Claudia Kouwenberg died from an aggressive form of cancer known as cancer of unknown primary (CUP). As CUP Awareness Week approaches, her husband Peter is telling their story in a bid to educate the public – as well as medical professionals – about why access to molecular diagnostics would have given them the answers they deserved
In March 2020, the world was coming to terms with the threat posed by the coronavirus pandemic, and in the Netherlands, Claudia Kouwenberg was dealing with a mild but troublesome case of eczema. Within weeks the world would be in lockdown and Claudia would be in a wheelchair, no longer able to walk unassisted. Within 6 months, she died.
The cause of Claudia’s death was cancer of unknown primary (CUP), an advanced/metastatic form of cancer which affects at least two areas of the body, but this was not realized for many months. Although more than 1,500 people in the Netherlands will be diagnosed with this form of cancer in a given year, a lack of awareness and access to cutting-edge molecular diagnostics means that diagnosis is often delayed or even missed. World CUP Awareness Week takes place every September in a bid to increase awareness of the cancer as well as imbue the public and medical community with a sense of urgency when it comes to its diagnosis.
Peter Kouwenberg is 55 and has decided to tell the story of Claudia’s final months. The eczema, in hindsight, was an initial sign, but the following month Claudia began to have trouble walking. An incorrect diagnosis of bursitis in the hip was offered, and physio and antibiotics were given, to no avail. Within a matter of weeks, her mobility was severely impaired and she began using a wheelchair. Peter’s frustration even at this early stage is palpable.
“We had already urged the GP several times for a referral to the hospital for further examinations,” Peter explains. “We also insisted on a blood test… Again and again, there was no response to our requests. We were worried because she wasn’t recovering and we wondered what was going on.”
Their GP’s uncertainty compounded the delays caused by the ongoing pandemic. When Claudia was no longer able to sleep because of her pain, she finally received a neurology referral, but during the appointment, her hip suddenly broke when she was trying to get up from the examination table.
“An upper leg does not just break, we soon took cancer into account,” Peter admits. “After a few nerve-wracking days, we were told that it was indeed cancer, but it was not clear what the primary location was and the tissue taken was no longer usable for research because it had already died.”
A host of examinations followed, including CT scans, PET scans, MRI scans, mammography, ultrasound, lung X-rays and blood tests. Once again, they were told it was cancer but the primary source was not known. As the investigations continued, Peter said he was almost overcome with feelings of despair. “You are powerless. You stand there but can’t do anything. Really powerless.”
This is unfortunately a typical journey for patients with CUP. While the eventual outcome may not have been different, Claudia’s last months were spent in grave pain as her condition deteriorated rapidly. She had swallowing problems, a rapidly deteriorating appetite which made supplementation with a protein drink and nutridrink necessary, rapidly deteriorated vision, presumably due to medication. Bladder infections were also common. By August 2020, they had been told that Claudia was too weak for an experimental clinical trial, and standard treatment was not possible as it was unclear what to focus on as the primary tumor was still unknown. She passed away weeks later.
For CUP patients like Claudia, battling to receive a diagnosis wastes precious time. The advent of whole genome sequencing (WGS) of tumors is promising and could help transform their care, as instead of treating cancer based on where it originated, doctors would instead devise a treatment regime based on the genetic characteristics of the tumor. This personalized approach is being rolled out for many cancer types, but access is patchy – or even non-existent. It is also critical that it is carried out early in the diagnostic process so as to improve outcomes.
Peter admits that while this may not have made a difference in his wife’s case, the answers it would have provided would have been invaluable.
“It takes six weeks until the results are available, so we probably would have had a diagnosis only after death. This could have eased the frustration of not knowing what it is, even though there was probably no treatment for Claudia as she was already too weak.”
Since then, the Dutch Parliament unanimously added extensive DNA-testing to the basic package of care that must be covered by health insurers and WGS has been reimbursed for CUP patients from April 2021. Yet it is not always a given that patients will receive prompt access to this testing, and in many countries around the world it is not offered at all.
SJK Foundation (Ireland) and Missie Tumor Onbekend (the Netherlands), are two national patient organizations dedicated to improving quality of care & life and providing information and support for patients. World CUP Awareness Week runs from 19-23 September 2022. Peter is a volunteer at Missie Tumor Onbekend.
This story is also part of the From testing to Targeted Treatments Precision Medicine Patient Stories Library, a repository of stories that aim to visualize each patient’s pathway according to a common framework, and highlight learnings and best practices. Discover the visual version of this story here.
Patient story: A cutting-edge DNA test put Inke Logtenberg on the right treatment path. Now she hopes others with Cancer of Unknown Primary (CUP) will have swift access to personalized care
Inke knew something wasn’t right. She had some swelling in a lymph node in her groin, prompting a trip to the doctor. After a physical examination, the doctor was not very concerned and recommended a ‘wait and soon’ approach.
‘One month later, it hadn’t gone away, so I went back to the doctor because I was worried that it might be more serious,’ Inke recalls. ‘I was referred to the regional hospital where I had blood tests and was given another appointment.’
In the meantime, while waiting for her next hospital visit, things went downhill. Swelling spread to Inke’s neck and she began to feel quite ill. ‘I was really unwell. At one point, I thought that I might collapse if I didn’t sit down immediately. Inside, I knew this was serious.’
That was mid-January 2021. The next time she saw a doctor, they could see that Inke’s condition had deteriorated. A series of blood tests and biopsies revealed metastatic cancer in the lymph nodes, but the original source was unclear.
‘After a while, the doctors said the cancer did not originate in the lymph. It was a mystery,’ she says. ‘I learned a new term: I had Cancer of Unknown Primary.’
Diagnosis guides treatment
For patients and doctors alike, this is often a diagnostic cul de sac. Without knowing where the cancer began, there is no off-the-shelf guideline to tell clinicians how to proceed. This can be dispiriting for doctors and deeply distressing for the person with CUP.
But Inke was in luck. She was referred to a specialist CUP clinic in Amsterdam where the latest advances in cancer testing are changing the prognosis for patients.
‘I went from the GP to the regional hospital and then to a specialist centre and it was frustrating to find that my personal health information sometimes took a week to follow me to a new doctor,’ she says. ‘It was ridiculous in the age of the internet.’
When she was eventually connected with the right specialists and offered access to appropriate testing, everything began to move more quickly. ‘The most important aspect of my story is a DNA test they did in Amsterdam. This led them to conclude that I most likely had cancer of the cervix.’
Without the DNA test, there would have been no such diagnosis. Inke showed no sign of cervical cancer, but by sequencing the genome of cancer cells found in her lymphatic system, doctors could proceed with a specific course of chemotherapy.
‘I feel lucky’
For six weeks, she had treatment three times a week as part of a clinical trial for CUP patients. Having finished this line of therapy in July, Inke is now feeling better and is in good spirits. Her cancer is stable and doctors are working to ensure it remains that way.
While the two-month wait for a diagnosis felt like an eternity at the time, Inke says she feels lucky to have had access to testing and treatment. ‘When you’re waiting from January to March for something to happen, it’s really difficult. There’s so much uncertainty,’ she says.
One month after Inke’s diagnosis, a new policy passed by Dutch lawmakers ensured that the whole genome sequencing (WGS) testing that put her on the path to treatment would be more widely available. The first centres are now offering this technique, and a growing number of other centres across the country are preparing to offer this test to people with CUP. This can help to end the uncertainty patients have faced in the past and give unprecedented hope.
‘I know not everyone has been lucky enough to have the tests and treatment that I had,’ Inke says. ‘By speaking about this, I hope it will help more people to access the right care for CUP.’
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.
Patients with rare disease often do not have a voice and rely on strong support from family, carers and trusted advocates. On Rare Disease Day 2021, FT3 speaks to advocates for those with a rare disease, who outline the barriers and roadblocks to obtaining a prompt diagnosis and the best possible personalized treatment.
Warnyta Minnaard is the co-founder of Missie Tumor Onbekend, the patient support and advocacy organization for patients with cancer of unknown primary (CUP) in the Netherlands.
Cancer of unknown primary is the fourth most common metastatic cancer in the Netherlands, with about 1,400 Dutch people each year diagnosed with CUP. Missie Tumor Onbekend advocates for a specialized diagnostic and care pathway for CUP patients, better access to innovative diagnostics and (curative/palliative) care. Furthermore, we provide support to patients, share information about CUP, raise awareness and support clinical research to try to find a solution for CUP. About 2.5 years ago my partner Hederik (age 32) suddenly became ill. It all started with a hanging eyelid and we started with a journey in the hospital to try to find out what was wrong. Unfortunately, he passed away in early January 2019 and I became a widow at age 29. 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. This is more often the case with a CUP diagnosis; you don’t understand that it is a diagnosis to have cancer without knowing the origins.
Patients with CUP are an outlier in the oncology community, as they are metastatic cancer patients but the origin of their disease is unknown and therefore unfortunately their chances towards accessing treatments is still rather limited. You would expect an outlier to be uncommon, but CUP is the eighth most common cancer in the world; because this is such a diverse group of patients, it is challenging to provide a single solution. But it is clear, these patients deserve solutions; it is unbearable to be part of a patient group without evening knowing you are part of the group as your diagnosis is cancer of unknown primary and if nothing is done you will not survive. Furthermore, most cancer therapies are based on the origin of the disease, which is exactly unknown for CUP patients. More than half of CUP patients in the Netherlands pass away in less than two months, so urgency is needed.
I believe the focus should be on improving or changing diagnostics so that there is no longer a strict need to know the localization of the tumor, rather the DNA defects of the tumor cells of the metastases found in the body should become clear. So that treatment can be provided on the basis of molecular patterns and patients get an outlook and a chance towards care instead of staying in a diagnostic trajectory with no end. The developments of personalized diagnostics and treatments are exactly what CUP patients are in dire need of.
Spinal Muscular Atrophy (SMA) is a motor neuron disease. The motor neurons affect the voluntary muscles that are used for activities such as crawling, walking, head and neck control, and swallowing. It is a relatively common “rare disorder”; approximately one in 6,000 babies born are affected, and about 1 in 40 people are genetic carriers.
SMA affects muscles throughout the body, although the proximal muscles (those closest to the trunk of one’s body – i.e. shoulders, hips, and back) are often most severely affected. Weakness in the legs is generally greater than in the arms. Sometimes feeding and swallowing can be affected. Involvement of respiratory muscles (muscles involved in breathing and coughing) can lead to an increased tendency for pneumonia and other lung problems.
Until very recently, there have been no treatments available for SMA patients. At diagnoses, they were simply told to take their children home and love them for as long as they had them. We at Cure SMA Canada offered support for newly diagnosed families, through life and in the event of end of life, we are there as well. We advocated for access to the first treatment that came available for SMA patients and were successful to receive approval in Canada. Unfortunately it wasn’t approved for all patients.
Every stepping stone along the path in the Canadian approval process was faced with barriers and the need for strong advocacy to justify patient access to the only treatment for SMA. The unfortunate loss of life and function during this process was devastating. With a progressive disease such as SMA, every day matters, every day is a loss of function and fear of what the future holds without treatment. We are now in the process of advocating for two new treatments here in Canada, we still have patients not accessing treatment because they fall outside the criteria for these treatments and we are advocating from square one again, justifying and waiting for approval while our patients continue to experience loss of function and experience high anxiety waiting to hear if the federal and provincial governments makes their life and death decisions. When you have a progressive disease, and are experiencing loss of physical abilities, it is even more devastating to know that other jurisdictions are approving treatment. In the meantime, we continue our work, to fight for our patient’s right to live their best life, to justify a life with treatment and hope that we are heard and considered partners in the decisions that will impact quality and quantity of life. Until we have a cure for SMA, the need for new and improved treatments will continue. Clearly involvement in clinical trials is essential for this information to be developed and available for Canadians. We must be participants and not bystanders.
February 28 2021 marks the fourteenth international Rare Disease Day coordinated by EURORDIS. This global event offers patients, families and caregivers the opportunity to raise awareness and share their experiences of living with a rare disease and the arduous journey they often face as they seek diagnosis and treatment for their condition.
It is thought that there are around 7,000 rare or “orphan” diseases, some of which can affect as little as a handful of people worldwide. Advocacy with these small numbers can be difficult, hence Rare Disease Day is a chance to shine a spotlight on all rare diseases as the rare disease community joins together.
The relationship between personalized medicine and rare diseases is a close one – in many circumstances, personalized medicine offered the first opportunity that these patients had of effective treatment for their condition. FT3 has chosen Rare Disease Day 2021 to highlight the struggles that these patients can often face in accessing timely diagnosis and appropriate treatment, and the daily battles that their advocates engage in on their behalf. Here we present some of their stories:
“It is grossly under and mis-diagnosed”
Blaine Penny is the director and co-founder of MitoCanada, a charitable organization formed in 2010 by a group of passionate Canadian parents whose previously healthy children were given a diagnosis of mitochondrial disease. Blaine’s son Evan was one of these.
“There are minimal treatments and no cure for mitochondrial disease. Very few front line clinicians are knowledgeable about mitochondrial disease and there are only a handful of specialists in Canada. It is grossly under and mis-diagnosed, which means people do not know the root cause of the problem, and hence are not getting the best available treatment. MitoCanada estimates that only 20-30% of people with Mito get a diagnosis.
“Current treatments consist of the Mito cocktail, which is a combination of vitamin supplements to help stabilize the mitochondrial function. The Mito Cocktail is the no. 1 prescribed treatment for mito patients but one of the big challenges with this is affordability as only one province in Canada, Ontario, has a provincial Inherited Metabolic Disease Program that covers the cost. Most patients/family are burdened with these costs. Exercise is considered one of the best therapies, but unfortunately many patients (like my son Evan who is a spastic quadriplegic) cannot exercise. Evan is in 11 different clinics, takes 14 different medications and supplements, and requires around the clock nursing care. This is pretty typical of the complex mito patient and puts tremendous pressure on families to coordinate and balance care.
There is some light at the end of the tunnel; NextGen DNA sequencing is proving to be increasingly effective in diagnosing patients. But access to specialists and testing is critical. Earlier diagnosis results in earlier interventions which improves health and quality of life outcomes.”
“Patients are challenged by finding health care providers that have a deep understanding of their rare disease”
Dr Leanne M Ward is Professor of Pediatrics, University of Ottawa and Medical Director, The CHEO Genetic and Metabolic Bone Disease Clinic
I am a pediatric endocrinologist specializing in pediatric bone diseases, of which most are rare diseases. My goal in caring for such patients is to relieve pain and restore mobility. Both surgical and medical management are needed to restore physical functioning in these disorders. But patients are challenged by finding health care providers that have a deep understanding of their rare condition, and gaining access to multidisciplinary care. They are also challenged because the existing treatments for their disease are often symptom-targeted, and do not address the pathobiology of the condition. By getting closer to the actual cause of the disorder and targeting that, we are better able to improve clinical outcomes in a meaningful way.
We need more education of health care professionals, with teams all working together to care for the patient, we need scientists working on the biology of the disease so that therapeutic targets can be identified, and we need clinical trials to be as streamlined and efficient as possible. As it is now, clinical trials are extremely difficult due to the multiple administrative and organizational layers that complicate the already-challenging medical care issues for those patients undergoing trials. I like the idea of “rare disease centers of excellence” that could be beacons of light for patients with rare disorders.
“There are hurdles to overcome at every stage of the BRCA journey”
“Breast, bowel and ovarian are some cancers that can run in families, and occur when faulty genes pass down through generations. The lifetime risk for a woman with a BRCA1 mutation is 60-90%. These women additionally have a 40–60% lifetime risk of developing ovarian cancer. Men are often forgotten in discussions about BRCA, but they can carry cancer-causing faulty genes. A man with a BRCA1 mutation may be 3 or 4 times more likely to develop prostate cancer by age 65.
In recent years, largely thanks to the availability of genetic testing and awareness, a growing number of men and women have discovered they have the faulty BRCA gene as a result of pre-symptomatic screening. In my case, screening was offered to me and my siblings when my older sister, then 37 years, was diagnosed with breast cancer. Sadly, this was not the first or last woman in our wider family to receive this diagnosis. Having the knowledge that you are at high risk for breast and ovarian cancer is both a blessing and a burden. Like me, many opt to reduce the risk of developing cancer through surveillance and surgical procedures such as bilateral mastectomy and removal of the ovaries and fallopian tubes. Yet taking this route to protect your health is fraught with challenges at every step of the way.
There are hurdles to overcome at every stage of the BRCA journey. The first is navigating a health service that is not fit for purpose for genetic cancer patients. Getting a referral is not straightforward and often comes about by indirect channels. If you meet the eligibility criteria for genetic screening, you can choose to join a public or private waiting list for genetic counselling. As the clinical genetics service is so poorly resourced in Ireland, this can take many years. If you opt for private genetic counseling, the cost is high. With few exceptions, your care and treatment ends up occurring in silos; breast care clinic, gynaecology clinic, plastic surgery clinic, and psychology services. It is both an art and a science navigating multi-disciplinary care for a person with a faulty BRCA gene.