A new blood test for cancer of unknown primary

Classified information

At its core, CUPiD is a machine learning algorithm called a classifier. Classifiers do what they say on the tin, they analyse data and classify them into discrete categories – in this case, into a cancer type. 

That may sound straightforward: take a blood sample, extract the tumour DNA, analyse the methylation, identify the cancer type.  

Unfortunately, it’s a little more complicated than that, for two reasons.  

The first is that the amount of DNA present in a blood sample is extremely small, which doesn’t give researchers a lot to work with. 

The second is that tumour cells aren’t the only cells that release DNA into the bloodstream when they die. Healthy cells do that too. And that means a lot of the free DNA in the bloodstream of a person with cancer isn’t tumour DNA. 

So, we need a way of accurately sifting through a very small amount of DNA to find an even smaller amount of tumour DNA. 

Luckily, that’s exactly the kind of thing CUPiD has been trained for. 

Training camp for CUPiD

CUPiD is actually what’s called an ensemble classifier, which is lots of individual classifiers put together. That allows it to perform multiple analyses at once. But to perform these analyses, classifiers need to be trained on existing datasets.  

In CUPiD’s case, a big existing dataset.  

The computer scientists in the team trained CUPiD using information from The Cancer Genome Atlas, a large scale, freely accessible database containing the genetic information of over 20,000 samples representing 33 cancer types.  

That way, CUPiD learned to recognise pieces of DNA from each type of cancer, and it could then use that information to classify unknown samples it was given. But to be clinically useful, it needs to work on very small amount of DNA. 

So, how did it fare? 

The team tested CUPiD on 170 DNA samples from blood. That included 143 samples from people with cancer, representing 13 different tumour types, and 27 samples from people without cancer. 

And CUPiD correctly identified the tumour type in 121 of those samples, a success rate of 84.6%.  

Importantly, the test had a high accuracy. When CUPiD makes a tumour prediction it is correct 96.8% of the time.  

The researchers then applied CUPiD to blood samples banked from patients with CUP. 

CUPiD made a tumour prediction in 32/41 (78.0%) cases. For 88.5% of cases the primary tumour predicted by CUPiD was consistent with the clinically suspected cancer type or subsequent primary cancer found through other tests. 

Every minute counts

The results the team saw with CUPiD, published last week in Nature Communications, were exciting but we’re still a little way from rolling it out in the clinic. 

This research was what’s called a proof-of-concept test.  

The team have shown that CUPiD can work in the lab using known samples, but we need to make sure that it could identify a wider range of cancer types using samples from real patients.  

The team are now recruiting for a trial to validate their results in a much bigger cohort of real patients with known cancer types as well as testing in a larger group of patients with CUP. 

But while it’s in early stages, a liquid biopsy like CUPiD has the potential to completely change the diagnostic journey of someone with CUP. 

“The beauty of the test in my eyes is that you could introduce it right at the beginning of the diagnostic journey for patients with metastatic cancer,” says Conway. 

“Patients often get a scan that shows multiple lesions that look like cancer, but they don’t see an oncologist until it’s been confirmed where that cancer has come from.”  

“And that sometimes isn’t straightforward. Sometimes patients have multiple biopsies, maybe they’ll need more scans, maybe they’ll have an endoscopy, and still, nobody is quite sure where this cancer came from.  

“So, even if all of those investigations found a primary tumour, the blood test could have done it a lot quicker.” 

Every minute counts when it comes to starting cancer treatment. The sooner a person with cancer can start their treatment, the more likely it is to be successful. 

That’s why developing tests like CUPiD, which could greatly reduce the time it takes to get a primary diagnosis, is so crucial for people with CUP. 

People like Lee. 

Living with cancer of unknown primary: Lee’s story 

Lee was diagnosed with CUP in January 2022, more than 3 months after he first found two lumps and made a GP appointment. After an initial ultrasound, he was referred to his local hospital for investigative tests. 

“I had an MRI scan, a CT scan, chest x-rays, and blood tests and everything was coming back inconclusive,” he says. “So, the last stop was a biopsy on these lumps. 

“The biopsy suggested I had cancer, so I went for a PET scan to confirm that. 

“The doctor said, ‘it’s cancer of unknown primary’. I didn’t understand what that meant, I thought cancer was just cancer. He said it’s incurable, and because of where it is it’s inoperable.” 

After his diagnosis, he was referred to the Christie NHS Foundation Trust in Manchester, where Conway and her team are based, in February 2022. 

“I had more blood tests, and they offered me a clinical trial. They told me to go away and think about it, but I didn’t have to. I wanted to get straight on it, because even if it didn’t help me, it could help people in the future.  

“We wouldn’t be where we are today if people hadn’t gone on trials years ago.” 

Once it was confirmed he was eligible for the trial, Lee started treatment with a new chemotherapy drug in March of that year. After the first 3 sessions, his tumour had shrunk by almost half. When he’d completed the 6 rounds of chemotherapy, he was moved onto a different trial using a less invasive immunotherapy treatment. 

Lee, now 57, knows just how revolutionary a test like CUPiD could be for people with CUP. 

“I’ve had loads of tests, loads of tissues taken and sent everywhere, blood tests, everything,” he says. “And they still can’t find the primary cancer.” 

“There’s no doubt a test like this would’ve made things better for me, but I’m so fortunate. And I’m so grateful for the team at the Christie. If it weren’t for them, I don’t think I would be here today.  

“The prognosis for cancer of unknown primary isn’t very good. I got told I had 9 months, but it’s been 2 years now. 

“Every day is a bonus. You wake up every morning with a smile, because you’ve got another day.” 


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