Increased breast cancer risk for patients with multiple sclerosis: a nationwide population-based cohort study.

Increased breast cancer risk for patients with

multiple sclerosis:

a nationwide population-based cohort study

L.-M. Sun

*, C.-L. Lin

, C.-J. Chung

*, J.-A. Liang

, F.-C. Sung

and C.-H.

Kao

aDepartment of Radiation Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung; bManagement Office for

Health Data, China Medical University Hospital, Taichung; cInstitute of Public Health, College of Public Health, China Medical University,

Taichung; dDepartment of Health Risk Management, China Medical University, Taichung; eDepartment of Medical Research, China

Medical University Hospital, Taichung; fDepartment of Radiation Oncology, China Medical University Hospital, Taichung; gGraduate

Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung; and hDepartment

of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan

Introduction

Multiple sclerosis (MS) is a demyelinating disease involving the central nervous system [1]. Its etiology is still not well known but it is believed to be an

immune-mediated disorder mediated by a complex interaction between a person’s genetics and as yet unidentified environmental insults [2]. It affects women more than it does men and is most commonly diagnosed amongst people aged between 20 and 50 years. The distribution of MS worldwide varies considerably with a wide prevalence ranging between 2 and 150 per 100 000 people [3]. MS is known to be more common amongst Caucasian populations, particularly those of Northern European ancestry,

whereas Asians are at low risk of developing it [4]. The prevalence of MS in Taiwan reaches the lower limit: 1.9 per 100 000 people [5].

Autoimmune disease comprises many different diseases, which may have local or systemic manifestations.

The association of autoimmune disease with

cancer has been explored for several years, and reports have appeared suggesting an increased cancer risk in some autoimmune diseases [6,7]. The role of chronic inflammation in the development of cancer has also been a topic of intense debate in both epidemiological and experimental studies [7,8], which suggests that the positive association between autoimmune disease and cancer might also be observed in patients with MS. However, earlier research found that MS patients were not at a higher risk of developing cancer overall [9,10] or were even at a lower risk than the general population [11,12]. A literature search found only one study

that documented a higher overall cancer rate amongst MS patients [13]. Concerning cancer cases, a possible association between MS and nasopharyngeal carcinoma, lymphoma, brain tumor and breast cancer has

been suggested [10,14,15]. Because MS is relatively uncommon in Asia, studies seldom focus on Asian patients with MS. Therefore,

this study focuses on exploring the relationship between MS and subsequent cancer risk in Taiwan, and on conducting a population-based retrospective cohort study to investigate this issue. The original database was generated from the National Health Insurance (NHI) System in Taiwan.

Methods

Data sources

Taiwan began its single-payer NHI program in March 1995 and consolidated 13 insurance programs into a universal healthcare system for all of its residents. This insurance program covers 99% of more than 23 million people in Taiwan. It entered into contracts with 97% of the hospitals and clinics in Taiwan [16]. The insurance programs were connected by scrambling the identification details of residents to find data suitable for public use. The residents’ identification

was used to link three data files, including the registry of beneficiaries, the catastrophic illness program (abbreviated as HV) and inpatients’ claims. Previous studies have shown that the diagnoses in the NHI research database (NHIRD) are highly valid [17,18]. The International Classification of Disease, Ninth

Revision (ICD-9) was used to define the diagnosis disease codes. With the NHI’s and China Medical University’s approval, this study was exempted by the

Institutional Review Board (CMU-REC-101-012).

Study participants

For both inpatients and outpatients to be registered in the HV, they required the approval of the insurance authority. In all, 1292 patients with newly diagnosed MS (ICD-9 code 340) from the HV for 1997–2010 were identified as the MS cohort. The date of MS diagnosis was used as the index date to estimate the follow-up time. The MS patients who were diagnosed with cancer (ICD-9 codes 140–208) before the index date, or who lacked information about their age or sex, were

excluded. For each identified MS case, four comparison controls were randomly selected from the whole

insured population. The selection was frequencymatched with age (within 5 years), sex and index year,

excluding those with a history of MS and cancer.

Outcome definition

Any participant with a cancer diagnosis (ICD-9 codes 140–194 and 200–208) was identified from the HV. The person-years of the follow-up were estimated for this study’s participants beginning from the index date until the cancer diagnosis or censored because of

death, failure to follow-up, withdrawal from the insurance system, or 31 December 2010. After considering

the sample size of cases, the cancer was divided into five groups: lung cancer (ICD-9-CM code 162), breast cancer CM code 174), uterus cancer (ICD-9-CM codes 179–184), thyroid cancer (ICD-9-(ICD-9-CM code 193) and others. The baseline comorbidities including

diabetes mellitus (ICD-9 code 250), hypertension (ICD-9 codes 401–405) and hyperlipidemia (ICD-9 code 272) were identified from the inpatient claims data.

Statistical analysis

The demographic data and comorbidities between cohorts with and without MS were compared and the data were tested using a chi-squared test. The mean age was also measured and tested using a t test. The sex-, age- and comorbidity-specific incidence rates of cancer per 1000 person-years of follow-up for each cohort were calculated. The MS to non-MS incidence rate ratio (IRR) and a 95% confidence interval (CI) were estimated by sex, age and comorbidity by using the Poisson regression model. Cox proportional hazards regression was used to assess the cancer risk associated with MS, adjusting for cofactors significantly related to MS. To assess the difference in the breast-cancer-free rates between the two cohorts, Kaplan–Meier analysis and the log-rank test were applied. The Kaplan–Meier survival curve was plotted using R software (version 2.14.1; R Development Core Team, Vienna, Austria). All analyses were performed using the SAS statistical package (version 9.1 for Windows; SAS Institute Inc., Cary, NC, USA). A two-tailed P value of <0.05 was considered statistically significant.

Results

Demographic characteristic data are shown in Table 1. The MS cohort included more women than men (76.3%) and, because the cohorts were matched on sex, so too did the control cohort. Approximately 46% of participants were ≤34 years of age. Patients

with MS had a higher prevalence of all baseline comorbidities (P < 0.0001). Table 2 shows the incidence

rate of cancer and adjusted hazard ratio (HR) amongst the MS cohort and the comparison cohort. The overall incidence rate of all cancer types was

cohort (5.29 vs. 3.09 per 1000 person-years) with

an adjusted HR of 1.85 (95% CI 1.26–2.74). The incidence rate was higher in men than in women in

both cohorts. It showed a significantly higher risk (2.07-fold) of developing overall cancer compared with the comparison cohort in women (95% CI 1.30– 3.27). The age-specific relative risk was higher for the older sub-cohort with an IRR of 1.82 (95% CI 1.30– 2.55). However, younger patients (≤50 years of age; adjusted HR 1.81, 95% CI 1.08–3.04) showed a significantly higher risk of developing overall cancer. The

incidence rate of overall cancer increased when patients had no comorbidity. However, there was no significant association between MS and overall cancer risk for those with any comorbidity. The site-specific analyses on the subdivision of cancer between the MS and the control cohorts are shown in Table 3. Compared with the control group, almost half (18 cases)

of all cancer cases in the MS group were lung cancer and breast cancer. The adjusted HR of the statistically significant development of breast cancer was 2.23-fold for patients with MS (95% CI 1.11–4.46). Kaplan– Meier survival analysis showed that patients with MS had significantly higher rates of breast cancer than their comparative cohorts (Fig. 1).

Discussion

The results from this population-based cohort study show that patients with MS were at significantly higher risk of developing overall cancer and breast cancer in particular. However, other individual cancer risks were non-significantly different between cohorts. Following cardiovascular disease, cancer is the second

leading cause of death in the USA. Data from the US National Cancer Institute’s Surveillance, Epidemiology

and End Results show that the overall cancer incidence rates in the past 5 years (2004–2008) decreased by 0.1% per year [19]. In Taiwan, however, cancer statistics show a reverse trend. The ageadjusted

incidence rate has increased steadily from

249 new cases per 100 000 in 2002 to 276 per 100 000 in 2008 in the island of Taiwan [20]. Cancer has been the leading cause of death in Taiwan for almost three decades. This issue remains a big challenge for public health in Taiwan; it has aroused the attention of the government, promoting substantial population-based research on cancer epidemiology and prevention. The Taiwan NHI program is a useful resource and provides valuable materials for specialists to approach

population-based studies. Earlier, it was used to

evaluate the risk of malignancy for patients with systemic lupus erythematosus, and it was found that residents in Taiwan with this condition have a marginally

significantly higher risk of developing cancer [21]. The results encourage us to explore the possible association between other autoimmune diseases and cancer.

To the best of our knowledge, this is the first population-based study in Taiwan that has used the NHIRD

and attempted to identify a relationship between MS and the risk of developing cancer.

The relationship between types of autoimmune disease and a higher risk of developing cancer has been

suggested [6,7]. Hemminki et al. [6] found that an increased risk of developing digestive tract cancer was observed in patients with several autoimmune diseases. Landgren et al. indicated that a history of autoimmune disease with localized alimentary tract effects

generally increased cancer risks in the organ(s)

affected by the autoimmune disease. Conversely, autoimmune diseases without localized alimentary tract

effects were generally not associated with alimentary tract cancer risk [7]. These differing impacts on cancer risk might be attributable to chronic inflammation, as well as the medications administered [6,7]. Documented cancer-related autoimmune diseases include

rheumatic arthritis, systemic lupus erythematosus, scleroderma/systemic sclerosis, Sjogren’s syndrome,

myasthenia gravis, ulcerative colitis and reactive arthritis [6–8].

In comparison with Caucasians, MS in the Southern Chinese (including Taiwanese) is characterized by a lower prevalence, more common optic and spinal involvement, relatively rapid progression, and a lower frequency of raised IgG index and oligoclonal bands in the cerebrospinal fluid [5,22–24]. Most researchers have found that patients with MS do not have an

altered risk of cancer overall [9,10] or even show a reverse direction (lower risk) [11,12]. Sumelahti et al.

[9] published a paper with a 35-year follow-up for MS patients and found no difference for the overall or individual cancer risk between MS patients and the general population. Fois et al. [10] also concluded that patients with MS do not have an altered risk of cancer overall. Kingwell et al. [11] used a large Canadian MS cohort to investigate a population-based study and found that the standardized incidence ratio (SIR) for overall cancer was 0.86 (95% CI 0.78–0.94.) A meta-analysis conducted by Handel and Ramagopalan [12] also found a significantly lower risk of developing all cancer types in the MS cohort relative to the control (P = 0.004). In contrast to these studies, our

investigation revealed a significantly higher overall cancer risk in MS patients. In addition, this is consistent with a study that reported significantly more cancer cases than expected based on the national rates of Denmark, with a relative risk of 1.29 [13].

Our study reveals that the most common cancer type amongst MS patients is breast cancer, followed by lung cancer. Breast cancer is one of the most common malignancies amongst women in Taiwan since

1996, and the age-adjusted incidence rate for breast cancer was 62.4 per 100 000 amongst females in 2008 [20] compared with 123.8 per 100 000 in the USA in 2006_2010 [25]. For lung cancer, it was 32.2 and 61.4 per 100 000 in Taiwan and the USA [26], respectively.

The reason our results show a different direction from most studies is unclear. The underlying genetic and environmental factors in Taiwan, which differ from those of western countries, might play an undetermined role. Another possible explanation is that the

number of breast cancer patients in our study is 29.8% of the total number of cancer patients. This is not the normal pattern of cancer distribution for the general population, and breast cancer might contribute more than expected to the overall cancer risk.

Because of the characteristics of MS patients (relatively young, affecting women more than men) and

because breast cancer in Taiwan is characterized by a striking recent increase in its incidence and a relatively young median age (45–49 years) at diagnosis [27], more breast cancer patients can be expected in our groups. To clarify this concern, the data were re-analyzed after excluding breast cancer patients. The IRR

of cancer in MS patients decreased from 1.71 to 1.63, but it is still statistically significant (95% CI 1.37– 1.94). Table 2 also shows a significantly higher overall cancer risk for female MS patients, as well as younger MS patients. Breast cancer might partially account for this phenomenon. In addition, the SIRs were calculated with the indirect methods of standardization of

Breslow and Day [28] and similar patterns were acquired compared with the IRRs in Table 3. However, there were positive associations between MS and overall cancer and between MS and breast cancer after adjusting for other potential confounders.

Our findings are compatible with those in the population-based registry studies from Norway and Denmark, which showed that female MS patients had an increased risk of breast cancer (SIR 1.70, 95% CI 1.05–2.60, and SIR 1.21, 95% CI 1.05–1.39, respectively). The possible contributing factors included reproductive factors, socioeconomic status and surveillance biases; however, in those studies none

of these could be shown to be contributing factors [14]. Our report cannot verify these possible factors either. Figure 1 further shows the consistently higher risk amongst the MS cohort over time. For other individual cancer types, the Epstein–Barr virus infection

has been implicated in MS, as well as nasopharyngeal carcinoma and lymphoma [29,30]. However, our observations, based on the limited numbers for both nasopharyngeal carcinoma (three cases) and lymphoma (one case), cannot confirm this. Several studies

have found more brain tumors amongst MS patients [9,10]; chronic neurological inflammation, surveillance bias and misclassification between MS and brain tumors might account for this. Again, a relatively low number of brain tumors (one case) in our study might have resulted in inadequate power to detect statistical differences between groups.

The main strength of this study is the populationbased design with its generalizability. However,

several limitations should be considered in the interpretation of our results. First, information regarding

the lifestyle or behavior of patients is lacking in the

NHIRD and thus it is impossible to adjust for healthbehavior-related factors such as smoking and alcohol

consumption, which are well-recognized risk factors for some cancer types. Hern_an et al. [31] found that smoking is associated with an increased risk of MS. It is also suggested to be an independent but modifiable risk factor for early conversion to clinically definite MS [32]. In addition, smoking is an important source of bias in MS patients [33]. Conversely, smoking has been suggested to aggravate MS symptoms [34]. Thus, a decreased risk of cancer types of the respiratory system could be associated with smoking abstinence

amongst MS patients. However, more sophisticated tests adjusting for variables that were not recorded could not be conducted. Secondly, the NHIRD did not provide cancer-screening information; therefore,

whether any difference in the percentage of cancerscreening tests exists between the MS and the non-MS

groups could not be evaluated. Studies indicate that

women with various types of chronic disabling conditions are less likely to participate in routine breast

cancer screening compared with those without disabling conditions [35,36]. Alternatively, MS patients

could be in closer and more regular clinical follow-up, raising the possibility of a surveillance bias [14]. Thirdly, treatment information is unavailable in the database and immunomodulatory therapy in MS patients might interfere with the possible relationship between MS and cancer [37,38]. Finally, interpretation of the risk estimates for individual cancer types should be approached cautiously because of the small number of cancer events in certain subgroups. Despite our

meticulous study design with adequate control of confounding factors, a key limitation was that biases

could still remain because of possible unmeasured or unknown confounders. Nevertheless, the data

obtained on MS and cancer diagnoses were highly reliable.

Overall, our study indicated that MS patients are at increased risk of overall cancer and breast cancer. However, many undetermined questions remain about the relationship between MS and cancer risk, and the number of cancer types observed in this study might be too sparse to draw firm conclusions. Furthermore, large-scale studies will help improve our understanding.