Why is cancer discovered in the late stage?

Speaking of cancer, what I remember most vividly is an old man who lived not far from my home when I was a child. I often saw him on the street. He was very kind to us children and often entertained us. Suddenly one day, I heard that he was diagnosed with cancer, and he passed away within a few months.

At that time, I thought cancer was so scary. Later, as I grew up, I kept hearing about people dying from cancer. My biggest puzzlement at that time was why cancer was already in the late stage when it was discovered, and why it was basically incurable.

Later, I left my hometown and went to university to study biology. I have been in this pit until today, and I have a certain understanding of this issue. Today, I will talk to you about why cancer is often found in the late stage and whether early detection and early treatment are really useful?

01. Why is cancer diagnosed in the middle or late stages?

Because many people often do not take the initiative to get tested, but instead go to the doctor after symptoms appear. By the time cancer develops to the point where there are obvious symptoms, it is basically in the middle or late stages.

So, when my friends ask me for health advice, I basically tell them that they must have a physical examination every year. This is because for a disease like cancer, the incidence rate gradually increases with age, and the probability increases significantly when you are over 40 years old. Early detection and early treatment can be said to be the only way.

In fact, this is also an important consensus in the academic community regarding cancer prevention and treatment. After all, once clinical symptoms appear and a huge tumor grows, the number of cancer cells in the body has reached at least hundreds of millions, and there is a high possibility that the cancer cells have spread to other locations through the blood and lymph circulation, making it difficult to cure.

02. Can early detection really detect cancer in time?

Some people may ask, can early detection really detect cancer in time? The answer to this question is basically yes.

In fact, it is not difficult to draw a conclusion based on the principles of the emergence and development of cancer.

Cancer cells themselves are also normal cells in our human body, but due to many factors such as gene mutation, chromosome damage, epigenetics, etc., normal cells begin to lose control and mutate into cancer cells.

However, the presence of cancer cells does not mean that you have cancer. We have immunity and other mechanisms in our bodies to prevent cancer, so this war continues. Cancer cells will continue to strengthen in the battle. For example, some cancer cells do not even need the 23 pairs of chromosomes of our normal cells. They can discard many unnecessary genes to allow themselves to continue to evolve and deteriorate, and then begin to form cancer cell clusters. It takes a long time for one cancer cell to replicate and proliferate into a tumor composed of hundreds of millions of cells.

As long as we can detect and treat the tumor in its early stages, there is a great possibility of preventing it from further worsening.

But most people do not take the initiative to get checked, thus missing the chance to discover the disease. What is even more frightening is that many cancers do not have obvious symptoms in the early stages. Even if they do, they are easily confused with daily "minor illnesses", such as the foreign body sensation in the throat of esophageal cancer, which is similar to pharyngitis; the cough of lung cancer is similar to bronchitis, which is very confusing. As the disease progresses, cancer cells begin to invade normal tissues. In more serious cases, they begin to migrate to other parts of the body through the circulation of blood and lymph (that is, metastasis).

When this happens, it is often already in the middle or late stages and is difficult to deal with.

Therefore, many studies in the biomedical field are currently focusing on how to achieve the problem of early detection of cancer, the earlier the better. This depends on understanding the characteristics of cancer.

03. One of the strategies for early detection of cancer

Currently, one of the most common early cancer detection strategies in clinical practice is alpha-fetoprotein and carcinoembryonic antigen. I believe many people have seen these two indicators during physical examinations.

Why can they predict early cancer to a certain extent? The principle is that the body cells of normal adults have basically stopped expanding, that is, they have stopped developing, so the proteins related to cell replication and proliferation are rarely expressed in the body. However, this phenomenon is completely different in cancer patients. Once cancer cells begin to proliferate uncontrollably, some factors related to cell replication and proliferation will increase accordingly. Therefore, as long as the relevant indicators are detected, it can be observed to a certain extent whether the cells in the body are undergoing a large number of rapid proliferation, thereby judging whether there is a possibility of cancer.

It can be said that some blood screening indicators in physical examinations have become one of the common strategies for early cancer detection, and have also helped many people successfully detect cancer in the early stages and intervene in time.

However, these indicators also have shortcomings, such as sensitivity (no missed diagnosis) and specificity (no misdiagnosis). As a result, although there are more and more indicators related to early cancer detection, if there is no targeted blind screening, the detection difficulty and sensitivity of different indicators are problems, and they cannot be widely applied.

04. Next-generation gene sequencing technology based on cfDNA methylation

For this reason, researchers have been working hard to develop some new technical means in recent years. One of the more promising trends is the second-generation gene sequencing technology based on cfDNA methylation.

This name may be unfamiliar to you, so we will take some time to introduce it here.

The so-called cfDNA is the abbreviation of circulating free DNA. Cells undergo many basic biological processes, such as replication, proliferation and apoptosis, that is, programmed cell death, and cell DNA will be released into the circulatory system after shedding or apoptosis.

(Photo source: Burning Rock Medical)

Cancer cells are also cells in nature, and they are not immortal. As mentioned earlier, when cancer occurs, the number of cancer cells has often reached a large scale, but they will continue to die and be reborn, releasing DNA that is specific to cancer cells - circulating tumor DNA (ctDNA) into the blood. It is only when the number of new cells far exceeds the number of dead cells that they show malignant proliferation.

Based on this principle, we can also detect the presence of ctDNA in the blood. Therefore, the first step of this detection technology is to identify cfDNA in the circulatory system and distinguish ctDNA from it, so that we can determine whether there is a malignant tumor. The next step is to identify which organ these ctDNA come from.

At this time, another technology needs to be used, which is methylation.

Methylation refers to the addition of a methyl group to the base cytosine. It may seem ordinary, but it has extraordinary effects in biology.

This methylation modification directly affects gene expression and regulation.

Methylation is acquired and specific

These two factors together determine that the DNA methylation patterns of cancer cells and normal cells will be different, and the organ traceability of ctDNA can be achieved through methylation signals.

I have always been very interested in this research direction, which is also the current international cutting-edge technology direction. In fact, the current research on cfDNA methylation can provide great help for the early detection of certain specific cancers. This year, a related research result was published in Nature Biomedical Engineering (impact factor: 25.671), jointly published by Union Hospital, Shanghai Jiaotong University Affiliated Chest Hospital and Burning Rock Medicine, on the ultra-sensitive detection of ctDNA methylation for cancer.

(Photo source: Burning Rock Medical)

This study itself used ELSA-seq technology, which can capture weak signals from early tumors in the blood, accurately identify cancer-related methylation fragments in extremely small amounts of DNA, and use machine learning to assist in signal processing, thereby achieving early detection of cancer.

ELSA-seq technology overview: sample preparation → library preparation → deep sequencing → noise reduction → feature selection → machine learning (Image source: Burning Rock Medical)

The biggest challenge of early detection is how early it can be detected. For example, if you cut off the rotten part of a rotten apple, although the remaining part looks intact, it is still not recommended to eat it, because mold spots that are invisible to the naked eye have actually formed. The smaller the mold spots are, the harder it is to detect, and it requires the use of microscopes and other means. The same is true for the growth and development of tumors. In the early stages of cancer, clinical symptoms have not yet appeared. The key to detecting cancer signals as early as possible lies in the accuracy of screening technology.

ELSA-seq has significantly improved performance compared with mainstream commercial kits (Image source: Burning Rock Medical)

The core of ELSA-seq is to accurately capture methylation fragments related to cancer signals in extremely small amounts of DNA. Its uniqueness lies in the high-fidelity amplification and high-efficiency capture of signals. Compared with the performance of current mainstream commercial kits, it can efficiently capture cancer signals even in cfDNA as low as 0.5 ng.

ELSA-seq performance verification results (Image source: Burning Rock Medical)

Its detection accuracy is even one order of magnitude higher than the current most sensitive ddPCR for liquid biopsy, demonstrating its superiority.

At present, the academic community is still developing early detection technology for cancer, and researchers are also working hard to develop detection methods with higher precision and better accuracy to provide more options for early detection of cancer.

Although most Chinese people are still afraid of cancer, for most cancers, early detection and early treatment are the best strategies. As the World Health Organization mentioned, 1/3 of cancers are preventable, 1/3 of cancers can be detected and cured early, and the remaining 1/3 of cancers can be treated to reduce pain and prolong life.

As long as it is discovered early enough, cancer does not mean a terminal illness.

ref.

Liang, Naixin, et al. "Ultrasensitive detection of circulating tumor DNA via deep methylation sequencing aided by machine learning." Nature Biomedical Engineering(2021): 1-14.

World Health Organization International Agency for Research on Cancer (IARC): Latest global cancer burden data in 2020.