Why do many lung cancer patients who have never smoked have worse treatment outcomes?

It is well known that smoking is the main cause lungs’ cancer World. Approximately 80% of these tumors are diagnosed in Smokers. However, there is a small proportion of people who have never tried tobacco and who, unfortunately, respond less well to treatment. How can it be?

This has long been a mystery to scientists. Before we think that tobacco causes mild lung cancer, no, that is not the answer. Smoking does not protect us from developing aggressive cancers, but rather increases the likelihood of developing these tumors. The problem, as scientists have discovered over the years, is quite genetics.

After all, people who develop lung cancer without smoking or engaging in any other risky behavior usually do so because they are genetically programmed to do so. predisposed. This leads to the suspicion that these mutations confer resistance to anticancer treatments. Team scientists from UCL, the Francis Crick Institute and AstraZeneca wanted to check what was happening with these mutations, and indeed, they found the key to this terrible resistance.

Figures about smoking and lung cancer

In Europe and the USA, approximately 80% of lung cancer cases occur in smokers or former smokers. This figure is similar in other regions of the world, and in some places even higher. It is also estimated that 80% of lung cancer deaths occur in people who have ever smoked.

Therefore, these people are expected to respond less well to treatment. But, curiously, the opposite usually happens. Most cases of lung cancer in non-smokers are so-called non-small cell lung cancer (NSCLC). In the UK, where this study was conducted, 15% of NSCLC cases They carry a specific mutation in epidermal growth factor receptor (EGFR) gene. Most of them are non-smokers.

Lung cancer with this mutation is treated with a class of drugs called i.EGFR inhibitors. They carry 15 years are used and usually give very good results in smokers or former smokers. However, in patients who have never smoked, tumors do not shrink, and in some cases even grow.

What’s wrong with AstraZeneca?

Previous studies have shown that in nonsmoking patients, in addition to the EGFR mutation, there is usually another mutation in a tumor suppressor gene known as p53. This may be why it shows such high resistance to lung cancer. But how does this resistance develop?

To prove this, scientists from UCL and the Francis Crick Institute analyzed clinical trials conducted by AstraZeneca with an EGFR inhibitor called Osimentinib. They saw that all patients who only had the EGFR mutation experienced a significant reduction in tumor size. However, those who also had the p53 mutation (most of them non-smokers) were not so lucky. Some of their tumors stayed the same, while others grew. This is what is known as mixed answer. One person exhibits different behavior in different tumor cells.

Experiments to find the cause

It was clear that the p53 mutation was critical. All that remained was to find out why. So they developed in the laboratory genetically modified mice carry one or both mutations and analyze their behavior both in front of the drug and in front of tumor cells. So they saw that many of those who had two mutations genome duplication tumor cells. This allowed them to more easily avoid treatment and, having twice as many chromosomes, continue to reproduce with the same resistance.

They were then analyzed Human lung cancer cell cultures with one gene or both. The same thing happened again. These two mutations contributed to genome duplication, which gives tumor cells a second chance to escape treatment.

Why is this research so helpful for lung cancer patients?

For both lung cancer and other types of tumors, patients typically undergo genomic testing to determine the best treatment. For example, if they have an EGFR mutation, an inhibitor such as AstraZeneca is used. You can also determine if they have a p53 mutation and therefore if they have a p53 mutation. increased risk of resistance.

But not all patients with two mutations duplicated their genome. So we now know that to use alternative treatments, we also need to do tests to determine whether the genome is duplicated in tumor cells. So you can act faster before treatment fails. Survival from lung cancer largely depends on the stage at which it is detected, so it is important to act early. Now oncologists have a different criterion for this.