Updates in Cancer Prevention and Screening for 2025: A Pharmacist Primer
The Mystery Rise Of Lung Cancer In Non-smokers
The number of lung cancer cases in people who have never smoked is increasing. The disease is different from lung cancer caused by smoking, so what causes it?
Martha first realised that something was wrong when her cough changed and the mucus in her airways became increasingly viscous. Her doctors put it down to a rare disorder she had that caused her lungs to become chronically inflamed. "No worry, it must be that," she was told.
When she finally had an X-ray, a shadow was detected on her lung. "That set the ball rolling," Martha recalls. "First, a CT scan was done, then a bronchoscopy [a procedure that involves using a long tube to inspect the airways in a person's lungs] to take tissue samples." After the tumour was removed, about four months after she'd first reported symptoms to her GP, she received the diagnosis: Stage IIIA lung cancer. The tumour had infiltrated the surrounding lymph nodes but had not yet spread to distant organs. Martha was 59 years old.
"It was a total shock," says Martha. Although she would occasionally light up a cigarette at a party, she never considered herself a smoker.
Lung cancer is the most common cancer worldwide and the leading cause of cancer death. In 2022, about 2.5 million people were diagnosed with the disease and more than 1.8 million died. Although tobacco-related lung cancers still account for the majority of diagnoses worldwide, smoking rates have been declining for several decades. As the number of smokers continues to fall in many countries around the world, the proportion of lung cancer occurring in people who have never smoked is on the rise. Between 10 and 20% of lung cancer diagnoses are now made in individuals who have never smoked.
"Lung cancer in never-smokers is emerging as a separate disease entity with distinct molecular characteristics that directly impact treatment decisions and outcomes," says Andreas Wicki, an oncologist at the University Hospital Zurich, Switzerland. While the average age at diagnosis is similar to that of smoking-related lung cancers, younger patients with lung cancer are more likely to have never smoked. "When we see 30- or 35-year-olds with lung cancer, they are usually never-smokers," he says.
Another difference is the type of cancer being diagnosed. Until the 1950s and 1960s, the most common form of lung cancer was squamous cell carcinoma – a type which begins with the cells that line the lungs. In contrast, lung cancer in never-smokers is almost exclusively adenocarcinoma – a type which starts in mucus-producing cells – which is now the most common form of lung cancer in both smokers and never-smokers.
Like other forms of lung cancer, adenocarcinoma is usually diagnosed at an advanced stage. "If there's a 1cm (0.4in) tumour hidden somewhere in your lungs, you won't notice it," says Wicki. The early symptoms, which include persistent coughing, chest pain, shortness of breath or wheezing, often only appear when the tumour is larger or has spread. In addition, the historically strong link between smoking and lung cancer may inadvertently lead non-smokers to attribute symptoms to other causes, says Wicki. "Most cases in never-smokers are therefore only diagnosed at stage 3 or 4."
The smoke from cooking fuel and fumes from cooking oil can increase a person's risk of lung disease, including lung cancer (Credit: Getty Images)
Lung cancer in never-smokers is also more common in women. Women who have never smoked are more than twice as likely to develop lung cancer as male never-smokers. Aside from lung anatomy and environmental exposures, at least part of the answer may lie in genetic mutations that are more common in women, especially in Asian women. One of the most prevalent is a mutation known as EGFR.
Lung cancer cells in people who have never smoked usually have a number of mutations that could be causing their cancer, explains Wicki – so-called driver mutations. These genetic changes drive tumour growth, such as the EGFR gene which codes for a protein on the surface of cells and is called epidermal growth factor receptor. The reasons why these driver mutations are more frequently found in female patients, particularly those of Asian descent, are not entirely understood. There is some evidence that female hormones may play a role, with certain genetic variants that affect oestrogen metabolism being more prevalent in East Asians. This could potentially explain the higher incidence of EGFR-mutant lung cancer in Asian women, although the data is very preliminary.
Following the discovery of mutations which can lead to lung cancer in non-smokers, the pharmaceutical industry began to develop drugs that specifically block the activity of those proteins. For example, the first EGFR inhibitors became available around 20 years ago and most patients showed an impressive response. However, treatment often led to resistant cancer cells, resulting in tumour relapse. In recent years, much effort has been put into overcoming this problem, with newer types of drugs now entering the market.
As a result, the prognosis for patients has steadily improved. "The median survival rate of patients who carry such driver mutations is now several years," Wicki explains. "We have patients who have been on targeted therapy for more than 10 years. This is a huge step forward when you consider that the median survival rate was less than 12 months about 20 years ago."
As the proportion of lung cancer in never-smokers increases, experts say it is crucial to develop prevention strategies for this population. A number of risk factors have been implicated. For example, studies have revealed that radon and second-hand smoke can elevate the risk of lung cancer in non-smokers. Additionally, exposure to cooking fumes or to stoves burning wood or coal in poorly ventilated rooms may also increase this risk. Since women traditionally spend more time indoors, they are particularly vulnerable to this type of indoor air pollution. However, outdoor air pollution is an even more significant factor in the development of lung cancer.
Particulate air pollution can increase a person's risk of developing lung cancer (Credit: Getty Images)
In fact, outdoor air pollution is the second leading cause of all lung cancer cases after smoking. Studies have revealed that people who live in highly polluted areas are more likely to die of lung cancer than those who do not. Particulate matter less than 2.5 microns in diameter (about a 30th of the width of a human hair), typically found in vehicle exhaust and fossil fuel smoke, seems to play an important role. And intriguingly, research has shown a strong link between high levels of PM2.5 and lung cancer in individuals who have never smoked and who carry an EGFR mutation.
At least one study has shown an association between wildfire exposure and increased incidence of lung cancer – Christine BergHow air pollution may trigger lung cancer in never-smokers carrying the EGFR mutation has been the focus of research at the Francis Crick Institute in London. "When we think about environmental carcinogens, we usually think about them as causing mutations in the DNA", says William Hill, a post-doctoral researcher in the cancer evolution and genome instability laboratory of the Francis Crick Institute. Cigarette smoke, for example, damages our DNA, thus leading to lung cancer. "However, our [2023] study proposes that PM2.5 doesn't directly mutate DNA, rather it wakes up dormant mutant cells sitting in our lungs and starts them on the early stages of lung cancer."
In their experiments, the researchers showed that air pollutants are taken up by immune cells called macrophages. These cells normally protect the lung by ingesting infectious organisms. In response to PM2.5 exposure, macrophages release chemical messengers known as cytokines, which wake up cells carrying the EGFR mutation and causes them to proliferate. "Both air pollution and EGFR mutations are needed for tumours to grow," says Hill. Understanding how PM2.5 acts on the microenvironment of cells carrying EGFR mutations to promote tumour growth, he adds, could pave the way for new approaches to preventing lung cancer.
The association between air pollution and lung cancer is not new. In a landmark paper establishing the link between smoking and lung cancer in 1950, the authors suggested outdoor pollutants from the burning of fossil fuels as a possible cause. But policies to date have focused almost exclusively on tobacco control. But 75 years later, air pollution is finally coming into focus.
…99% of the world population lives in areas where air pollution levels exceed WHO guideline limits – Ganfeng LuoAir pollution levels in Europe and the US have fallen in recent decades. But the effect of changes on lung cancer rates has not yet become apparent. "It probably takes 15 to 20 years for changes in exposure to be reflected in lung cancer rates, but we don't know for sure," says Christine Berg, a retired oncologist from the National Cancer Institute in Maryland, US. Moreover, the picture is not static: climate change is likely to have an impact in the future. "With the increasing risk of wildfires, air pollution and PM2.5 levels are rising again in certain regions of the US," says Berg. "At least one study has shown an association between wildfire exposure and increased incidence of lung cancer. Transitioning away from coal, oil and gas is therefore crucial not only to slow global warming but also to improve air quality."
In 2021, the WHO halved the annual mean air quality guideline for PM2.5, meaning it has adopted a more stringent approach to particulate matter. "But 99% of the world population lives in areas where air pollution levels exceed [these updated] WHO guideline limits," says Ganfeng Luo, a postdoctoral researcher at the International Agency for Research on Cancer (IARC) in Lyon, France.
In a recent study, IARC researchers estimated that approximately 194,000 cases of lung adenocarcinoma worldwide were attributable to PM2.5 in 2022. "The highest burden is estimated in East Asia, especially in China," says Luo.
Exposure to radon is one of the leading causes of lung cancer worldwide (Credit: Alamy)
In the future, the number of lung cancer deaths attributable to air pollution could increase in countries such as India, which currently has some of the highest levels of air pollution, according to the WHO. In Delhi, the average PM2.5 levels are above 100 micrograms per sq m, which is 20 times above the WHO air quality guidelines.
In the UK, 1,100 people developed adenocarcinoma of the lung as a result of air pollution in 2022, the IARC study found. "But not all of these cases will be in never-smokers," says Harriet Rumgay, an epidemiologist and a co-author of the study. Adenocarcinoma also occurs in smokers, especially in those using filtered cigarettes. "There's still a lot we don't know," says Rumgay. "More research is needed to disentangle the different factors and also to understand, for example, how long you would need to be exposed to air pollution before developing lung cancer."
As treatments continue to improve, lung cancer in never-smokers is becoming more survivable. It is conceivable that this type of lung cancer will one day become the most common form of a disease that has historically been associated with older male smokers, changing the way we think about the disease in popular culture; "…the idea that they [patients] are at least partly to blame for their disease is unfortunately still widespread," says Wicki.
Martha was found to have an EGFR mutation and has been taking an inhibitor since her diagnosis almost three years ago. "It's definitely not a vitamin pill," she says. The drug has some nasty side effects: chronic fatigue, muscle pain, skin problems. Balancing the risks and benefits of drug treatment and maintaining a reasonable quality of life is not always easy, she says. But the drug is working. "And the fatalistic view of the disease is changing, and that is good."
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What Causes Chest Pain On The Right Side?
Right-sided chest pain can occur due to many different conditions and injuries. Below, we discuss 18 potential causes.
1. Anxiety or stress
Severe anxiety or stress can trigger an anxiety attack or a panic attack. A person who has previously had a panic attack may develop panic disorder, in which they fear another panic attack.
People who experience panic and anxiety may also have symptoms that resemble those of a heart attack, such as:
Some individuals also experience anxiety, stress, and panic because of a health condition, such as heart disease.
Anyone who suspects they may have symptoms of a heart attack should seek immediate medical advice.
2. Muscle strain
Many different muscles make up the chest wall. A person can strain or sprain these muscles during exercise. As a result, the chest will feel painful and tender to the touch.
Research shows that 28% of visits to the emergency room for chest pain are due to musculoskeletal issues, such as muscle strain.
3. Trauma
A traumatic injury, such as a fall, a blow to the chest, or a motor vehicle accident, can damage the structures that make up the chest and the heart, lungs, and other internal organs.
There may be bruising or swelling, and a person may have difficulty breathing.
It is best to seek emergency help following a chest injury. Damage to the internal organs may not be visible but can be life threatening.
4. Costochondritis and other inflammatory conditions
Costochondritis refers to inflammation of the cartilage that connects the ribs to the breastbone. It can lead to severe pain that may be worse when a person is:
Costochondritis usually goes away on its own, but people may need extra rest, pain relievers, and hot or cold compresses to aid recovery.
Other inflammatory conditions that can lead to chest pain include:
5. Rib fracture
A rib fracture is a break in the bones that protect the internal organs in the chest.
It can be very painful and lead to serious complications. One broken rib will not usually lead to complications, but multiple fractures can be life threatening.
Rib fractures usually result from a fall or blow to the chest, but severe coughing can also cause a fracture. A break on the right side can cause pain, swelling, and tenderness in that area.
6. Pneumothorax
Pneumothorax occurs when air escapes from the lung and gets into the space between the lung and the chest wall. It can lead to a collapsed lung.
This makes it difficult for the lung to expand when breathing and can cause sudden and significant pain or discomfort.
Someone with this condition might also experience shortness of breath, a rapid heartbeat, and dizziness. Anyone with these symptoms needs urgent medical attention.
7. Pleurisy
Pleurisy is inflammation of the membranes that surround the lungs. This inflammation causes friction between these two layers of tissue.
Usually, there is a thin, fluid-filled space between the linings of the lungs and the chest cavity. When breathing in and out, the lungs glide smoothly over this tissue.
In pleurisy, the friction can lead to sharp and severe pain when breathing.
The condition can occur for various reasons, including:
Treatment and prognosis will depend on the cause. A person should seek immediate medical help if they have difficulty breathing or dizziness due to low oxygen levels.
8. Pleural effusions
In pleural effusion, fluid builds up between the layers of tissue outside the lungs. It can cause chest pain and shortness of breath.
Breathing may get more difficult over time, so seeking help from a doctor is essential.
9. Pneumonia
Pneumonia is an infection of the lungs by bacterial, viral, or fungal organisms.
Chest pain can occur when a person is breathing and coughing. Individuals with suspected pneumonia should seek prompt medical help. Some people will need to spend time in the hospital, as the condition can result in life threatening complications.
10. Pulmonary hypertension
11. Pulmonary embolism
A pulmonary embolism is a blood clot that becomes lodged in the lungs. It can be life threatening if a person does not receive treatment quickly.
If it occurs in the right lung, it can cause right-sided chest pain.
The pain and other symptoms of a pulmonary embolism usually come on suddenly and require emergency medical attention.
12. Lung cancer
Chest pain can occur with lung cancer and cancer that has spread to the lungs from another part of the body.
Around 20% to 40% of individuals with lung cancer experience chest pain.
13. Chest tumors
Whether they are cancerous or not, growths within the chest or chest wall can also cause chest pain.
As the tumor grows, it will put pressure on nearby nerves or blood vessels, causing pain or discomfort.
14. Heart disease
While most people associate left-sided chest pain with a heart attack or other heart ailments, right-sided pain is also possible, especially if heart disease affects the right side of the heart.
Pain due to a heart condition can also affect the right shoulder or jaw.
15. Shingles
If a person has had chickenpox in the past, they may develop shingles later. This is because the same virus causes both conditions, and it can reactivate.
Shingles involves inflammation in a section of nerves and the surrounding area. This can lead to sensations of:
If shingles affects nerves in the chest, it can cause chest pain. Shingles tends to affect only one side of the body.
Early symptoms include a fever with pain and sensitivity in one area. It will later develop into a painful, itchy rash.
16. Heartburn or acid reflux
Heartburn, also known as acid reflux, is when stomach acid passes back from the stomach up into the food pipe or esophagus.
The food pipe is located in the chest and can cause general chest pain, including on the right side.
Acid reflux is common, affecting around 20% of people in the United States. If it happens often, however, a person should seek medical advice. A doctor can prescribe medication to help manage it.
17. Liver, gallbladder, and pancreatic issues
These structures, located at the top of the right side of the abdomen, are important for digestion and other essential functions.
18. COVID-19
COVID-19 can cause a variety of symptoms, including:
What Are The Complications Of Lung Cancer?
Lung cancer can cause a variety of problems that are sometimes related to the disease itself but may also be side effects of treatment.
Recognizing the signs of certain lung cancer complications can help your doctor devise a plan to treat your symptoms.
Lung Cancer ComplicationsMany times, people don't notice symptoms of lung cancer until a tumor has grown large or the cancer has spread, according to the American Cancer Society.
When lung cancer spreads to different parts of your body, it's known as metastasis.
MedlinePlus says lung cancer most commonly metastasizes to the brain, bones, liver, and adrenal glands.
That can lead to undesirable symptoms not only in your lungs and chest, but also in other affected organs and systems.
PainPain can occur in the chest or anywhere the lung cancer has spread.
For example, the American Cancer Society says it may hurt to breathe deeply, cough, or laugh. Cancer that has metastasized to the brain or bones can cause a headache, or pain in the back and hips.
At first, the discomfort might come and go, but over time, it may become persistent.
Your doctor can offer treatments and strategies to help you manage the pain.
Shortness of BreathIf the cancer blocks your airways, you might experience shortness of breath, according to Mayo Clinic.
Sometimes, breathing difficulties are caused by pleural effusion (fluid buildup around the lungs). When fluid accumulates, it makes it harder for your lungs to fully expand when you take a breath. That fluid can be drained to make breathing easier.
Certain types of lung cancer can also trigger a large production of mucus, which can lead to breathing problems.
Additionally, bleeding in the airways can cause some people with lung cancer to cough up blood.
The advocacy group GO2 for Lung Cancer offers some suggestions for managing shortness of breath, including:
Talk to your doctor about whether you might benefit from supplemental oxygen or a device called an incentive spirometer that helps you practice breathing more deeply.
Nerve ProblemsLung cancer can sometimes grow into and damage nerves, which can result in many different types of symptoms, including nerve-related pain, also known as neuropathy. Cancer treatments may also be to blame for this complication.
Symptoms of neuropathy include pain, numbness, tingling, or weakness. Treatments are available to help relieve these unwanted effects, though a review published in the journal Practical Pain Management points out that neuropathy is difficult to treat, and often treatments do not completely get rid of the symptoms.
The American Cancer Society notes other possible neurological effects. If cancer grows into the nerves of the neck or face, it can cause Horner syndrome, a condition that's characterized by a drooping eyelid, a small pupil, and little or no sweating on the affected side of the face.
If the brachial plexus (a network of nerves that branches from the neck into the shoulder and arms) is damaged, you can develop Pancoast syndrome. This condition can cause weakness, pain, or numbness in the hand, arm, or shoulder.
Lung tumors can also impact the nerves that are connected to your voice box. If this happens, you can develop hoarseness or voice changes.
Heart IssuesSome lung tumors can grow near the heart or major vessels in your body. When this happens, certain veins and arteries may become blocked, which can cause swelling in the chest, neck, or face.
You might also experience headaches, dizziness, vision issues, and fatigue.
Tumors that grow near the heart can affect its rhythm and may cause fluid buildup.
Swallowing DifficultiesIf cancer grows near the esophagus (the tube that connects your throat to your stomach), you might experience trouble swallowing.
Some people also report feeling more pain when eating or drinking.
People who receive radiation to their tumors can often experience these issues. Radiation can also temporarily damage the lining of the esophagus.
This discomfort could interfere with your nutrition, so be sure to tell your doctor if you have any problems swallowing your food.
Weakening of the BonesCancer that spreads to the bones can weaken them and lead to fractures. The American Cancer Society lists several medications you may be given to stop bone loss and prevent more damage.
HypercalcemiaBone damage from metastatic lung cancer can lead to a condition called hypercalcemia. This happens when cancer causes too much calcium to be released from your bones or retained in your blood. Symptoms may include weakness, nausea, constipation, vomiting, confusion, and fatigue. It can also be treated with bone-strengthening drugs.
HyponatremiaIf lung cancer has caused your body to retain water, your blood sodium level can fall too low. Common symptoms of hyponatremia are weakness, confusion, and sometimes, seizures.
FatigueEveryone gets tired, but if you have lung cancer, you might feel overwhelming exhaustion that doesn't go away. This could be due to the cancer spreading in your body or the therapies used to treat the disease.
Go2 for Lung Cancer has some strategies to help with fatigue, including:
Talk to your doctor about any symptoms you have. Some lung cancer complications can be treated with medication or a medical procedure. Others may improve with cancer treatment. Your doctor may also recommend you make some changes to your lifestyle or adopt healthful habits that can bring you relief.
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