Why Lung Cancer Is On The Rise In Women Who’ve Never Smoked

It’s easy to assume that if you’ve never smoked, lung cancer is just not a risk for you, unless you got very unlucky with an asbestos-laden environment or such.

And yes, smoking is indeed the most overwhelmingly strong risk factor:

❝It is estimated that cigarette smoking explains almost 90% of lung cancer risk in men and 70 to 80% in women❞

Which is a lot (and we’ll address that discrepancy by sex shortly), but meanwhile first let’s mention:

❝Compared with non-smokers, smokers have as much as a 30-fold increased risk of developing cancer.

31% and 26% of all cancer deaths in men and women, respectively, result from lung cancer in the United States.

Overall 5-year survival is only 15%, and 1-year survival is approximately 42%.

In total, lung cancer is responsible for more deaths than prostate, colon, pancreas, and breast cancers combined❞

Source: Smoking and Lung Cancer

Sobering statistics for any smoker, certainly.

But, “smoking is bad for the health” is not the breaking news of the century, so we’ll look now at the other risk factors.

Before we do though, let’s just drop this previous main feature of ours for anyone who does smoke or perhaps who has a loved one who smokes:

Which Addiction-Quitting Methods Work Best? ← it’s not specific just to smoking, but it does cover such also

So, Why the extra risk for women, even if we don’t smoke?

Let’s reframe that first statistic we gave, now presenting the same information differently:

Women who do not smoke are 2–3x more likely to get lung cancer than men who do not smoke.

So… why?

There are three main reasons:

Genetic risks

Cancer often arises from genetic mutations. In the case of lung cancer, genes such as ALK, ROS1, TP53, KRAS, and EGFR are implicated, and some of those are much more likely to mutate in women than in men.

In some cases, it’s because if you have XX chromosomes (as most women do), there are genes you have redundant copies of that people with XY chromosomes don’t. Other less common karyotypes, such as XXY, probably carry higher risks, but that’s just a hypothesis we’re making based on “more copies of a gene = more chances for it to mutate”.

See also: Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma

In other cases, it’s because estrogen interacts with the gene mutations, making lung cancer more likely to develop in women over time:

See also: Lung cancer in never-smoker female Asians is driven by oncogenic mutations, most often involving EGFR

Hormonal risks (but not what you might think)

When something affects women more, it’s easy to blame hormones, but, as researchers have concluded…

❝A reduced lung cancer risk was found for OC and HRT ever users. Both oestrogen only and oestrogen+progestin HRT were associated with decreased risk. No dose-response relationship was observed with years of OC/HRT use. The greatest risk reduction was seen for squamous cell carcinoma in OC users and in both adenocarcinoma and small cell carcinoma in HRT users.❞

OC = oral contraceptive
HRT = hormone replacement therapy

Note: we snipped out the statistical calculations for readability and brevity, so if you are interested in those, check out the paper below:

Source: Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO)

Meanwhile, another research review of 22 studies with nearly a million participants found:

❝Current or ever HRT use is partly correlated with the decreased incidence of lung cancer in women.

Concerns about the incidence of lung cancer can be reduced when perimenopausal and postmenopausal women use current HRT to reduce menopausal symptoms.❞

Source: The association between different hormone replacement therapy use and the incidence of lung cancer: a systematic review and meta-analysis

So, the problem seems to at least a lot of the time be not estrogen (notwithstanding what we mentioned previously about mutations—sometimes a thing can have both pros and cons), but rather, untreated menopause being the higher risk factor.

This is very reminiscent of what we talked about in one of our main features about Alzheimer’s disease:

Alzheimer’s Sex Differences May Not Be What They Appear ← Women get Alzheimer’s at nearly 2x the rate than men do, and deteriorate more rapidly after onset, too.

Chronic inflammation

For reasons that have not been tied to genetics or hormones*, women suffer from autoimmune diseases at much higher rates than men.

*presumably it is at least one or the other, because there aren’t a lot of other options that seem plausible, but (as with many “this thing mainly affects women” maladies), science hasn’t yet determined the cause.

Because cancer is in part a disease of immune dysfunction (cells fail to kill cells they should be killing), having an autoimmune disease, or indeed chronic inflammation in general, will result in a higher risk of cancer.

For general theory, see: Cancer and Autoimmune Diseases: A Tale of Two Immunological Opposites?

For specifics, see: Non–Small Cell Lung Cancer: Role of the Immune System and Potential for Immunotherapy

And this one is the most likely explanation of why lung cancer in women who’ve never smoked is on the rise—it’s because chronic inflammation in women is on the rise. While people regardless of gender are getting chronic inflammation at increased rates nowadays (probably due in large part to the rise of ultra-processed food, as well as the higher stress of modern life, but again, we’re hypothesizing), if all other factors are equal, women will still get it more than men.

However!

Like the consideration of HRT’s protective effects (and unlike the genetic factors), this is one we can do something about.

For how, check out: How to Prevent (or Reduce) Inflammation

Want to know more?

For lung health in general, see:

Seven Things To Do For Good Lung Health!

Take care!