Warnyta Minnaard lost her partner, Hederik, to Cancer of Unknown Primary (CUP). Heartbreak inspired her to spearhead a campaign for the reimbursement of whole genome sequencing in the Netherlands so that others might be spared the same fate
Hederik was just 32 when he became ill three years ago. It began with a drooping eyelid and prompted him to go to hospital in search of answers. Doctors were able to confirm after several months that he had cancer, but could not determine where it began. This matters because diagnosis informs treatment.
‘Unfortunately, he passed away in early January 2019 and I became a widow at age 29,’ Warnyta recalled. ‘Even though he was severely ill, we had no idea he was going to die as we were in the midst of an ongoing diagnostic trajectory that already took seven months.’
Hederik was one of about 1,500 Dutch people each year who are diagnosed with Cancer of Unknown Primary (CUP). For patients with CUP – an advanced/metastatic form of cancer which affects at least two areas of the body – time is of the essence. However, lack of access to cutting-edge diagnostics is a barrier to diagnosis and effective treatment which could prolong and improve lives.
The advent of whole genome sequencing (WGS) of tumours promises to transform cancer care, making it more personalized and more effective. Instead of treating cancer based on where in the body it began, doctors would select a treatment based on the genetic characteristics of the tumour.
Warnyta co-founded Missie Tumor Onbekend, a patient support and advocacy organization for patients with CUP in the Netherlands. The charity advocates for a specialized diagnostic and improved care pathways for CUP patients, better access to innovative diagnostics, and better treatment. The organization also offers support to patients, clinical research and awareness raising campaigns.
Legislators in the Dutch Parliament had been working on personalized medicine for some time in an attempt to update health insurance rules to keep pace with rapid advances in medical science. Warnyta and colleagues saw an opportunity to ensure that the interests of CUP patients were reflected in any legislation agreed by policymakers.
Following a series of events to engage with experts and members of Parliament and key decision-makers, Missie Tumor Onbekend and a team of clinical experts helped to secure a significant amendment to proposed legislation which has now come into force.
Petur Snaebjornsson, a clinical pathologist at the Netherlands Cancer Institute, helped to make the case to policymakers by explaining the technology and sharing early data from a large study. He argues that WGS is better than routine DNA testing which can sometimes leave out rare but relevant biomarkers.
‘WGS offers two main advantages. Firstly, in this all-in-one DNA test you can detect all genetic biomarkers that are used to guide so-called targeted treatment or immunotherapy, which are new types of cancer treatment compared to chemotherapy,’ he said.
‘Secondly, WGS can be used to predict the location of the primary tumour. Finding the primary tumour location is of importance because it guides the choice of chemotherapy. So WGS represents a win-win test for patients with cancer of unknown primary.’
In February 2021, the Parliament unanimously added extensive DNA-testing to the basic package of care that must be covered by private health insurers as part of their mandatory offering available to each citizen in the country. This led to WGS being reimbursed for CUP patients from 24 April 2021.
Petur said the campaign and subsequent changes to reimbursement rules have increased awareness of CUP, raised the profile of patient advocates, and prompted the establishment of a Dutch expert platform called CUPP-NL. ‘The platform aims to raise awareness and collaboration, pool current knowledge, stimulate research and improve diagnostics and treatment options for patients with CUP,’ he added.
It was a remarkable achievement for the small group of activists behind a relatively new advocacy organization. However, campaigners are not yet ready to celebrate as there is still work to do before the new rules have the desired impact. Some patients have reported a slow response to the new rules, with families struggling to access the testing they need.
Petur said performing WGS early in the diagnostic process is vital to improving outcomes. Some hospitals have opened CUP clinics and access would improve if more hospitals followed this example.
For Warnyta, this cannot come quickly enough: action must follow the policy shift announced in April. ‘We are now strong on policy but the coordination to reflect the policy change in care pathways is still missing at a central level. In specific parts of the country, hospitals are now taking a coordinator role for patients in their catchment areas but access needs to be arranged at a country-wide level so that it does not matter where you live,’ she said.
This is a source of deep frustration and sadness for campaigners and people living with CUP. As time ticks on, lives are lost. And that motivates Warnyta and other CUP patient advocates to continue to strive for more awareness and support for CUP.
World CUP Week: Researchers are screening hundreds of tumour genes in search of drug targets that could open the door to more personalised cancer care
Most cancers are named – and treated – according to where the first tumour is found. But for some patients, tumours are detected in various organs of the body but the origin of the disease remains a mystery.
People with Cancer of Unknown Primary (CUP) are up against it. Their disease is advanced at the time of diagnosis and there are no specific treatment options available. As time is of the essence, they are usually offered several drugs at once – an approach known as polychemotherapy – in the hope that one of them may work. The outcomes are often poor and therapies affecting all of the body’s cells can make patients feel very unwell.
‘We would like to see a more personalised approach to therapy in patients with CUP,’ explained Dr Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute (IJC) in Barcelona. ‘For common cancer types, such as colon cancer and lung cancer, some hospitals screen patients for genes which help them select a targeted therapy. In CUP, we don’t yet know which genes to look for.’
To rectify this, Dr Esteller is running the CUPP-On project which will analyse samples from 50 patients with CUP. The team are looking for up to 500 genetic mutations or copy number variations (CNV) frequently observed in solid tumours, for which there are already approved therapies available.
‘In selected cases, we will take a sample of the patient’s tumour and grow it in mice where we can then test existing therapies to establish whether it reduces tumour growth,’ Dr Esteller said.
Clinicians may consider using this information to change their patients’ treatment plan. Looking at the bigger picture, the study could offer clues about the origins of CUPs. ‘Is the original tumour small or hidden? Is there something special about these tumour types? Are certain genes responsible for a proportion of CUP cases? We hope to find out,’ said Dr Esteller.
Other advances could flow from the project, such as the inclusion of CUP patients in so-called basket trials where patients are recruited to clinical studies based on having a tumour with a specific mutation which can be targeted by a drug.
‘Basket trials don’t care about tumour type or location – they include patients based on the presence of certain mutations,’ Dr Esteller said. ‘If we show that some CUP patients have mutations that are actionable by a drug, it becomes possible to join these kinds of trials.’
He said targeted therapy also brings benefits beyond survival as treatment tends to be well tolerated, helping to preserve quality of life. If the study proves successful, the results could be translated into clinical practice relatively swiftly as the drugs are already approved for human use. What’s more, as the cost of gene sequencing is much lower than it was a decade ago, there are fewer barriers to access in hospitals with sufficient lab capacity.
The CUP-On project is supported by the Sarah Jennifer Knott Foundation, a charitable organisation devoted to promoting awareness, education and research of CUP. ‘Support from charitable foundations is critical right now as it can be challenging to attract large grants from public agencies for rare tumours,’ Dr Esteller said. ‘Foundations can make a big difference by jump-starting research initiatives like this one.’
Tanya Knott, Director of the Sarah Jennifer Knott Foundation said patients diagnosed with cancer of unknown primary desperately need greater access to genomic profiling and potential targeted treatments. ‘The potential diagnostic and treatment opportunities that Dr Esteller’s research study will bring for CUP patients is incredible and we feel honoured to contribute to his amazing work.’
CUP Awareness Week: connecting researchers, clinicians and patient advocates
Cancer is usually diagnosed and treated based on where it began. If the disease originates in the lung, it is called lung cancer even if it spreads to the bones or the liver. This matters because it informs treatment decisions, prompting oncologists to follow standard pathways of care.
However, the primary site of cancer is not always easily determined. This results in people being told that they have Cancer of Unknown Primary (CUP), leaving them without a clear treatment trajectory. In some cases, this translates into poor outcomes: mortality rates in CUP are among the highest in the field of oncology. CUP accounts for between 3% and 5% of cancers and is the sixth most cause of death in the UK, making it more common than cervical cancer and more deadly than kidney cancer. One in 64 people will be diagnosed with CUP during their lifetime (UK data).
Despite this, and the heavy toll it takes on patients and their families, the burden of the disease is underappreciated by the public, policymakers and many clinicians. Unlike breast cancer or bowel cancer, CUP is an area that has not traditionally been a hive of research activity and rarely makes the news headlines.
Information hub & patient support
CUP Awareness Week aims to change all of this. Running through the last full week of September (20-26 September 2021), it seeks to build momentum behind a shift towards treating cancer based on genomic information rather than solely on the initial location of a tumour. The first event of its kind, the awareness week will help to connect researchers and clinicians in this fast-moving field, while keeping patients at the centre of the conversation.
‘Access to information and support can be a real challenge for patients with CUP. This need will be highlighted by CUP Awareness Week through the World CUP Awareness website. It aims to serve as a hub for all information regarding CUP for healthcare professionals, researchers, industry, patients, patient organisations and all those with an interest in CUP,’ said Tanya Knott of the Sarah Jennifer Knott Foundation, an advocacy group supporting education and research. ‘We will run webinars which are open to the public and allow experts and patients alike to learn more about CUP.’
Redefining cancer based on genomics
The practice of classifying cancers based on their anatomical location is a legacy of the pre-genomic era: physicians labelled cancers according to the organ they first affected because it was the only information available. That has been changing, with genomics opening the door to a more precise approach to classifying and treating disease based on the genomics of a tumour.
While scientific advances take time to filter down into daily practice, there are some positive signs that progress may be under way. Dr John Symons, who founded the Cancer of Unknown Primary Foundation in 2007, sees the 2010 publication of NICE Guidelines as a pivotal moment in England.
‘In the 10 years prior to that, progress had been slow, despite advances in genomics,’ he recalls. ‘Frankly clinicians were not terribly interested in CUP: there was no solution, no guidelines, and it was not a major research area. Treatment was ad hoc and the outlook for patients was poor.’
The NICE Guidelines offered evidence-based treatment pathways which boosted recognition of CUP among clinicians, creating a managed pathway for patients to take. Perhaps unsurprisingly, not every doctor in every hospital follows – or is aware of – the guidelines. ‘We have seen some enlightened scientists come to view cancer as a disease of the genome rather than a disease of the anatomy, but healthcare systems lag science by a long way,’ John said. ‘We speak about it at conferences and it gradually filters into the health service, but it’s not there yet.’
Test, test, test
Central to the changes required to turn this approach to cancer into better outcomes is the use of molecular profiling which would inform treatment decisions. Some hospitals in the UK routinely run whole genome sequencing on tumour samples for research purposes but the practice is far from widespread. Indeed, testing is usually paid for privately rather than through centrally-funded health services.
‘Molecular profiling is available in Ireland where there is a therapeutic indication for example in breast and lung cancer, however for other cancers genomic testing is hugely under-resourced,’ Tanya explained. ‘Ireland has fallen behind and the gap is widening. Ireland needs a formalised national policy in genomic testing.’
In the Netherlands, the Parliament passed legislation in February 2021 which added extensive DNA-testing to the basic package of care that must be covered by private health insurers. This led to Whole Genome Sequencing (WGS) being reimbursed for CUP patients specifically from April and followed a vigorous campaign led by Warnyta Minnaard, co-founder of Missie Tumor Onbekend, a support and advocacy organization for CUP patients.
Despite this, some patients have been frustrated to find that the policy change has not yet been matched with action countrywide. ‘We are now strong on policy but the practicality to make the test readily available to all patients everywhere in the country is missing,’ she said. ‘Patients are still faced with bureaucracy when they try to get tested. Meanwhile, time will pass and people will die of CUP. That is why we need awareness of the urgency of the situation.’
Warnyta also hopes to see greater standardisation in care within and between countries, with more hospitals following best practice and applying the latest tools to diagnose and treat CUP. ‘I hope CUP Awareness Week can prompt more people to reach out to us, to talk to their doctor, and to get tested,’ she said. ‘And, ultimately, I hope it gives more people a clear pathway and a better chance of survival.’
Tanya Knott, Director, SJK Foundation, spoke to Danielle Barron about her vision of personalized medicine and the personal tragedy that drives her to make it a reality.
Tanya Knott – Sarah Jennifer Knott Foundation
Tell us more about you
I am the founder and director of the Sarah Jennifer Knott Foundation. I established the foundation with family and friends in 2016 following the death of my sister Sarah aged 31 from cancer of unknown primary also known as CUP. The aim of the foundation is to raise awareness, education and research into CUP. This is an unusual type of cancer where the patient presents with a secondary cancer but the origin of the cancer is unknown. If the primary is unknown, the treatment is unknown. In Ireland, cancer of unknown primary affects up to 400 patients annually. Approximately 3-5% of all cancers are cancer of unknown primary, making CUP the fourth most common cause of death from cancer worldwide.
My background is in healthcare, I am a registered nurse and worked for many years in the pharmaceutical industry. Throughout Sarah’s illness I realized the huge gap in care for patients like Sarah with CUP and armed with this knowledge I set up the foundation in an effort to address the unmet needs for patients diagnosed with this devastating illness.
What does personalized medicine mean to you?
In the future, where the cancer began will not be the treatment priority, and instead treatment will be tailored to the unique genetic make up found by genomic profiling. Enabling targeted treatment options specific to the individual patients needs. For patients with cancer of unknown primary and unusual cancers, genetic profiling offers a vital opportunity for targeted treatment. Studies have shown that relevant mutations are observed in 30-85% of patients with cancer of unknown primary. Genomic profiling is opening up access to clinical trials and access to revolutionary new treatments; unfortunately, despite these benefits, the transition to personalized medicine is slow.
Why do you believe this topic is important?
I believe access to personalized medicine is vital as it has the potential to transform patient’s lives, especially for patients with limited treatment options. Personalized medicine is a rapidly evolving field, with more and more targeted treatments available, but without the diagnostic profiling some of these therapies are not being considered for patients where they could be of huge benefit.
So much has changed since Sarah was ill, that if she was alive today there is a high chance that through genomic profiling an actionable mutation may have been found and she could have lived longer with controlled disease and many more treatment options.
Why is your organization interested in participating in this multi-stakeholder collaboration?
SJK are honored to be founding members of this multi-stakeholder collaboration. One of our main objectives at SJK is to advocate for access to genomic profiling for all those who need it. Our goal is completely aligned with this global project. I quickly realized that to ensure patient access to genomic profiling I would need to be a part of something bigger! The barriers are so great and diverse it needs a multi-stakeholder collaboration to understand and overcome all the many obstacles. Through the multi-stakeholder approach we have the solutions to the barriers, we know where to focus for change.
The patient benefit is that they are given the option. Personalized medicine may not be an option for all patients, but to have the opportunity to be fully informed and to have the opportunity to discuss and understand the option with their HCP is a great benefit. Patients can also benefit from more accurate diagnoses, targeted treatments, with greater survival than perhaps their current treatment and with potentially less side effects. Patients can benefit from access to clinical trials and patients and their families can benefit from preventing hereditary cancers.
What makes this collaboration unique?
This is a unique collaboration as it is bringing together all the multi-stakeholders required to make personalized medicine a reality. As a global initiative, we can learn from best practices in countries and share these learnings with other countries. All stakeholders come with their expertise, the drive to overcome the obstacles, identify the solutions and implement the changes needed.