If you have never puffed on a cigarette in your life, you may think you won’t get lung cancer. And it’s true that the odds of avoiding lung cancer are in your favor—but some nonsmokers get it anyway. According to the American Cancer Society, as many as 20 percent of people in the United States who died from lung cancer in 2018—a total of roughly 30,000 people—never smoked.

A nonsmoker is a person who doesn’t currently smoke, but may have smoked 100 or so cigarettes at some point in their life. There are also people who are considered never-smokers, who have never smoked or who have smoked fewer than 100 cigarettes in their lifetimes. Smokers and non/never-smokers tend to develop different types of lung cancer; the latter group is more likely to develop lung cancer as a result of a genetic mutation or abnormality.

In the past five to 10 years, new knowledge about lung cancer has changed the way it is treated in both smokers and nonsmokers. 

“We used to think all lung cancers were the same, but now we understand that there are different kinds,” says Anne Chiang, MD, PhD, a Yale Medicine thoracic medical oncologist, and chief network officer and deputy chief medical officer for the Smilow Cancer Hospital and its Care Centers. “The good news is that the types of lung cancer that nonsmokers tend to get are usually driven by a molecular change or mutation that can be detected in the tumor, and there are drugs and therapeutics available for them. At Yale, we have a very active research program aimed at targeting those cancer cells that contain the mutation.” 

Lung cancer, one of the most common cancers in the world, is a leading cause of cancer-related death in men and women in the United States. While smoking cigarettes is by far the most common cause of lung cancer, risk factors also include a family history of lung cancer and certain environmental contributors.  

Like all cancers, lung cancer begins at the cellular level and is the result of abnormal cells that reproduce rapidly and out of control. It can start in one area of the body (in this case, the lungs) and spread (or metastasize) to other organs or the bones.

Primary lung cancer refers to cancer that starts in the lungs, of which there are two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Named initially for how the cancer cells look under the microscope, these two types account for most of the 230,000 newly diagnosed cases of lung cancer in the U.S. each year.

Smokers tend to get a type of NSCLC called squamous cell (which accounts for more than half of lung cancers diagnosed in smokers). Most nonsmokers, on the other hand, are diagnosed with a different non-small cell type known as adenocarcinoma.

Adenocarcinoma, the most common lung cancer diagnosed in nonsmokers, often starts in the outer areas of the lungs, in mucus-producing cells that line the small airways, called bronchioles. Adenocarcinoma has a different shape than other types of lung cancer, says Daniel Boffa, MD, a Yale Medicine thoracic surgeon. 

He offers a helpful way to visualize the difference between the two: “If you are a smoker, you can think of your lung as a bag of white marbles, and cancer is like putting a black marble in there. The type of cancer a nonsmoker gets is more like putting in black sand. Instead of a spot or a lump, it’s more like a hazy area. It’s more diffuse.”

Another difference is that cancers in nonsmokers tend to grow more slowly. But while they may be less likely to spread (or metastasize) to other parts of the body, they still can recur, even after successful surgery. 

There may not be a single cause behind a particular case of lung cancer in a nonsmoker—rather, there is often a combination of factors contributing to the disease, says Dr. Boffa.

One of the strongest predictors can be a genetic mutation in the tumor, also known as a “somatic” mutation, that drives the development of cancer. This is different that a “germline” mutation, that is present in all of your normal DNA. Numerous studies have shown that such somatic mutations or abnormalities can play a key role in the development of lung cancer, especially in nonsmokers.

Beyond that, the American Cancer Society lists the following environmental risk factors that may contribute to a diagnosis of lung cancer in a nonsmoker:

Radon gas: Exposure to radon gas is considered to be one of the causes of lung cancer in nonsmokers, accounting for about 21,000 lung cancer deaths each year. Radon is invisible and doesn’t have a smell, but it occurs naturally outdoors. It has been found in concentrated amounts inside some homes that were built on soil that contains natural uranium deposits. The Environmental Protection Agency publishes a guide on how to test for radon gas in your home.

Secondhand smoke: This is the smoke you breathe in from another person’s burning tobacco product, which is linked to an estimated 7,000 lung cancer deaths each year in the U.S. Researchers are also studying “third-hand smoke,” or the film (usually invisible) of nicotine and chemicals that may be left on furniture, walls, clothing, and other surfaces.

Cancer-causing agents at work: This is a special concern for those with prolonged and repeated exposure to such carcinogens as asbestos, heavy metals, and diesel exhaust.

Air pollution: While scientists link indoor and outdoor air pollution to lung cancer, the risk of lung cancer from air pollution is believed to be low in the United States, where air quality is regulated, compared to many other countries in which it is not.

Most nonsmokers have no early signs of lung cancer, which means it is often not diagnosed until it has spread—but some do have symptoms in the early stages. These are similar to the symptoms in smokers and may include the following:

• A cough that doesn’t go away or gets worse over time
• Coughing up blood
• Chest pain or discomfort
• Trouble breathing
• Wheezing
• Hoarseness
• Loss of appetite
• Weight loss for no reason
• Fatigue
• Trouble swallowing
• Swelling in the face and/or the neck
• Recurrent lung infections, including pneumonia

When nonsmoker lung cancer is diagnosed early, surgeons can usually treat it by removing the affected tissue or tumor. People who don’t smoke typically tolerate surgery better because they have better lung function.

It’s best to treat cancer when it’s caught early and confined to a local area, which makes it easier to remove entirely, Dr. Boffa says. The surgeon will remove not only the abnormal nodule, but also some of the normal tissue around it, along with the lymph nodes, which can carry cancer to other parts of the body. (Cancer that is found in the lymph nodes helps the pathologist determine the stage of the cancer, or how advanced it is.) 

“This guides us as far as helping to make decisions about additional therapy, such as targeted therapy or chemotherapy after surgery,” Dr. Boffa says. 

In many cases, this is driving treatment choices. At Yale, all lung cancer patients—smokers, nonsmokers, and never-smokers—undergo genetic testing. If tumor profiling shows a particular gene has mutated or become abnormal, an oncologist may treat it with targeted therapies. These are anti-cancer drugs that can kill specific cancer cells without harming normal cells. 

“This is a vast improvement over chemotherapy, which also affects healthy cells, resulting in difficult side effects,” says Dr. Chiang.

Some specific gene mutations that contribute to lung cancer have been identified in the past five to 10 years. Young people and nonsmokers who get lung cancer often have a mutation in a gene called epidermal growth factor receptor (EGFR), which can be treated after surgery with a targeted therapy in the form of an oral pill. Other genetic abnormalities that may respond to targeted therapies are rearrangements in genes known as ALK or ROS1.

But medical treatment before or after surgery still depends on the stage and aggressiveness of the cancer, which is determined by a pathologist, says Dr. Chiang. “If the tumor is aggressive, the doctor might recommend chemotherapy after surgery. If a large tumor has spread to lymph nodes in the chest, the treatment might be a multimodality therapy, which combines surgery, radiation, and chemotherapy or immunotherapy.”

There has been exciting progress in treating lung cancer with immunotherapy, which activates the body’s immune system to specifically kill cancer cells. But clinical studies have shown that this treatment tends to work better in smokers than in nonsmokers, Dr. Chiang says.  

This can be a difficult question, as there are no symptoms of lung cancer in its early stages, and it is still uncommon enough that routine screenings are not recommended for nonsmokers and never-smokers. Most often, when early-stage lung cancer is found in nonsmokers it is due to “incidental findings,” Dr. Boffa says. “Most had an X-ray or CT scan done for some other reason and the radiologist sees something on the lung,” he says.

But family history is important, and people can talk to their doctors if they are concerned about a family history of lung cancer—if there is a first-degree relative or multiple family members who had the disease, or a family member who was diagnosed at a young age. It’s also important to bring up concerns about exposure to secondhand smoke, radon, industrial pollution, or other known contributors.

Patients who seek treatment at the Yale Cancer Center at Smilow Cancer Hospital have access to new cancer therapies that are in development. Through clinical trials, patients may be able to benefit from groundbreaking treatment options not available elsewhere. “At Yale, we have led the way in developing important therapies for lung cancer patients by designing and implementing clinical trials that try to improve outcomes for our patients,” says Dr. Chiang.

Important research is being conducted through Yale Cancer Center’s Specialized Program of Research Excellence (SPORE) for lung cancer. This is one of only three lung cancer-focused SPOREs funded by the National Cancer Institute to study non-small cell lung cancers, which include the adenocarcinoma that is common in nonsmokers. The Yale Medicine program brings together experts in oncology, immunotherapy, pharmacology, molecular biology, pathology, epidemiology, and addiction science to attack lung cancer. “There is a lot of research going on here,” says Dr. Chiang.