cancer has increased steadily in Taiwan over the past several decades; only 9% to 10% of women with lung cancer and 79% to 86% of men with lung cancer are tobacco smokers. In a matched case–control study conducted between 2002 and 2009, several epidemiologic factors of lung cancer in never-smokers differed between men and women. The risk for lung cancer was higher for people exposed to environmental tobacco smoke (odds ratio, 1.39; 95% CI, 1.17–1.67) with a history of pulmonary tuberculosis and with a family history of lung cancer in first-degree relatives (odds ratio, 2.44); people with a history of hormone-replacement therapy and who used fume extractors when cooking were protected. For men, only a family history of lung cancer in first-degree relatives was significantly associated with risk of lung cancer (odds ratio, 2.77).

A case–control study in China included 399 lung cancer cases and 466 controls, of which 164 cases and 218 controls were female nonsmokers. Among nonsmoking women, lung cancer was strongly associated with multiple sources of indoor air pollution, including heavy exposure to environmental tobacco smoke at work (adjusted odds ratio, 3.65), high frequency of cooking (adjusted odds ratio, 3.30), and use of solid fuel for cooking (adjusted odds ratio, 4.08) and heating (adjusted odds ratio for coal stove, 2.00). In addition, housing characteristics related to poor ventilation, including single story homes, less window area, absence of a separate kitchen, lack of a ventilator, and limited time with windows open, were associated with lung cancer.

Smokers

A prospective evaluation of 50-year trends in smoking-related mortality in the United States demonstrated that the relative and absolute risks of death from smoking continue to increase among female smokers. The relative risks of death from lung cancer, chronic obstructive pulmonary disease (COPD), ischemic heart disease, any type of stroke, and all causes are now nearly identical for female and male smokers. The risk of death from lung cancer among male smokers appears to have stabilized since the 1980s, whereas it continues to increase among female smokers. For women aged 60 years to 74 years old, the all-cause mortality rate is now at least three times as high among current smokers as among never-smokers.

Currently, no conclusive data are available on the susceptibility of lung cancer among female smokers. Some studies have shown a greater risk of lung cancer for female smokers than for male smokers. Data generated by the American Health Foundation database indicate that the odds ratio for the major lung cancer types is consistently higher for women than for men at every level of exposure to cigarette smoke. The dose–response odds ratios for lung cancer among women are 1.2-fold to 1.7-fold higher than among men. A Canadian case–control study of gender differences in lung cancer from 1981 to 1985 showed that with a 40-pack-year smoking history (compared with lifelong nonsmokers), the odds ratio for the development of lung cancer was 27.9 for women and 9.6 for men. In both of these studies, the increase in lung cancer risk held for all major histologic types. In a pooled analysis that included 13,169 cases and 16,010 controls from Europe and Canada, the odds ratio for different histologies of lung cancer was assessed. For male current smokers (average of 30 cigarettes per day), the odds ratios were 103.5 (95% CI, 74.8–143.2) for squamous carcinoma, 111.3 (95% CI, 69.8–177.5) for SCLC, and 21.9 (95% CI, 16.6–29.0) for adenocarcinoma. For female current smokers, the corresponding odds ratios were 62.7 (95% CI, 31.5–124.6), 108.6 (95% CI, 50.7–232.8), and 16.8 (95% CI, 9.2–30.6).

Other studies have shown comparable risks for men and women when controlling for smoking exposure. A gender-smoking interaction in association with lung cancer risk within a population-based case–control study (Lombardy, Italy, 2002–2005) was evaluated in 2100 cases with incident lung cancer and 2120 controls. Lung cancer odds ratios for pack-years (categorical) were higher for men than women, with a negative gender-smoking interaction for women ( p = 0.0009). For medium (20–29 pack-years) and high (40 pack-years or more) categories, the risk of lung cancer was similar for men and women.