Knowing whether a tumor might grow or spread to other parts of a patient’s body might be key to survival – and now scientists are one step closer to unlocking the flexibility to predict just that.

In a series of seven papers published today (Weds April 12) in Nature and Nature Medicine, Cancer Research UK-funded researchers based on the Francis Crick Institute and University College London (UCL) describe how changes to cancer cells’ DNA are enabling them to anticipate how those cells will behave in the long run.

This includes where and when cancer will spread to other parts of the body in a process referred to as metastasis, which is accountable for most cancer deaths worldwide.

The findings could at some point allow doctors to make use of a blood test to predict how a patient’s cancer may grow and spread, enabling them to trace it and rapidly adapt treatment in real-time. It also offers a possible route through which clinicians could analyze the disease’s risk of returning following surgery.

While the research was carried out on patients with lung cancer, the scientists say their findings may be applied to other cancer types, reminiscent of skin cancer or kidney cancer.

These studies are the culmination of 9 years of research from Cancer Research UK’s £14 million TRACERx study – the primary long-term study of how lung cancer evolves. TRACERx is a nation-wide research effort, involving greater than 800 patients in clinical trials and a community of 250 investigators who based at 13 hospital sites across the UK.

Lead researcher based on the Francis Crick Institute in London, UCL and Cancer Research UK’s Chief Clinician, Professor Charles Swanton, said:

“TRACERx recognises that cancer will not be static and the way in which we treat patients shouldn’t be either.”

“What makes the TRACERx project particularly powerful is that it treats tumors as ever-changing ‘ecosystems’ made up of diverse cancer cell populations.

“By taking a look at the tumor in its entirety, we are able to observe how these cell populations interact and even compete with each other, which helps us to glean worthwhile insights into the likelihood that a tumor will return and when this might occur. We can even observe how the tumor is prone to evolve over time, spread and reply to treatment, offering hope to thousands and thousands of patients in the long run.”

In these seven studies, researchers on the Crick and UCL followed 421 of the 842 TRACERx participants from after they were diagnosed to observe how their tumors modified over time. The patients had non-small cell lung cancer (NSCLC), probably the most common variety of lung cancer.

Amongst the key findings within the seven papers, the researchers found that:

• Tumors may be made up of many alternative populations of cancer cells which carry sets of genes which are always changing. The more diverse these tumors are, the more likely the patient’s cancer will return inside 1 yr of treatment.
• Some patterns of DNA changes when observed in a patient’s tumor indicate what their cancer might do next.
• These patterns could illustrate to doctors which parts of a tumor might grow and spread to other parts of the body in the long run.
• Blood tests might be used to observe these changes to tumor DNA in real time, helping doctors pick up on early signs that cancer is returning or not responding to treatment.

Constant changes to cells allow tumors to thrive

Tumors are made up of various “populations” of cancer cells which all carry different genetic mutations. The more diverse these mutations are, the more that tumors can evolve and gain resistance to treatments.

The researchers found that specific patterns of genetic mutations in cell populations enable the cancer to return in a patient quicker — inside 1 yr of surgery.

These patterns of mutations also indicate whether a tumor is more prone to spread to other areas of the body beyond the lungs and chest.

Armed with this information, doctors could at some point predict if someone with early-stage cancer, who must be treated successfully with surgery, may find yourself seeing their cancer return.

In one other discovery, researchers found that the genetic diversity of cell populations inside a tumor not only stems from genetic changes, but in addition from the way in which that genes are expressed.

Changes in gene expression can affect necessary elements of cancer biology, including whether a tumor will return after surgery.

On this instance, the researchers suggest that doctors treating lung cancer patients could intervene early by identifying those whose cancer is most prone to returning after surgery and following up with further treatment, to assist prevent the cancer from coming back.

Identifying what leads cancer to spread

The researchers also looked more closely at how lung cancer spread within the TRACERx participants.

They identified which cells in a tumor were probably to be accountable for a cancer spreading (metastasis) in the long run because these cells were more prone to harbor certain changes of their genes. These indicate that a cell has the next probability of leaving the tumor and moving to other parts of the body, where it then grows right into a recent tumor.

Metastasis is accountable for nearly all of cancer deaths, so understanding which parts of the tumor are accountable for triggering this process could allow researchers to focus on treatments specifically to stop cancer from spreading.

Transforming how we track people’s cancers

The TRACERx scientists also investigated whether or not they could track changes within the tumor and features of its genetic diversity without the necessity for surgery or biopsies, a variety of invasive medical procedure that involves taking a small sample of tissue and examining it in a lab.

By analyzing DNA released into the bloodstream from tumor cells, referred to as circulating tumor DNA (ctDNA), they found that the presence of ctDNA within the blood before or after surgery suggested that the patient’s cancer was highly prone to return in the long run.

The presence of tumor DNA within the blood isn’t the one indicator that cancer might spread or come back. Researchers found that microscopic patterns created by the arrangement of tumor cells are linked with the chance of cancer returning.

A blood test that reads ctDNA could let doctors track someone’s cancer in real time, allowing them to personalize treatments to that patient.

Currently, the most effective option now we have to observe a patient’s tumor is to extract tissue either through a biopsy or during surgery. Each are invasive and time-consuming options which give us a limited snapshot of how that tumor is behaving at a given time limit.

Evaluation of ctDNA would give us a fuller picture of how the tumor is changing over the course of the patient’s disease using minimally invasive blood tests. It will allow doctors to treat people more proactively, taking swift motion to alter a treatment plan that’s not working.”

​​​​​​​Dr Iain Foulkes, Executive Director of Research, Cancer Research UK

TRACERx has already entered its next phase, referred to as TRACERx EVO, which is able to receive slightly below £15 million in additional funding over the following seven years to further our understanding of tumor evolution and use that knowledge to alter how patients with cancer are treated.