Researchers have followed lung cancer from diagnosis to death and found that more than half the metastases they studied did not come from the original tumour but from other metastases. Metastases are therefore not only signs that the cancer has spread. They can become new starting-points for cancer, and the longer they remain in place, the greater the risk that the cancer will move on again – but perhaps also the wider the window for intervening.
Cancer rarely kills because a single tumour grows in one place but because cancer cells break away and settle in new parts of the body.
But determining which route the cancer takes through the body has been difficult.
In the new study, researchers did exactly that for people with non–small cell lung cancer: they read the genetic material in both the original tumour and the metastases – from diagnosis to death.
The metastases were not simply copies of the primary tumour. They continued to develop on their own and could become new starting-points for what makes cancer deadly.
“What struck me most was how different the patterns were from patient to patient,” says Sonya Hessey, clinical lecturer at the UCL Cancer Institute, University College London, United Kingdom.
The study has been published in Nature.
501 samples revealed the cancer’s route
The study is based on 501 tissue samples from 24 patients – taken from both the original tumour and from metastases in various parts of the body.
Many were collected after death through the PEACE autopsy programme. Such a complete view is almost impossible to obtain from living people, because taking samples from every place in the body the cancer has reached is not usually feasible. This means that tracking the disease from beginning to end is rarely achievable.
The pattern was clear: more than half the metastases did not come directly from the original tumour but from other metastases. Many were therefore not final destinations but waypoints on the cancer’s journey through the body.
For just under two thirds of the patients, several groups of cancer cells from the primary tumour had also broken away separately and founded their own metastases. This finding is not based on a single genetic family tree alone. The scans showed the same sequence, and specific genetic losses – changes the cells do not simply regain – followed the cells as they spread.
“Our data show that, like the original tumour, metastases can be a source of cancer cells that carry the disease further. They may therefore become targets for treatment – not merely traces of a cancer that has already spread. Surgery or local treatment of a metastasis may reduce the risk of new attacks, but this needs to be tested in clinical trials. Previous data suggest that this strategy works best for patients from whom the original tumour has been removed and the disease returns in only a few places,” says Sonya Hessey.
The longer a metastasis remains, the more dangerous it can become
Time also played a role: the longer a metastasis remained in place, the greater the likelihood that it would become a new starting-point.
This may open a window of time in which a metastasis is not just something doctors can see on a scan but something they may still be able to stop before it sends new cancer cells onwards.
This fits with the fact that, in some Phase 2 trials, local treatment of a few remaining metastases has improved outcomes for people with metastatic lung cancer. However, the picture is not clear-cut: a more recent study did not find the same benefit among people treated mainly with immunotherapy.
“Our data are consistent with there being a window in which intervening before a metastasis spreads further is possible. The challenge is that we do not know whether that window is still open when the metastasis can be seen on a scan or whether it has already sent cells elsewhere,” says Sonya Hessey.
Metastases can change while treatment is trying to hit them
After the cancer had spread, the genetic material of the metastases had also changed markedly. This may affect how long treatment continues to work.
They had picked up new cancer-driving mutations, and some had doubled their entire genome. This fits with a pattern also emerging in other types of cancer: one biopsy may be enough to find the mutation that determines the choice of targeted medicine but not necessarily enough to capture the full development of each metastasis.
“All the mutations that were important for the choice of treatment were present in all the cancer cells. Therefore, a single sample from either the primary tumour or a metastasis was sufficient to select the right targeted treatment,” explains Sonya Hessey.
In addition, the findings show that the metastases are still developing.
“Because each metastasis follows its own path, resistance can arise differently from one site to another. Combination therapies may therefore be beneficial for patients with widespread disease,” she elaborates.
Unstable chromosomes may help cancer reach farther afield
In most cases, the cancer remained in the same area of the body.
The clusters of cancer cells that broke out of the chest and settled in more distant organs stood out by having particularly unstable chromosomes – in other words, many major changes in the structure of their genetic material.
“This instability probably makes the cancer cells more adaptable, enabling them to survive more easily in a distant organ than in the lung. It may also alter how visible the cells are to the immune system. Recent research has shown that these kinds of chromosomal changes can be used as markers for prognosis and treatment, but we do not yet know how they should be used in clinical practice,” says Sonya Hessey.
The study is based on a relatively small number of people, and most had already received treatment. Nevertheless, several independent parts of the data point in the same direction: the relationship between the cancer cells, the location of the metastases in the body, their age, the scans taken along the way and the chromosomal changes in the cells that spread furthest.
Now, TRACERx EVO, with more patients and broader criteria, will test whether the cancer’s route can be used to predict where the disease is heading – and where it can be slowed.
“We hope that the larger scale and broader criteria of TRACERx EVO will reveal which molecular features predict different patterns of spread, and when treatment stops working. The aim is to better predict the course of the disease and select the right treatment for each individual patient, so that we can slow down metastatic lung cancer or stop it from progressing further,” says Sonya Hessey.
