Scientists have unveiled clues into why some cancer patients develop a serious heart condition after chemotherapy

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The new research, from a team of international scientists led by Imperial College London, Royal Brompton Hospital and the MRC London Institute of Medical Sciences, shows the heart condition may be linked to a faulty gene called titin.

In the study, published in the journal Circulation, the scientists analysed the genes of more than 200 cancer patients – most of who had breast cancer – who had been diagnosed with a type of heart condition called cancer-therapy induced cardiomyopathy, or CCM.

The research team found patients who developed the heart condition were more likely to carry genetic faults linked to cardiomyopathy.

In particular, patients were more likely to carry a faulty version of a gene called titin. The faulty titin gene was found in 7.5 percent of CCM patients, compared to 0.7 percent of healthy individuals.

A faulty titin gene is carried by more than half a million people in the UK. The gene is crucial for maintaining the elasticity of heart muscle, and faulty versions are linked to a type of heart failure called dilated cardiomyopathy.

The scientists behind the study say the new insights may help understand why some patients develop CCM, and even identify patients at risk of the condition.

More women affected

Dr. James Ware, senior author of the research from Imperial’s National Heart and Lung Institute explains:

More patients than ever are surviving cancer, thanks to advances in treatment over the past decade or so.

However we now have a key problem where some patients who have survived cancer are developing serious heart conditions, sometimes within the first year after finishing treatment.”

He continues:

“Until now, scientists didn’t know why some patients developed heart damage, while others didn’t.

This new study suggests faulty genes may play a role – and means we could potentially test patients for faulty genes before starting cancer treatment, so that we know which patients are at risk.”

CCM affects up to one in ten cancer patients—with more women affected then men, and often strikes between six months and nine years after cancer treatment.

The condition is caused by the chemotherapy drugs damaging heart muscle, leaving it unable to pump properly.

Although many patients recover, it can lead to heart failure in around ten percent of patients.

Genetic clues

In the new study, funded by the Wellcome Trust, Medical Research Council, National Institute for Health Research and British Heart Foundation, the researchers tested 213 cancer patients with CCM for nine different types of faulty genes linked to the condition. Out of these patients, who were from Spain, the US, and the UK, 124 had breast cancer, 48 had other types of cancer, while 41 were children with acute myeloid leukaemia.

The vast majority of cases of CCM (90 percent) were linked with a type of drug treatment called anthracycline, and more than one in 20 patients (7.5%) were found to carry the faulty titin gene.

In further mouse studies, the team found that anthracyclines increased the risk of heart damage in mice with a faulty version of the titin gene.

Dr. Paul Barton, co-senior author from the Cardiovascular Research Centre at the Royal Brompton Hospital, said:

“Although scientists know that anthracyclines are associated with CCM, this is the first time we’ve also seen a link with faulty genes directly involved in cardiomyopathy. and could enable doctors to potentially prevent the condition from occurring.”

Protecting the heart

Dr. Alexander Lyon, Senior Lecturer in Cardiology at Imperial and Consultant Cardiologist at the Royal Brompton Hospital and co-author of the new study added: “The new field of cardio-oncology is dedicated to helping treat, and ultimately prevent, cancer therapy-induced cardiovascular disease.

This research provides a new opportunity to identify individuals at higher risk of developing CCM, and we believe this can lead to doctors being able to assess the individual risk of heart damage for each patient scheduled to receive potentially cardiotoxic chemotherapy.

By analysing their genetic risk we could ensure that a patient’s heart health is monitored by doctors during and after chemotherapy.”

The research team would now like to perform further studies investigating genetic links to CCM in different types of cancer, as most of the patients in the current study had breast cancer. They will also look at patients with different ethnic backgrounds, as most patients in this study were white European.

“You can climb a mountain with a broken heart”

Kreena Dhiman, 39, from Crawley had chemotherapy for breast cancer in 2013, after she was diagnosed age 33.

Three years after starting cancer therapy, she was diagnosed with heart failure. She explains:

“The first signs of heart failure were on a holiday to France in 2016, six months after I’d undergone reconstructive surgery following my cancer treatment.

I had been pretty fit before my diagnosis, but on this holiday I was finding stairs increasingly tiring, and struggled to ride a bike. At first, I blamed my breathlessness on the fact I was recovering from surgery.

A few months later I went to see friends in Vancouver, in what I hoped would be a trip of a lifetime, and a chance for my husband and I to celebrate my recovery.

But shortly after arriving, I found myself coughing constantly, and struggling to catch my breath.

By the third day we decided to go the walk in center, they referred me to a University hospital, where despite scores of tests they were unable to work out why I was so breathless, as my lungs were perfectly healthy.

Eventually I was transferred to Vancouver General hospital, after further tests, they called in a heart specialist, who took a scan of my heart. I’ll never forget the specialist asking me if I was given a red drug during my chemotherapy. I nodded yes—at this point I was too breathless to speak. I remembered the drug vividly, we used to jest at its toxicity warning on the chemo ward!

He turned to his colleagues and said ‘she has heart failure’ and I was transferred to an intensive care ward.

I was told the drug I was given to treat my breast cancer—called epirubicin (a type of anthracyclin), can cause heart damage, and this damage may have been slowly getting worse since my cancer treatment.

I was distraught—and immediately assumed heart failure meant I was going to die. I didn’t think I was going to make it home alive, and recorded voice notes to my family and friends telling them I loved them, and this was my final goodbye.

The days that followed were difficult, both physically and emotionally. My sister flew out to Vancouver to be with my husband and I and slowly but surely I responded to treatment.

At the time, I was advised that 50% of heart failure patients don’t make it beyond 2 years. That statistic scared me more than anything I’ve heard before. If I’m honest, it still scares me today.

I was also put on a strict zero-salt diet while in hospital, as salt works to retain fluid in the body, not good news for a heart failure patient as it places extra strain on the heart.

After two months in in Canada, I was allowed to fly home with medical assistance.

I referred to Dr. Lyon in his London clinic, who confirmed the chemotherapy drug was the most likely culprit of my heart failure, however there was likely a genetic predisposition that triggered the reaction

My total recovery took around a year, but my heart function is now within a normal range with medication supporting it.

Around a year after my own diagnosis my mother was also diagnosed with heart failure. Genetic tests revealed both of us were found to have mutation in a specific gene which may have triggered the condition, though neither of us carried the faulty Titin gene.

Despite the roller coaster of the last six years, my life is better than ever. My husband and I just celebrated the first birthday of our beautiful daughter Amaala, who was born via a surrogate after we decided to freeze embryos prior to cancer treatment.

And I’m soon to climb the Himalayas to raise money for a charity who raises awareness of breast cancer in younger women, because that is where my journey began, with a breast cancer diagnosis.

I also want show others that heart failure is certainly not a death sentence, and with support and expert care, you can climb a mountain with a broken heart!”


Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic stroke. In this review, the epidemiology and pathophysiology of stroke in cancer patients is discussed, while providing vital information on the diagnosis and management of patients with cancer and stroke.

Cancer may mediate stroke pathophysiology either directly or via coagulation disorders that establish a state of hypercoagulation, as well as via infections.

Cancer treatment options, such as chemotherapy, radiotherapy and surgery have all been shown to aggravate the risk of stroke as well. The clinical manifestation varies greatly depending upon the underlying cause; however, in general, cancer-associated strokes tend to appear as multifocal in neuroimaging.

Furthermore, several serum markers have been identified, such as high D-Dimer levels and fibrin degradation products. Managing cancer patients with stroke is a delicate matter. The cancer should not be considered a contraindication in applying thrombolysis and recombinant tissue plasminogen activator (rTPA) administration, since the risk of hemorrhage in cancer patients has not been reported to be higher than that in the general population. Anticoagulation, on the contrary, should be carefully examined.

Clinicians should weigh the benefits and risks of anticoagulation treatment for each patient individually; the new oral anticoagulants appear promising; however, low-molecular-weight heparin remains the first choice. On the whole, stroke is a serious and not a rare complication of malignancy. Clinicians should be adequately trained to handle these patients efficiently.

Introduction

Cerebrovascular diseases (CVDs) are common in cancer patients, significantly aggravating their condition and prognosis (1).

Approximately 15% of cancer patients have a concomitant CVD (2,3), and the frequency of cerebral infarcts is similar to that of cerebral hemorrhage (3). Stroke may either follow the initial cancer diagnosis (4) or may precede the diagnosis of cancerous disease (5).

The prevalence of an underlying cancerous disorder is higher in patients with ischemic stroke than in the general population (6,7) and cancer as a comorbidity is found in 1 out of 10 hospitalized patients with ischemic stroke in the United States (8).

Patients with cancer have been shown to have higher in-hospital post-stroke mortality rate (1,9,10) and patients with ischemic stroke with an active cancer have also been found to be of younger age, with more severe and more frequent cryptogenic strokes (1).

The connection between stroke and cancer has for long captivated the interest of the medical community.

The first large autopsy study was conducted in 1985 by Graus et al, showing that the most frequent complication of the central nervous system (CNS) in cancer patients, following metastasis, was cerebral infarction and hemorrhage.

In the same study, 14.6% of cancer patients had pathological evidence of CVD and approximately half of them were symptomatic (11). More recent studies, such as that among Hodgkin lymphoma 5-year survivors, demonstrated that 7% of patients developed an ischemic stroke in the 17.5-year follow-up period (12).

The underlying causes for the development of a stroke in cancer patients differ from those of non-cancer patients, and are associated with the cancer itself, as well as with the type of treatment (1,9,1319).

In general, hypercoagulopathy or other coagulation disorders are most often related to the development of ischemic/embolic stroke (9,15,19).

Cardio-embolism, large-vessel atherosclerosis and small-vessel occlusion have been reported as the major causes of ischemic stroke, while non-bacterial thrombotic endocarditis (NBTE) is rarely noted (9,17).

In the pathogenesis and prognosis of acute ischemic stroke, active cancer (recurrent malignant tumor, metastases, or ongoing chemo-/radiotherapy) plays an active role (1).

In survivors of childhood Hodgkin’s disease, who are at an increased risk for stroke, mantle radiation exposure is strongly associated with subsequent stroke and the potential mechanisms may include carotid artery disease or cardiac valvular disease (14).

Nevertheless, brain tumors always remain the main etiology for stroke or other neurological pathologies, while cases where the diagnostic misinterpretation of a brain tumor as a stroke or the diagnostic misinterpretation of an underlying malignancy as an incident of CVD, are not rare (13).

Stroke in cancer patients may be hemorrhagic or ischemic (16,20), while embolisms have been reported to be the most common cause of stroke (9).

In a wide, population-based Swedish study, the risk [expressed as standardized incidence ratio (SIR)] of hemorrhagic and ischemic stroke in the first 6 months following cancer diagnosis was 2.2 and 1.6, respectively. While the overall stroke risk decreased rapidly with time, it remained elevated even after a decade following the cancer diagnosis (16).

In that same study, metastasis was also associated with a greater risk of hemorrhagic and ischemic stroke (SIR=2.2 and SIR=1.5, respectively) (16).

In a similar vein, intracranial hemorrhages (ICHs) have been reported in 20 to 50% of patients with metastatic brain tumors (21).

In cancer patients, cerebral infarctions have been found to be more frequent than hemorrhage (11,22), whereas in patients with leukemia, hemorrhages have been found to be much more common than infarcts caused by coagulopathy or CNS infiltration (11,16,23).

The present review focuses on the possible pathophysiological mechanisms and causes of stroke in cancer patients, and aims to identify the most common and specific types of stroke. Moreover, clinical manifestations are discussed, and useful modalities to diagnose the cause of stroke in cancer patients are presented, while providing valuable information on treatment and prevention measures.

Cancer types associated with stroke

To date, several studies have attempted to elucidate which cancer types present a stronger association with the occurrence of stroke. A concise presentation is presented in Table I.

In a previous study, among 1,274 patients with stroke admitted to a stroke unit, 12% had an additional diagnosis of cancer, with urogenital, breast and gastrointestinal being the most frequent cancer types (15).

In addition, in patients diagnosed with lung, pancreatic, colorectal, breast and prostate cancers, a higher stroke incidence was reported (24). The stroke risk also seemed to be associated with the aggressiveness of the cancer; lung, pancreatic and colorectal cancers, which presented the highest stroke risks, are usually diagnosed at a later stage than breast and prostate cancer (24).

The aforementioned cancer types were also identified as the most common among patients diagnosed with cancer post-stroke (7). Lung/respiratory tract cancer had one of the strongest independent associations with death during a follow-up of patients under 49 years of age with ischemic stroke (25).

Among 820,491 Swedish patients with cancer, cancers of the small intestine, pancreas, lung, nervous system and endocrine glands, and leukemia, presented a >2-fold higher risk of ischemic stroke in the first 6 months post-diagnosis, and this risk remained increased even after a decade after hospitalization in cancer types, such as upper respiratory/digestive tract cancer, salivary gland, colon, rectum, nose, breast, prostate, urinary bladder, skin (squamous cell), nervous system cancers and non-Hodgkin lymphoma.

For hemorrhagic stroke, the cancer type pattern changed and a highly elevated risk was reported for cancers of the small intestine, liver, kidneys, nervous system, thyroid gland, endocrine glands, connective tissue, non-Hodgkin lymphoma, myeloma and leukemia (16). Similarly, patients with melanoma or renal cell carcinoma and brain metastasis were characterized by a 4-fold higher risk of ICH compared to patients with lung cancer with brain metastasis (21,25).

In general, melanoma, renal cell carcinoma, and choriocarcinoma are the cancer types considered to have a higher tendency for hemorrhaging (26).


More information: Pablo Garcia-Pavia et al. Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy, Circulation (2019). DOI: 10.1161/CIRCULATIONAHA.118.037934

Journal information: Circulation
Provided by Imperial College London

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