Association between chronic viral hepatitis infection and breast cancer risk: a nationwide population-based case-control study

Breast cancer is one of the most common cancers and the leading cause of death in women worldwide [1]. Over the past several decades, the incidence of breast cancer has increased globally [2, 3], with the greatest increase occurring in Asian countries [2, 4, 5]. Risk factors for breast cancer include benign breast disease, fertility, obesity, particularly after menopause, familial and genetic factors, and oral contraceptive use [6‐9]. The etiology and progression of breast cancer remain incompletely understood; therefore, novel routes of disease pathogenesis are important to consider.

Richardson proposed that breast cancer risk may be associated with late exposure to common viruses [10]. Zur Hausen stated that approximately 19% of the global cancer burden can be linked to five infectious agents, namely Epstein-Barr virus (EBV), human Papillomaviruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and helicobacter pylori [11]. His findings, therefore, suggest that viruses may be considered as a potential cause of breast cancer [11‐13]. Yasui et al. provided supporting evidence for the hypothesis that "delayed" exposure to Epstein-Barr virus is a risk factor for breast cancer [14]. Mazouni et al. also suggested that Epstein-Barr virus is a marker of biological aggressiveness in breast cancer [15]. In addition, de Villiers and his colleagues demonstrated the occurrence of HPV in nipple and areolar tissues in patients with breast carcinoma [12]. Besides the well established association with primary liver cancer, HCV infection has been associated with other neoplasms including non-Hodgkin lymphoma [16], and smoking and alcohol-related cancers, such as cancers of the pancreas, lung and kidney, and the oropharygeal cancer [17]. In the same token, HBV infection also has been associated with pancreas cancer [18], intrahepatic cholangiocaricinoma and non-Hodgkin lymphoma [19, 20]. Whether there is a potential link between chronic HCV or HBV infection and the risk of developing breast cancer has yet to be well investigated.

In Taiwan, the incidence of breast cancer has increased annually by 8% since 2003 [21]. In addition, the peak age for breast cancer is between 40 years and 50 years in Taiwan whereas the peak age in Western countries is between 60 years and 70 years [2]. Taiwan is a country in which HBV infection is endemic and a country with a high prevalence of HCV [22]. The fact that Taiwan is endemic for viral hepatitis and has a high prevalence of breast cancer provides an excellent setting in which to study the association of these 2 entities. Therefore, we used a nationwide population-based dataset to assess the possible association between chronic viral hepatitis infection and breast cancer as well as the possibility that chronic viral hepatitis is a risk factor for early onset breast tumors in Taiwan.

In this large-scale, population-based study in an area where both viral hepatitis and breast cancer are prevalent, we found no significant association between breast cancer risk and HBV or HCV seropositivity; however, age-stratification analysis showed that HCV patients aged less than 50 years had a significant two-fold greater risk of breast cancer.

Although breast cancer is mainly a postmenopausal disease, breast cancer in younger females often shows more aggressive clinical features and worse prognosis [3]. Studies have shown that high-risk and low-risk tumors present different age distributions, suggesting that breast cancer comprises a mixture of two different disease processes [3, 25]. The epidemiology of breast cancer in women living in Asia differs from that in women living in North America or Europe. The peak incidence age is between 40 years and 50 years among Asian women, whereas in the United States and Europe, it peaks among women in the sixth decade of life [2, 5, 26, 27]. This variation in peak incidence age may be due to multiple factors, including geographic variation, racial/ethnic background, genetic variation, lifestyle, environmental factors, socioeconomic status, utilization of screening mammography, stage of disease at diagnosis, and the availability of appropriate care [1, 21]

In 1997, Richardson proposed that breast cancer risk is associated with late exposure to common viruses [10]. Since then, numerous studies have shown that EBV, HPV, and cytomegalovirus infections are associated with the development of breast cancer [12, 14, 15, 28, 29].

Few studies, however, have evaluated the relationship between HCV or HBV infection and breast tumor development. A higher prevalence of HCV has been observed in elderly patients with tumors of the colon/rectum, prostate, breast, bladder, or kidney [30‐32] as well as in elderly patients with hepatocarcinoma [33] or non-Hodgkin lymphoma [16, 19]. Malaguarnera et al. reported that HCV RNA was detectable in sera in 11% of breast cancer patients and in 6.6% of control subjects, although there was no significant difference between the two groups [30]. Bruno et al. recently reported that HCV infection most likely plays an important role in the development of hepatocellular carcinoma as well as breast cancer [32]. In contrast, the results of a recent case-control study conducted by Larrey and his colleagues suggest that chronic HCV infection is not a strong promoter of breast carcinoma in adult females of any age [31]. However, a relatively small number of breast cancer patients in the control group may have masked the true significance of the infection after age stratification. Similarly, we found that chronic HCV infection was not significantly associated with breast cancer; however, after stratification by age (sub-grouped into <50 years and ≥50 years), chronic HCV infection was more prevalent among patients with early-onset breast cancer than among those with late-onset of the disease. This finding also suggests that breast cancer may comprise a mixture of two different disease processes, and that HCV may act as a promoter of carcinogenesis in young patients. Further studies are needed.

The mechanism responsible for the oncogenetic role of HCV is not well understood, but it involves immunity and autoimmunity disorders [30, 34, 35]. Mechanisms of direct and indirect carcinogenesis by which infections may contribute to cancer development have been suggested. Immunosuppression or induction of reactive oxygen species via inflammatory reactions have been suggested as the two most prominent pathways for indirect infectious carcinogens. Unlike the immunosuppressive mechanism induced by HIV, the mechanism by which Hepatitis B and C viruses contribute to cancer still remains obscure [11].

In this study, neither infection with HBV alone nor HBV/HCV coinfection was correlated with breast cancer. HBV and HCV are both hepatotropic viruses. Their coinfection is associated with clinically and histologically more severe liver disease and higher risk of the development of hepatocellular carcinoma [22, 36]. However, HCV infection has been reported to predispose patients to extrahepatic disorders involving renal, dermatologic, hematologic, and rheumatologic systems as well as autoimmune abnormalities [37‐39]. Extrahepatic manifestations may result from immunologic triggered mechanisms as well as virus invasion and replication that affect extrahepatic tissues and organs. Only HCV has the lymphotropic character that is assumed to be the cause of HCV-associated extrahepatic manifestation [40]. That may explain why we found that HCV, but not HBV, was associated with breast cancer. Further prospective cohort studies are required to verify this result.

This study has several important limitations. First, some hepatitis infected patients without obvious clinical symptoms might not receive medical services. As a result, some hepatitis infected subjects are included in the control group. However, if viral hepatitis infection is associated causally with breast cancer, this misclassification may lead the estimated HRs toward the null and further strengthen our finding. Therefore, we are confident of the positive association between HCV and early-onset breast cancer. Second, using ICD codes to select patients with diagnoses of breast cancer, HBV infection, HCV infection, or other comorbid medical conditions may be less accurate than selecting patients in a clinical setting. However, the BNHI randomly samples a fixed percentage of claims from every hospital and randomly interviews patients and reviews charts each year to verify the validity of diagnoses and the quality of care. Patients with confirmed breast cancer in Taiwan are placed in the category of "Catastrophic Illness", and the BNHI covers the treatment costs incurred by those patients. Hence, the diagnosis is relatively accurate and the patients are representative of the population in Taiwan. Third, the majority of the residents in Taiwan are of Chinese ethnicity. The ability to generalize the results to other racial/ethnic groups is unclear given that the transmission route of viral hepatitis infection in Chinese might not be completely the same as that in other ethnic groups. Finally, important variables that might be related to both hepatitis and breast cancer were unavailable in the insurance claims database, including family cancer history, body mass index, environmental exposure, nutritional status, physical activity level, hormone receptor status of breast cancer, cigarette smoking, and alcohol consumption. Therefore, we cannot rule out some of the potential confounding effects associated with these factors.

In summary, this population-based study suggests that chronic HCV infection is associated with early-onset breast cancer and that chronic HBV infection is not associated with breast cancer. Further studies are needed to apply our finding to other regions or races and to clarify the underlying pathophysiological mechanisms behind the association of chronic viral hepatitis with breast cancer.