From diagnosis to discovery: transforming care for cancer of unknown primary

Detective work and persistence are critical factors to Dr Natalie Cook unlocking the secrets to some of the world's most challenging cancers. The pioneering CUPID test, developed in collaboration with the CRUK National Biomarker Centre, traces back to where the cancer started in cases of Cancer of Unknown Primary (CUP), while her advocacy for genomic testing aims to revolutionise treatment. With a focus on expanding clinical trials and addressing health inequalities, Dr Cook's work offers new hope for patients and transformative progress in CUP research.

One of the biggest challenges I've faced as a cancer researcher is working with patients diagnosed with cancer of unknown primary (CUP). CUP is a devastating and complex disease, where patients present with metastatic cancer, but the original site of the tumour remains unidentified. By the time we see these patients, the cancer has already spread throughout the body, making it much more difficult to treat than cancers with a clear origin.

Not being able to see where the cancer started means that we do not have access targeted treatments or a more personalised approach to management. Right now, chemotherapy is the only option available for patients diagnosed with CUP, and while chemotherapy can help slow the spread of cancer, it's a far from perfect solution.

What makes CUP so difficult to treat is not just the late-stage diagnosis, but the fact that it is highly heterogeneous, meaning it can take many different forms and appear in many different places; cancers can originate in almost any organ in the body, from the lungs to the pancreas, liver, and rarer sites.

This makes it incredibly complex to figure out a universal treatment protocol, because different types of cancer respond to treatments in different ways. Most patients diagnosed with CUP survive only six to nine months after diagnosis. Despite being one of the leading causes of cancer-related deaths in the UK and an area of unmet need, CUP remains under-researched and under-funded.

Assessing the challenges

CUP research has faced several challenges, particularly in terms of access to diagnostic material. Traditional methods of diagnosing cancer usually involve tissue biopsies, where doctors take a sample of tissue from the patient to analyse it. However, these tissue samples are often used up in the diagnostic process itself, leaving little to no material available for further analysis as part of research.

This is especially problematic in CUP cases, as the cancer's origin could be from almost anywhere in the body, and we need to examine various possibilities in order to understand what's happening. The fact that CUP is so heterogeneous makes it difficult to develop standardised diagnostic and treatment protocols.

The way cancer is recorded and coded by health systems also presents challenges with inconsistent coding practices leading to CUP often being wrongly grouped with other cancer types, making it harder to track how many people are actually being affected by this condition. This lack of clear data creates challenges for researchers who need accurate statistics to understand the disease and its impact.

Limited access to advanced genomic testing further complicates the issue. Genomic testing is a method where doctors analyse the DNA of cancer cells to understand how they are behaving and how they might respond to different treatments. Unfortunately, most patients diagnosed with CUP don't have access to this kind of testing, and without it, doctors cannot access more personalised treatments.

Making progress

Despite these multiple challenges, I've made progress trying to improve outcomes and opportunities for patients diagnosed with CUP. One of my proudest achievements is helping to develop the CUPID test, a blood-based diagnostic tool that uses molecular 'fingerprinting' to identify the origin of the cancer. Essentially, this test allows us to analyse the DNA in a patient's blood and trace the cancer back to its original source, even when we can't locate the tumour itself.

This breakthrough could transform the way we treat CUP patients by helping us to find the site of origin and therefore offering more targeted therapies. Instead of using chemotherapy, which has limited effectiveness, we can begin to offer treatments tailored to the specific type of cancer, allowing this more personalised approach to treatment that has worked to improve survival in several other types of cancer.

I'm also working to integrate genomic testing into standard CUP care, hopefully by using a simple blood-based test. By identifying the specific mutations in the cancer DNA, doctors can prescribe treatments that are more likely to work.

Unfortunately, this type of testing is not yet standard practice for CUP, but I'm actively advocating for its inclusion in NHS guidelines. This would allow more patients to benefit from precision medicine, whereby their treatment is tailored to their unique cancer profile rather than relying on generalised treatments like chemotherapy.

Collaboration has been key to my research, particularly the work we have done in partnership with scientists at the CRUK National Biomarker Centre. I've partnered with institutions and experts from around the world, to share knowledge, best practices, and advancements in diagnostics. These international collaborations allow us to stay at the cutting edge of CUP research and to work together to find solutions quickly.

At The Christie, where I conduct my research, I've expanded our clinical trial programme significantly. When I first started, there were no trials available to patients diagnosed with CUP, and now we have increased trial options, improved access to the right diagnostic tests, genomic profiling and more personalised approaches to treatment.

These are major steps forward, and will enable patients to access new and potentially life-prolonging treatments that weren't available before.

Health inequalities

CUP disproportionately affects people from lower socioeconomic backgrounds, who often face delays in diagnosis due to fewer health resources or difficulties in accessing healthcare. These patients are more likely to miss out on the specialised diagnostics, treatments and trials that could improve their outcomes.

These challenges are not unique to the UK; globally, many underserved populations suffer from late-stage cancer diagnoses and limited treatment options. The combination of these health disparities, inconsistent data collection, and a lack of advanced testing all contributes to the struggles in improving CUP care and patient outcomes.

Beyond research, my focus has also been on ensuring that patients from underserved communities get the same access to diagnostics and treatments as patients from large teaching hospitals. Health inequalities remain a major challenge, and I'm working hard to bring advanced testing and education to hospitals across the north-west of England.

By offering educational and research programmes to clinical staff at centres across the north-west, I'm helping to ensure that patients in smaller, peripheral hospitals can access the same high-quality diagnostics and care as those in major centres like The Christie. We know patients prefer to have tests and treatment closer to home, and the trials we are currently offering will help this happen.

CUP is an incredibly tough disease to tackle, but I'm determined to improve outcomes for these patients. Every step forward in this research offers new hope - not only for the patients of today, but for future generations as well.

By developing groundbreaking tests like the CUPID test, pushing for genomic testing to become standard practice, expanding access to clinical trials, and addressing health inequalities, I believe we can begin to change the way CUP is treated, and ultimately improve survival rates for those affected by this devastating condition.