Lung cancer causes in people who have never smoked

Dr Ronwyn van Eeden helps us understand why people who never smoked get lung cancer.

You can listen to this article below, or by using your favourite podcast player at pod.link/oncologybuddies

Lung cancer is the fifth most common cancer worldwide but remains the leading cause of cancer-related death. 

When most people think of lung cancer, they immediately think of smoking. While smoking remains the most important risk factor for lung cancer, there is another group of patients who are often overlooked: people who develop lung cancer despite having never smoked.

As smoking rates have declined in many parts of the world due to awareness of the risks, the understanding of lung cancer has also changed. We now recognise that lung cancer in people who have never smoked isn’t simply the same disease occurring without the usual risk factor. In many cases, it has its own biological characteristics, causes and, importantly, treatment options.

Not all lung cancers are the same

Lung cancer is broadly divided into two main groups:

Small cell lung cancer (SCLC) accounts for approximately 15% of cases and is very strongly associated with smoking.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of cases.

NSCLC is further divided into several subtypes, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.

Adenocarcinoma is the most common type of lung cancer in never smokers (LCINS).

For research purposes, a never-smoker is generally defined as someone who has smoked fewer than 100 cigarettes during their lifetime. LCINS is seen more frequently in females and is also proportionally more common in Asian populations.

This is why a patient with lung cancer doesn’t necessarily look like the person we traditionally picture: an older male with chronic lung disease and a long history of smoking.

Unfortunately, never-smokers don’t form part of screening guidelines, despite the rising incidence of high-risk groups that can be identified. 

Challenges in never-smokers 

One of the challenges with lung cancer in people who have never smoked is that the diagnosis may not initially be considered. 

Symptoms can include a persistent cough, shortness of breath, chest pain, unexplained weight loss, fatigue, or recurrent chest infections. The important warning sign is often a symptom that persists or doesn’t improve despite appropriate treatment.

For example, someone may repeatedly receive antibiotics or treatment for allergies or asthma because they don’t fit the traditional picture of a person at risk for lung cancer.

This is particularly relevant in South Africa, where diseases such as tuberculosis (TB) are common and can sometimes produce symptoms or X-ray findings that resemble lung cancer. This can occasionally delay the correct diagnosis.

The message isn’t that every persistent cough is cancer. Rather, if symptoms continue despite appropriate treatment, they should be investigated further, even in someone who has never smoked.

Why does lung cancer occur in people who have never smoked?

LCINS is estimated to account for approximately 15–25% of lung cancers worldwide, although the proportion varies considerably between populations.

There is usually no single identifiable cause. Instead, several environmental, occupational, genetic, and biological factors may contribute. Some chronic lung disease, such as inflammatory lung diseases and sarcoidosis, may also have an association. 

Environmental and occupational risk factors include second-hand tobacco   smoke, as well as long-term exposure to air pollution, particularly tiny airborne particles known as fine particulate matter. Diesel exhaust, radon, asbestos, and silica exposure are also risk factors. Long-term exposure to these cause chronic inflammation and damage within the lungs over time and increase the risk of developing lung cancer.

Genetics may play a role as well. Having a first-degree relative with lung cancer is associated with an increased risk, although inherited genetic causes account for only a proportion of cases.

Previous radiation treatment to the chest can also increase the risk of developing lung cancer later in life.

Importantly, however, many people who develop lung cancer despite never smoking have no obvious environmental or inherited risk factor. They shouldn’t feel that there must have been something they did to cause their cancer.

Genetics of the tumour: key to treatment

One of the most important discoveries in modern lung cancer treatment is that cancers arising in people who have never smoked are particularly likely to contain specific genetic changes within the cancer cells, known as driver mutations or driver alterations.

A driver mutation acts rather like a faulty switch that tells the cancer cell to continue growing. If we can identify that switch, we may be able to use a treatment specifically designed to block it. 

This has transformed the treatment of lung cancer. Some of the best-known alterations involve genes such as EGFR, ALK, and ROS1. Other important targets include RET, MET, BRAF, HER2, and NTRK, among others.

These alterations are considerably more likely to be found in adenocarcinomas occurring in people who have never smoked than in smoking-related lung cancers.

Targeted therapy has changed the outlook of these cancers and can improve survival and quality of life in patients who receive these treatments.

Once a driver alteration is identified, treatment can often be matched specifically to it.

Many of these treatments are tablets called tyrosine kinase inhibitors (TKIs). Others are given intravenously and include specialised monoclonal antibodies, bi-specific antibodies, or antibody drug conjugates.

Unlike conventional chemotherapy, which attacks rapidly dividing cells more broadly, targeted therapy is designed to interfere with a specific abnormal pathway that the cancer depends upon for its growth.

For patients whose cancers contain these mutations, targeted treatments can produce very high response rates and may control the cancer for prolonged periods.

Some targeted therapies can also penetrate the central nervous system  (CNS) and are particularly effective against cancer that has spread to the brain. This is important because some oncogene-driven lung cancers have a significant tendency to develop brain metastases.

In certain situations, targeted therapy may also be combined with chemotherapy or antibody-based treatments to improve disease control and outcomes.

Interestingly, although immunotherapy has revolutionised the treatment of many forms of lung cancer, it’s often less effective in some of these oncogene-driven cancers, particularly cancers driven by alterations such as EGFR or ALK. This makes finding the underlying molecular driver before choosing treatment extremely important.

How do we find these mutations?

The best way to look comprehensively for these genetic alterations is through next-generation sequencing (NGS).

NGS allows us to analyse the DNA and RNA within a tumour and search for many different genetic alterations at the same time.

Testing is usually performed on a sample of the tumour obtained during a biopsy or operation. In some situations, we can also analyse fragments of tumour DNA circulating in the bloodstream through what is commonly called a liquid biopsy.

Modern comprehensive molecular testing is therefore an essential part of managing many patients with lung adenocarcinoma, particularly those who have never smoked.

Finding the correct mutation can completely change the treatment we offer.

The most important message

Perhaps the greatest misconception surrounding lung cancer is that it’s exclusively a smoker’s disease. It’s not.

People who have never smoked can and do develop lung cancer. Because they may  be younger, otherwise healthy, and lack the traditional risk factors, their symptoms can sometimes be overlooked or attributed to more common conditions.

Persistent or unexplained respiratory symptoms therefore deserve appropriate investigation, regardless of smoking history.

At the same time, advances in molecular testing and targeted therapies have transformed our understanding and   treatment of these cancers. For many patients, identifying the particular genetic alteration driving their cancer allows us to select highly effective, personalised treatments.

Lung cancer doesn’t always have a smoking history, and recognising that fact can lead to earlier diagnosis, appropriate molecular testing, and better treatment.

References:

• Murphy et al. Lung Cancer in non-smokers, 2025 Nov 25;334(20)
• Corrales et al. Lung cancer in never smokers: The role of different risk factors other than tobacco smoking , Critical reviews in Oncology/ Haematology, 2020 Apr , Vol 148
• Lu et al. Lung Cancer in Never smokers: Genetics, epidemiology, environmental exposures and distinct immune landscape, JTO, July 2026, Vol 21

Dr Ronwyn van Eeden is a specialist physician and medical oncologist in Rosebank, Johannesburg. She has a special interest in lung cancer, breast cancer, immuno-oncology, and precision medicine. 

For lung cancer, she currently serves as associate editor on the editorial board for the Journal of Thoracic Oncology. Furthermore, she is part of the Africa steering committee for lung cancer for the International Association of Studies for Lung Cancer and previous co-chair for the first Pan Africa Congress for Lung Cancer.

She also steers multi-disciplinary care meetings for patients with lung cancer and will present on awareness and advocacy for patients with lung cancer in Africa at the World Conference for Lung Cancer. 

Header image by Magnific