Non-Smoking Women Are Getting Lung Cancer

“This year, nearly 250,000 Americans will be diagnosed with lung cancer,” President Biden wrote to mark the beginning of National Lung Cancer Awareness Month, which takes place every November. Lung cancer is one of the most common cancers in and the leading cause of cancer death for both men and women – but the president’s proclamation didn’t include the fact that lung cancer is now affecting women, even non-smoking women, at a higher rate than men.

Historically, lung cancer was known as a men’s disease, due to their higher occupational exposure and higher smoking rates than women’s. Occupational hazards, such as exposure to asbestos, arsenic, benzene, cadmium, coal tar, disease fuel emissions, formaldehyde, and medical radiation, can all increase the risk of lung cancer. 5.3% of total cancer cases in men are linked to occupational exposure, compared to 2.3% of female cancer cases, since fields with high exposure, such as construction, freight handling, painting, pipefitting, and plumbing, are usually male dominated.

Similarly, men historically and currently smoke more than women. Cigarette smoking remains the most common cause of lung cancer across sexes, causing 90% of cases in men and 70-80% cases in women. As of 2021, about 13.1% of men smoke while 10.1% of women smoke.

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However, over 50% of women with lung cancer worldwide are non-smokers (compared to only 15-20% of men). Non-smoking women also have a higher incidence of lung cancer (19%) than non-smoking men do (9%). And, even when adjusted for smoking status, the female sex is associated with a higher risk of lung cancer. Lung cancer diagnoses have risen 84% among women – but have dropped 36% for men – over the past 40-plus years, and women between the ages of 30 and 49 not only are being diagnosed with lung cancer (when the average age at diagnosis is 70 years old) but also are being diagnosed at a higher rate than men of the same age.

And yet there isn’t any conclusive data explaining these sex-based trends. Possible and partial explanations include the makeup of cigarettes as well as women’s hormones, environmental exposure (to air pollution, cooking oil fumes, secondhand smoke, wood combustion, or other carcinogens) and genetics. For genetic specifically, a protein called CYP1A1, which activates carcinogens, is overexpressed in women. Women also have more frequent p53 mutations, which are responsible for 60% of lung cancers, than men do, and have an increased gastrin-releasing peptide receptor – GRPR – that stimulates cancer cell proliferation. These genetic differences may cause women to have a higher susceptibility to carcinogens – substances that increase an individual’s risk of cancer – and, subsequently, have higher rates of lung cancer than men have.

But this potentially higher susceptibility isn’t reflected in the current lung cancer screening guidelines or the studies that led to the development of those guidelines. The National Lung Screening Study, which started in 2002, recruited 55,000 participants but only 39% were women. Similarly, the NELSON study, which started in 2003, had over 15,000 participants but only 16% were women. Women were, thus, underrepresented in the former and current smokers recruited for these trials – and non-smoking women weren’t represented at all. As a result, lung cancer screening eligibility applies to individuals who smoke at least 20 packs a year and are at least 50 years old; there are no sex-based differences in these guidelines, despite the rising cases of lung cancer in both smoking and non-smoking women. As a 2022 review concludes, “The lack of guidelines and risk assessments for light or never smokers predisposes women with lung cancer in particular to be missed with current screening recommendations.”

In addition to being ineligible for screening, women, both smokers and non-smokers, may not even notice that they have lung cancer until it has progressed to a late stage. Women are more likely than men to develop lung adenocarcinoma (cancer that develops in the cells that line the outside of the lungs) while men are more likely than women to develop squamous cell carcinoma (cancer that develops in the cells that line the inside of the lungs’ airways). Both cancers’ symptoms can include a bloody cough, a recurrent or worsening cough, difficulty breathing or swallowing, hoarseness, and swelling in the face and neck veins. However, lung adenocarcinoma can also manifest in abdominal pain, bone pain, headaches, and/or mucus secretion: symptoms that aren’t necessarily specific to lung cancer and that may cause the cancer to be misdiagnosed.

In short, non-smoking women are doubly disadvantaged: they usually aren’t eligible for lung cancer screenings under the current guidelines because they don’t smoke, and their cancer may be missed or dismissed until a stage where it is near-fatal.

When their lung cancer is correctly diagnosed and treated, however, both smoking and non-smoking women have shown to respond better to lung cancer treatments than their male peers. Women see more positive results than men across various treatment options – including EGFR inhibitors, platinum-based chemotherapies, surgery, and radiotherapy. Women with lung cancer also survive significantly longer than men, in part due to their treatment and lifestyle choices and the characteristics of their tumor.

But, much like the rising rates of lung cancer in women, the main reason behind their improved survival rates is still unknown, serving only to highlight the sparse research in sex-related differences in lung cancer. Two articles, both published in 2021 echo this fact. One states, “The double-edged sword of female sex and lung cancer necessitates that future studies aim to better understand factors (environmental, genetic, hormonal) in addition to smoking intensity and duration that may affect risk”. The other argues for “targeted therapies” and “screening recommendations” that reflect the role of sex, noting that “the data regarding optimal care and outcomes is still lagging behind” for women.

These calls for sex-specific research, the rising rates of lung cancer in women, especially non-smoking women, and federal programs – including the reignited Cancer Moonshot program and recent White House Initiative on Women’s Health Research – all may help catalyze change and improve the lives of both smoking and nonsmoking women. As President Biden wrote in his proclamation on National Lung Cancer Awareness Month, “During National Lung Cancer Awareness Month, the First Lady and I have one message to the Nation: There is hope.”