Lung Cancer in Women Who Never Smoked

Lung Cancer in Women Who Never Smoked

Lindi Campbell remembers the date: Dec. 6, 2017. That was when she found out she had lung cancer. “I was so shocked,” she says. She had never smoked, and she didn’t know anyone with lung cancer, let alone any other “never-smokers” like her. That made her feel isolated.

So besides taking care of her own health, she set out to connect with other people who could relate. A year after her diagnosis, she founded Breath of Hope Kentucky, a nonprofit lung cancer advocacy and outreach group.

Campbell has connected with more than 20 never-smokers in or from her state. She noticed something unusual: Only one of those people is male.

It’s a small example of a pattern that’s stumped scientists: Why are women much more likely than men to get lung cancer if they never smoked?

Cigarette smoking is, by far, the top cause of lung cancer. But about 15% to 20% of cases in the U.S. happen in never-smokers — people who’ve never lit up or smoked fewer than 100 cigarettes in their life.

In the U.S., women make up about two-thirds of lung cancer cases in never-smokers, says Alice Berger, PhD, a laboratory researcher at the Fred Hutchinson Cancer Research Center in Seattle.

That’s unusual. Cancer is generally more common among men.

“In the last 5 years, there’s been a lot of attention on, Why is this happening? And why are women disproportionately affected?” Berger says.

You might remember when Dana Reeve, the wife of the late actor Christopher Reeve, died of lung cancer at age 44. Reeve had never smoked. Her cancer was already at stage IV when it showed up after she got an X-ray because she had a cough that wouldn’t go away. That was back in 2006 — and cases like hers are still hard to explain.

The reasons why aren’t clear. It could be differences in the immune system between women and men, Berger says. She and other scientists are looking into other factors: gene variants, hormones, and things in the environment like air pollution or radon.

“But that research is still in the early stages,” Berger says. A mix of factors may be involved.

Although Campbell wasn’t a smoker, she had been exposed to secondhand smoke. “I grew up in a home of smokers. There were nine people, and only two of us had never smoked. I was the youngest and the only one who got lung cancer.”

Lung cancer tumors in people who have never smoked are often different from those that occur in poeple who have smoked. “There are distinct differences in the immune landscape,” says Ramaswamy Govindan, MD, a professor of medicine at Washington University in St. Louis.

Most never-smokers with lung cancer — as many as 78% to 92% of them — have a “targetable” gene change, or biomarker, that may respond to an FDA-approved drug, according to research by Govindan and his colleagues. The epidermal growth factor receptor (EGFR) mutation is a common one, especially in female never-smokers.

Never-smokers with lung cancer need to get high-quality biomarker testing, Govindan stresses. These tests are needed to see what immunotherapy medications could target the tumors — and potentially save lives. And these simple genetic tests don’t always check for all the options.

Govindan has this message for doctors: “You have to look diligently for a potential targetable mutation by doing appropriate testing,” he says. “Sometimes we don’t get enough material and we only look for a few genes. If they’re not there [with the first sample], don’t stop there.”

These biomarkers are inside the cancer’s DNA. They’re not something you’re born with. Govindan says only about 5% to 6% of never-smokers tend to inherit a gene that makes them more likely to get lung cancer.

Cancer deaths had their steepest drop in the U.S. from 2016 to 2018. That was largely due to a drop in lung cancer deaths, thanks to targeted therapies and immunotherapy, says Joy Feliciano, MD, an associate professor of oncology at Johns Hopkins University School of Medicine.

Targeted therapies are different from chemotherapy. They go after certain parts of your tumor’s DNA, like those biomarkers. These drugs don’t help everyone and aren’t a cure. But they work by blocking instructions that tell your cancer cells to keep growing.

“If you’re a nonsmoker and you have a targetable mutation, you can get an oral drug,” says Roy Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center/Smilow Cancer Hospital. “About 70% to 80% of the time, the tumor will shrink.”

Campbell had surgery to remove the original tumor from her right lung. But a few nodules showed up in her lung’s left lobe a year after her surgery. In 2020, she had the tissue removed. It was cancer. This time her doctor did genetic testing, which showed that Campbell had a gene mutation called the EGFR-exon-19 deletion. She’s been taking a targeted medication called osimertinib (Tagrisso) ever since. Her lung cancer hasn’t spread outside of her lungs.

Immunotherapies are drugs that work on your immune system to help it fight off cancer cells. There are different types. These include “checkpoint inhibitors” to block a protein common in smoking-related tumors.

But “these tend to not work as well in nonsmokers because there’s not as much inflammation to target,” Berger says. And like targeted therapies, they don’t work for everyone. But in the right people, they can make a big difference.

Anyone who has lungs can get lung cancer. But it’s much more likely for some people than others — especially those who smoke.

Yearly screenings are only recommended for certain high-risk groups. That’s usually heavy smokers who are 50 to 80 years old.

There are no clear guidelines on how to screen for lung cancer early in never-smokers, even if you have a family history of the disease. Experts agree that’s a big problem. But it’s not one they know how to solve, yet.

Screening involves getting a scan. But if the scan shows something abnormal, you usually have to get an “invasive” procedure, such as a biopsy, to find out if it’s cancer, Feliciano explains. “So any screening test that becomes widely used has to be something where the benefits outweigh the risks,” she says.

Those risks include repeated exposure to low-dose radiation (if you get several scans over the years) and lung surgeries to find out that you don’t have cancer. “It’s not like a breast biopsy where you can do it really simply, right at the time of the mammogram,” Herbst says.

“We need some sort of early detection methods,” Campbell says. “If we represent 20% of 230,000 people a year in the U.S. getting diagnosed, that’s close to 45,000 people. That’s a big number.”

Many never-smokers with lung cancer are diagnosed by chance. A doctor may order a chest X-ray for another health problem and find something unusual in the lungs. That’s what set Campbell on the path to her diagnosis.

She had a little chest pain she blamed on acid reflux, a passing symptom she thinks was unrelated to her cancer. “But thankfully, my doctor said, ‘Let’s just do a chest X-ray to be sure everything else looks good.’ ”

A follow-up CT scan showed a 1.2-centimeter nodule in Campbell’s right lung. She says that didn’t “set off alarm bells” for her first pulmonologist. It took another 2.4 years and at least six doctors and nine scans to find out she had lung cancer.

“Everything it took to get that early diagnosis for someone who’d never smoked, it’s a miracle I even got to that point, and they did catch it early,” Campbell says.

You may not have any symptoms early on, or they may be vague. Campbell had only a very mild cough by the time they found her tumor. And it’s something she would’ve blamed on allergies had her primary doctor not ordered those first scans.

But lung cancer symptoms in females who never smoked are the same as for anyone else. Here are some things Campbell says she and other women in her lung cancer community had before their diagnosis:

  • An ongoing dry cough
  • Coughing up blood
  • Hoarseness or total loss of voice
  • Shortness of breath
  • Lung or throat “infections” that didn’t respond to antibiotics

Some other signs included:

Experts agree you should look into any health problem that doesn’t go away. Tell your doctor if you have a family history of cancer, and push for more tests until you get the reason behind your symptoms.

“I would be persistent,” Herbst says. If a scan shows an abnormal growth, “you need a biopsy to figure out what’s going on.”

In 5 to 10 years, Herbst predicts we’ll know a lot more about what raises the odds for lung cancer in people who don’t smoke. He says screening and detection methods, including cancer-sensitive blood tests, are sure to get better, too.

“I think someday soon, we’ll be able to tell just from the X-ray whether it’s benign or malignant,” he says.

Campbell hopes for a cure. But for now, she swallows a pill every night and gets scans and bloodwork every 3 months. She’s had one recurrence of her lung cancer, a year after her first operation. Once a year, an MRI takes pictures of her brain to check for tumors. She’s thankful her treatment helps her live longer. But she wants more funding and research devoted to lung cancer among nonsmokers.

Campbell’s home state ranks highest in the U.S. for lung cancer deaths. And unlike her, few get an early diagnosis. The native Kentuckian hopes her nonprofit advocacy group can help erase the stigma that comes with the disease and raise awareness about nonsmoking survivors like her.

“It’s like the Dr. Seuss book with the dust speck: We’re here! We’re here!” she says.


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