Lung cancer: a worrying epidemic for women

There is a continual increase in cases of lung cancer for women in most European countries, linked to women smoking en masse which began in the 1960s. Women’s lung cancer has its own characteristics, such as different risk factors and profile.

Women’s lung cancer: continually on the rise

The number of cases of lung cancer has gone down for men in most developed countries but it is showing a steep increase for women, resulting in a high increase in fatalities for women with this type of cancer. Lung cancer is in fact a cancer that has a poor prognosis. Between 1985 and 1995, the number of cases of lung cancer practically doubled in France. (1) In Switzerland, the number of women affected by lung cancer doubled between 1983 and 2007. (2)

In Europe, the mortality rate for lung cancer is on the way to overtaking breast cancer. A recent study on the estimation of mortality rates reveals that deaths caused by lung cancer have gone up 9% in Europe and that the number of deaths attributed to lung cancer in women is likely to be higher than the number of deaths caused by breast cancer in 2015. (3) The exact figures won’t be known for a few years yet. The United Kingdom and Poland have the highest number of deaths due to lung cancer in women, namely 21 and 17 cases per 100,000 women respectively. In the United States, lung cancer has already been responsible for more deaths than breast cancer since 1987. The lung cancer epidemic for women will increase yet further over the next 30 years in a number of European countries, France included, linked to the history of women’s smoking.

Women’s lung cancer: an epidemic linked to smoking which seems to be more harmful for women

The principal risk factor for lung cancer is smoking. The increase in the prevalence of women’s lung cancer is linked to the evolution in women’s smoking habits. Women’s smoking has progressively increased since the end of the Second World War. However, lung cancer is a cancer which appears after 20 to 30 years of smoking. In the United States where women began smoking at the end of the Second World War, the rates of lung cancer went up 266% between 1968 and 1999. (4)

Up until the 1970s lung cancer was uncommon for women in France, then as the female population that had been exposed to tobacco grew older, the number of occurrences increased. The number of cases of lung cancer was 3.6 per 100,000 women in 1980 and 12.6 per 100,000 women in 2005, which represents an annual variation of 5.1%. The increase was most notable between 2000 and 2005 with an annual variation of 5.8%. (5)

As with men, the occurrence of lung cancer in women is determined by the length of time they have smoked, the number of cigarettes smoked each day and the age that they began smoking. A tripling of the number of cigarettes smoked per day increases the risk of lung cancer by 3, whilst a tripling of the time spent smoking increases this risk by 100. (6) There is no minimum level of consumption under which the risk of lung cancer is zero. (7) The risk of lung cancer is also increased depending on how young the person was when he/she started smoking. (8) The relative risk of having lung cancer is 7.6 times more for a woman who smokes than for one who does not, Gandini (9)

However, a number of studies have shown a more tenuous link for women, between lung cancer and smoking, than for men. Tobacco only explains 70% of women’s lung cancers. 70% of non-smokers who have lung cancer are women. (10) The magnitude of growth in lung cancer risk in women and the weaker link with tobacco consumption suggests that there are perhaps biological and genetic predispositions as well. A number of studies, in particular from North America, have shown that smoking presents a risk of developing lung cancer for women 1.5 to 3 times that for men. (11) Furthermore, 3 times as many women as men who are non-smokers have lung cancer, doubtless in part linked to the effects of passive smoking. (12) Women seem to be more sensitive to the carcinogens in tobacco smoke. Different mechanisms have been suggested to explain this possible predisposition (as yet unproven). The adducts of DNA induced by tobacco smoke are more often found in women’s lungs than in men’s and the ability for repairing DNA is inferior in the case of women (13); women present a greater incidence of the gene CYP1A1 whilst this gene encourages the carcinogenic effect of products contained in cigarette smoke; women have reduced activity of GTSM1 (Glutathione S-transferase M1) which leads to less effective detoxification of tobacco carcinogens (14); the widespread presence of gastrin-releasing peptides (rGRP) in women, peptides that play an important role in the stimulation of cellular proliferation, could also explain the extra sensitivity to tobacco carcinogens (15)... The possible role of hormones, particularly oestrogens, is also called into question. Various studies have shown that early menopause, having fewer than three children, short menstrual cycles, taking of hormone-replacement therapy (HRT) and hormone-dependent cancer antecedents are risk factors in women’s lung cancer and that there is a correlation between oestrogen and tobacco. (16) (17) (18) (19) (20) A study of various European registers has shown that women, particularly younger women, who had had lung cancer were more at risk of developing breast or ovarian cancer. (21) On the other hand, studies showed a beneficial effect of anti-oestrogens. (22)

It seems that oestrogen can encourage chromosome and genetic mutations (the interaction between EGFR and oestrogen in particular) which can lead to adenocarcinomas. Oestrogen can also be a direct carcinogen. It is, in fact, possible that oestrogen encourages the formation of DNA adducts. Experimental elements such as the presence of oestrogen receptors (ERβ) in healthy lung tissue as well as in tumour cells confirm the possible role of hormones in the occurrence of lung cancers. (23)

Lung cancer: a different profile of lung cancer in men

The risk of lung cancer is increased in relation to deficiencies in respiratory function (chronic bronchitis, emphysema…). This risk is even greater for women than for men, as women have a greater chance of developing respiratory illnesses. (24) Lung cancer tends to occur in women at an earlier age. Different clinical studies have shown that women are usually diagnosed with cancer at a younger age than men. (25) A Mayo Clinic prospective study showed that women were significantly younger than men when they were diagnosed: 66 as opposed to 68 years. (26)

Women have more adenocarcinomas than men (one of the three sub-types of non-small cell lung cancer). Nearly 50-65% of women suffering from non-small cell lung cancer have an adenocarcinoma (versus 25-40% of men). (27) This could be partly explained because more women smoke ‘light’ cigarettes. These encourage deeper inhalation and penetration of smoke and tar. (28) Lung cancer in women produces more activating mutations of the EGFR (Epidermal Growth Factor Receptor). Studies have shown that the mutation of the EGFR gene is only found in adenocarcinomas. A specific treatment can be suggested when this EGFR mutation is detected. Another mutation is also more common in women, that of the K-RAS gene (20% of women having an adenocarcinoma as opposed to 17% of men) but there is currently no treatment for this molecular target. (30)

Finally, women with lung cancer show fewer clinical signs than men. (31)

In conclusion, specific biological, genetic and hormonal factors relating to lung cancer in women are leading to new research, with the hope of finding specific treatments for women. One of the most advanced lines of research is hormone treatment, in particular associated with EGFR tyrosine kinase inhibitors.

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