2024-03-24 04:30:00
In the case of metastases, the outlook for cancer patients is still poor. In the future, however, it could be possible to prevent tumor cells from spreading throughout the body. Zurich researchers play an important role in this.
From a tumor on the surface via the blood system to other areas of the body: how cancer cells spread. (Illustration)
Gunilla Elam / SPL / Keystone
The idea is firmly anchored in many people’s minds: once a cancer has spread, the chances of survival are minimal. This is matched by the frightening figure that we read again and again: around ninety percent of cancer deaths are due to metastases. It is impossible to predict whether and when it will happen. But in some tumors, cells begin to detach sooner or later. They manage to get into the blood vessels or lymphatics, migrate through the body and settle elsewhere – as metastases. These are found particularly in the liver, brain, lungs and bones. But are metastases actually a death sentence?
“The outlook is better today not only for those affected by cancer in general, but also for some patients with metastases,” says Richard Cathomas, head of oncology at the Graubünden Cantonal Hospital. Thanks to novel targeted therapies and immunotherapies, the chances of survival for certain types of tumors have been increased. “We now achieve a five-year survival rate of up to fifty percent for melanomas with metastases. Around ten years ago this was less than five percent,” says Cathomas. The outlook for colon tumors with metastases in the liver is also much better today: “It used to be almost a dogma: If even a single metastasis has formed, treatment is no longer successful. Today we know that there are situations in which this is possible.”
The challenge remains
Cathomas is still cautious about talking about healing: “Especially with metastases, there is a great risk that they will return.” The survival rate for metastases is still significantly lower than for a tumor without metastases. “But even if a cure is rare, depending on the type of tumor, we can now control the disease much more often so that a good quality of life is possible for many years,” says Cathomas. Accordingly, there are not only more “cancer survivors”, but also more “metastasis survivors” – even if they may need therapy again in certain phases so that the cancer can be kept under control.
“Now it’s a matter of transferring the positive results of immunotherapy that have been achieved in certain tumors that have metastasized to other types of cancer,” says Olivier Michielin, head of oncology at Geneva University Hospital. Despite the progress made so far, it is clear: “Metastases remain life-threatening.”
The figures from the National Cancer Registration Office confirm that the challenges are still great. For example, in colon cancer that has metastasized, only minor improvements have been achieved over the past twenty years. The survival rate five years after diagnosis increased from around thirteen to sixteen percent. The improvement in lung cancer was somewhat more pronounced, but the survival rate is still very low today at less than ten percent.
The most aggressive cancer cells
Metastases are generally more difficult to treat than the so-called primary tumor. This is because it is locally limited and therefore accessible to a wider range of treatments. In the best case scenario, it can be removed surgically, irradiated or destroyed with heat or cold. However, cancer cells detached from the tumor spread throughout the blood and lymphatic system. In imaging, they can only be detected as established metastases larger than three to five millimeters. Such macrometastases can sometimes be removed surgically. But there is a great risk that countless micrometastases will already be present in the body. In this respect, systemic therapy is required that works throughout the body – for example in the form of chemotherapy.
And even then it is not certain that you will catch all the migrating cancer cells. Because they can stay hidden in a sleeping state. Sometimes they only begin to multiply years after successful treatment of a primary tumor. In addition, the cells from metastases are considered to be the most aggressive cancer cells. They have gone through a selection process and prevailed against the immune system and any therapies as they travel through the body. In this respect, they are particularly fit and therefore difficult to combat.
Clusters are more successful
For around twenty years, cancer research has increasingly focused on metastases. It is now clearer why and how certain tumors metastasize. We now understand better what happens at the level of genes and proteins. In addition, it is now known that not only primary tumors, but also metastases themselves can form offshoots.
One of the leading international metastasis research groups is the team led by Nicola Aceto, Professor of Molecular Oncology at ETH Zurich. His group was able to show that the common image of individual cells detaching from the tumor and circulating in the body is outdated. It is not these separate cells that are particularly successful in forming metastases, but so-called clusters. Such accumulations of cancer cells form in parts of tumors that are particularly poor in oxygen. They come off the tumor as small lumps. Aceto’s group discovered how genes play a role in this process and that the day-night rhythm is also important. Using breast cancer patients as an example, they demonstrated that the clusters detach from the tumor, especially during sleep. This provides new starting points for blocking the formation of metastases.
An extra pill
Because it is so difficult to kill the aggressive metastatic cells, Aceto wants to take a different approach: prevent the formation of clusters or break them up and break them down into individual cells again, ideally before they leave the tumor. Nicola Aceto’s vision: If a person is diagnosed with a tumor in the future, the best possible therapy will be used. If the risk of metastases is increased depending on the type of tumor, the person can also take a pill that breaks up clusters.
His laboratory at ETH Zurich has already taken the first step towards this vision. At the end of 2023, Aceto successfully completed an initial clinical study with a small number of breast cancer patients in collaboration with three Swiss hospitals. A heart drug was tested that had previously been able to resolve clusters in animal experiments. In fact, the drug had the same effect on the patients in the study. Now the researchers want to further improve the active ingredient and are planning the next study with more participants. “Even if everything continues to work, it will still be years before a corresponding drug is available,” says Aceto.
New approaches in sight
Following the previous improvements in the treatment of metastases from individual tumors, there are new approaches that could be helpful in the future. Knowledge of molecular and genetic mechanisms in the formation of metastases has provided starting points for novel targeted therapies. “Corresponding therapies are currently being developed and will come onto the market in the next few years,” says Aceto. Above all, Olivier Michielin from the University Hospital of Geneva also expects that immunotherapy will be available in the future for other tumors that have metastasized.
In addition, diagnostics are likely to continue to improve. “Blood tests that detect circulating cancer cells and clusters could replace some imaging in the future,” says Richard Cathomas from the Cantonal Hospital of Graubünden. However, this will also raise new questions. Because mutations are constantly taking place in our bodies and potential cancer cells are emerging. Our immune system usually manages to eliminate them in time. If a highly sensitive blood test detects such cancer cells and clusters – what does that mean? Should it be better to preventively take a pill that will hopefully exist in the future or let the immune system do its work first? This will need to be clarified.
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