Study links cancer in scleroderma to timing and autoantibodies
Findings support targeted cancer screening for SSc patients
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Different types of cancer that affect people with scleroderma occur at different times during the disease course and are associated with distinct self-reactive antibodies and complications, according to a large international study.
Breast cancer, for example, tends to occur closer to scleroderma onset and is linked to anti-POLR3 antibodies, while lung cancer more often develops later and is associated with interstitial lung disease, smoking, and anti-topoisomerase 1 antibodies. Gastrointestinal cancers also tend to occur later in the disease course and are linked to older age, being male, and intestinal (gut) symptoms.
Overall, cancer was associated with poorer survival, particularly when diagnosed at least three years after scleroderma onset.
“As cancers diagnosed during follow-up are major determinants of death, our findings inform the implementation of stratified cancer surveillance in [scleroderma],” researchers wrote.
The study, “Cancer in systemic sclerosis: clinical associations and prognostic impact from the EUSTAR registry,” was published in the journal Arthritis & Rheumatology.
Cancer a major cause of death in scleroderma
Scleroderma, or systemic sclerosis (SSc), is an autoimmune disease characterized by inflammation, blood vessel abnormalities, and excessive scar tissue (fibrosis) that can affect the skin and internal organs. In the lungs, this can lead to interstitial lung disease (ILD), which involves inflammation and scarring.
Cancer occurs more often in people with SSc than in the general population and is a leading cause of death.
In people with SSc, self-reactive antibodies, or autoantibodies — which mistakenly target the body’s own tissues — are linked to particular disease features. Some may also help identify people with different risks of cancer. The strongest established link is between anti-POLR3 antibodies and cancer diagnosed around SSc onset, particularly in people with early diffuse SSc, a form marked by more widespread skin involvement.
Aiming to know more, an international team studied clinical features and their association with autoantibodies and cancer in SSc.
Cancers classified based on their timing relative to SSc onset
The researchers analyzed data from the European Scleroderma Trials and Research (EUSTAR) registry. The study included 908 adults from 32 centers, comprising an equal number of SSc patients with or without a history of cancer, matched for age and disease duration.
Breast cancer was the most common cancer type, affecting 32% of cancer patients, followed by lung (16%) and gastrointestinal cancers (13%). Lung and gastrointestinal cancers more often occurred later in the scleroderma disease course.
Cancers were classified according to their timing relative to SSc onset. Those diagnosed within three years before or after scleroderma onset were called synchronous, while subsequent cancers developed more than three years after scleroderma onset and previous cancers occurred more than three years before scleroderma began.
Of all 454 patients with cancer, 51% were classified as subsequent, 29% synchronous, and 20% previous.
Anti-POLR3 antibodies were associated with about a twofold higher risk of synchronous cancer. That risk was even higher, at nearly 3.5 times, in patients with anti-U1RNP, also a type of scleroderma-associated autoantibodies. Smoking was also linked to synchronous cancer. In contrast, digital ulcers, open sores affecting the fingers or toes, were significantly less common in participants with synchronous cancer.
Breast cancer was associated with anti-POLR3 antibodies, particularly in people with diffuse SSc, and with being female. Lung cancer was associated with smoking, longer scleroderma duration, ILD, and anti-topoisomerase 1 autoantibodies. Gastrointestinal cancers were associated with being older, male sex, and SSc-related intestinal symptoms.
Overall death rate was higher among scleroderma patients with cancer
In an analysis focusing on cancer that developed after patients had joined the registry, results showed that older age at scleroderma onset, longer disease duration, smoking, and having ILD were all associated with increased cancer risk. ILD was associated with almost three times the risk of developing cancer overall during follow-up.
Regarding treatment, cancer was 2.6 times more common among patients who had received the immunosuppressant cyclophosphamide.
“Focused studies should investigate whether the association between cyclophosphamide and cancer reflects a cause-effect relationship or mirrors the higher malignancy [cancer] risk observed with severe SSc,” the scientists wrote.
Conversely, the use of methotrexate and mycophenolate mofetil, two other immunosuppressants, was less common in patients with cancer.
Cancer impacts patients’ survival, particularly when diagnosed years after SSc onset. These patients deserve special attention, and developing tailored algorithms for stratified cancer screening should be regarded as a priority.
Radiation therapy for cancer was not associated with a greater likelihood of developing ILD or with poorer survival.
The overall death rate was higher among scleroderma patients with cancer than among those who were cancer-free — 37 versus 20 deaths per 1,000 patient-years (a measurement that combines the number of people in a study with the time each person spends in that study). The difference was particularly evident among people whose cancer developed more than three years after SSc onset.
“Cancer impacts patients’ survival, particularly when diagnosed years after SSc onset. These patients deserve special attention, and developing tailored algorithms for stratified cancer screening should be regarded as a priority,” the investigators concluded.
Amy Hall
I was diagnosed with breast cancer , anti- Pol3 the same time I developed diffuse SSC- I went to Johns Hopkins and Dr Wigley literally saved my life. So grateful for the research!