Following CUPiD’s arrow: A new blood test to find cancer of unknown primary

One of the most nefarious things about cancer is its ability to spread. 

This is also called metastasis, and happens because cancer cells can break away from a tumour and travel in the bloodstream. From there they can settle in another part of the body, where they start to grow a new tumour, making the cancer more difficult to treat. 

But while it might sound confusing, cancer growing in a second part of your body doesn’t mean you then have two types of cancer. 

For example, if someone’s cancer starts in their breast and spreads to their lung, it doesn’t mean that they have lung cancer.  

Instead, it’s called a secondary breast cancer. It’s made of the same cancer cells that were growing in their breast, only now they’re growing in their lung. 

In most cases where a person is diagnosed with a secondary cancer, we can use special imaging tests to find where the cancer originates, known as the primary cancer. 

But in rare instances, doctors can’t tell from any tests where the primary cancer is. They can only see the location of the secondary cancer. 

In these cases, the patient is diagnosed with cancer of unknown primary (CUP). 

Sometimes, doctors are able to identify the primary cancer after diagnosing a person with CUP. But that involves a long road of diagnostic tests for the patient, and unfortunately is only successful in the minority of cases. 

A team of researchers we funded at the Cancer Research UK National Biomarker Centre, part of the University of Manchester, and the Christie NHS Foundation Trust, are working to change that. 

Into the unknown

There are a couple of theories on why the primary cancer is difficult, or even impossible, to find in cases of CUP, but there isn’t a clear answer. 

“Sometimes when you look at the cells under the microscope, you can clearly see it’s a breast cancer, for example. You just can’t find that breast cancer in the breast,” explains Dr Alicia-Marie Conway, an academic clinical lecturer at the University of Manchester. 

“Some people think that there was a primary tumour that has regressed, or the immune system found and destroyed it, but the metastatic sites continue to grow. And we do have evidence of that in tumour types like melanoma. 

“Another theory is that the primary tumour is just difficult to find; it’s remained really small.”  

But whatever the reason, not knowing where a person’s primary tumour is presents a unique set of challenges when it comes to treatment. 

As treatments have developed over the past decade, they’ve become more targeted, meaning they’ll only work on cancers with certain mutations. Often these mutations will be specific to certain types of cancer or will affect one tissue differently to another. 

For example, the drug vemurafenib targets a mutation called BRAF in certain types of melanomas, but this drug is ineffective in treating bowel cancer with the same BRAF mutation. 

And that means targeted treatments, which are likely to be more effective, can’t be used to treat cases of CUP where we can’t find the primary tumour as we can’t be confident that they’ll work. 

What we need is a way of easily identifying where cancer cells first started growing, so we can determine what treatments would work best for them. 

That’s exactly what Conway and her team have been investigating. 

They’ve been exploring how we can use something called DNA methylation to reveal where the primary cancer started growing. And all they need is 2 tablespoons of blood.  

It shouldn’t come as a surprise to learn that having skin cells growing in your liver would be a bad thing. 

So, our bodies use DNA methylation to stop that from happening. 

While each cell contains all our genes, which are made up of strings of DNA, they can switch certain ones on or off depending on the jobs they need to do in the body. There are a few different ways that cells can do this, but one of them is DNA methylation.  

To do it, cells stick small molecules called methyl groups onto specific parts of DNA to make a particular pattern.  

That way, when one of your cells comes to read the sequence of your DNA, it can see which genes are switched on and off and knows to ignore those that are switched off. 

And that pattern will be the same in all cells of the same type, like a unique code that can be used to identify them.  

Often, mutations to DNA are not consistent across a cancer type, so it’s difficult to tell what the primary cancer is from that information alone. Methylation pattern, however, is distinct to a tissue type, making it much more useful in CUP. 

That’s a good start, but there’s a catch. 

The problem of scale in cancer of unknown primary

The way we traditionally examine tumour cells, and in these cases, look at the DNA methylation patterns, is by taking a biopsy of the tumour. Biopsies can be invasive for the patient, and often can only collect a small sample of tissue. 

“One of our big challenges currently is that the biopsies that we get from people with CUP are often quite poor quality, and don’t have very much tissue,” Conway explains. 

“And that means we don’t have enough tissue to look for the methylation patterns very easily in these patients’ cells.” 

So, to overcome that problem, the team looked to find an alternative to invasive biopsies, a way to easily take sample from patients but still get the same data needed from the tumour’s DNA. 

And there’s a good candidate for that: liquid biopsies. Or, as they’re more commonly known, blood tests. 

Cancer blood tests 

Interest in how we could use blood tests in cancer research has been growing over the past few years.  

In September 2021, a new blood test that has the potential to detect over 50 kinds of cancer began trials in the NHS, and earlier this year, researchers working on our flagship lung cancer study TRACERx published results showing how we could use a blood test to track the evolution of lung cancer. 

But to recap, let’s go through how they work. 

As a tumour grows, cells die, and new cells grow in their place. These dead cells get broken down and their contents, including their DNA, gets released into the bloodstream.  

These chunks of tumour DNA in the blood are known as circulating tumour DNA (ctDNA). 

Therefore, we can analyse ctDNA that we get from a blood test to determine information about the tumour, like what mutations it carries and, if we’re tracking it over time, how it’s changed. 

But in this case, it’s the methylation patterns that we’re interested in. If we look at the patterns on the pieces of ctDNA we collect in the blood samples, we may be able to identify which tissue or cell type they came from.  

And that would lead us to the site of the primary cancer. What we need is a test that combines finding tumour DNA in a blood test with identifying patterns in methylation and matching them to specific cancer types, or methylation profiling. 

So, Conway, with the team of researchers at the Cancer Research UK National Biomarker Centre, directed by Prof Caroline Dive CBE, have developed one. 

It’s called CUPiD.