Time trend and age‐specific gender difference in the incidence of liver cancer from 2009 to 2018 in Taiwan

Liver cancer has a significant impact on global health. Taiwan is a country with a high incidence rate of liver cancer. Efforts in primary prevention and treatment of chronic hepatitis B and C are projected to decrease the liver cancer incidence in Taiwan. We used the Taiwan Cancer Registry data to explore the time trend of liver cancer incidence over the last decade, which showed a decreasing trend of 21% in males and 26.1% in females from 2009 to 2018. Both genders aged 30‐39 years had the greatest decrease in liver cancer incidence, while those >70 years old had the least decrease. Our study also showed gender disparity in liver cancer with a persistent male predominance over time. In the past decade, the liver cancer incidence had a 2.5 to 2.7 sex ratio (male to female) and varied gender differences at different ages. Sex ratios peaked at age 40‐49 years and gradually decreased as age increases. The pattern of age‐specific gender differences was similar between 2009 and 2018. This finding implies that female sex hormones may play a protective role in the development of liver cancer.


| INTRODUCTION
Liver cancer is the sixth most common cancer and the third leading cause of cancer-related mortality worldwide, with an estimated 841 000 new cases and 782 000 deaths in 2018. 1 The incidence rate of liver cancer shows geographic variations. Taiwan has a high incidence of liver cancer, and the rate is expected to decrease following the efforts in primary prevention by using public health programs and achieving breakthroughs in the treatment of chronic hepatitis B and C.
In addition, male predominance in liver cancer incidence has been recognized. 2,3 Gender disparity in liver cancer may be attributed to sex hormones and their interaction with environmental risk exposures. Therefore, sex hormones, such as estrogen, which are involved in the carcinogenesis of the liver, should be varied at different ages. However, age-specific gender differences in the incidence of liver cancer have rarely been reported and discussed. Thus, we aimed to use the Taiwan Cancer Registry data to understand the time trend of liver cancer incidence from 2009 to 2018. We also further analyzed the age-specific gender differences in liver cancer and its secular trend over the past decade.

| METHODS
The Taiwan Cancer Registry is a nationwide populationbased cancer registry system established by the Ministry of Health and Welfare in 1979 and is one of the highest quality cancer registries globally with 98.4% completeness. 4 The incidence of liver cancer from 2009 to 2018 was extracted from the Taiwan Cancer Registry Annual  Report, and liver cancer cases were defined using the C22  code by the International Classification of Diseases for  Oncology, third edition (ICD-O-3). Data from patients <30 years old were not used in the study because of the paucity of such cases. The age of patients was categorized into five groups (30-39, 40-49, 50-59, 60-69, and ≥70 years old). The 2000 World Standard Population was used to calculate age-adjusted incidence rates.
Because this study used the data from the publicly released annual report by the Taiwan Cancer Registry, which do not include any identified individual information, the informed consent was waived. Our study followed the principles outlined in the Declaration of Helsinki.  Figure 1A shows the time trend of decreased incidence of liver cancer over the past decade, and the declining trend is similar for males and females. The age-standardized incidence rate (per 100 000 population) of liver cancer in males decreased by 21.0% (from 53.60 cases in 2009 to 42.33 cases in 2018), while that in females decreased by 26.1% (from 21.69 cases in 2009 to 16.02 cases in 2018) ( Figure 1B). Tables 2 and 3 present the age-specific liver cancer incidence rates among males and females separately from 2009 to 2018, wherein the incidence of liver cancer increased with age and peaked at >70 years old for both sexes. Figure 2 shows that the pattern of increased incidence of liver cancer by age is persistent over the past 10 years without any changes. The incidence in males increases nearly linearly with age, while in females, it slowly increases with age when age is <60 years and increases after ≥60 years.

| RESULTS
The overall age-adjusted incidence rate of liver cancer declines in the past 10 years. Furthermore, the agespecific incidence of liver cancer for different age groups also declines over time. Figure 3 shows the change in age-specific incidence rate over time for both genders in different age groups. The incidence rate of liver cancer in males decreased by 56.7%, 33 Table 4 presents the overall and age-specific sex ratio (male to female) in the incidence of liver cancer from 2009 to 2018. The sex ratios were around 2.5 to 2.7 without significant changes over time. However, the sex ratios were significantly different at various age groups with a  Figure 4). The highest sex ratios occurred in the age group of 40-49 years (6.0-8.6), and the sex ratios gradually decreased with age. The lowest sex ratios were observed in the age group of ≥70 years (1.5-1.7). Moderate changes in age-specific sex ratios have been observed over the past 10 years. Sex ratios slightly decreased for those aged <50 years from 2009 to 2018, particularly from 6.0 to 4.7 in the age group of 30-39 years and from 6.9 to 6.0 in the age group of 40-49 years. In contrast, sex ratios slightly increased from 3.9 to 5.1 in the age group of 50-59 years. However, no significant changes in the age group of 60-69 years and >70 years from 2009 to 2018.

| DISCUSSION
A previous study had showed a decreased trend in liver cancer incidence for both sexes between 2004 and 2014 in Taiwan. 5 Liver cancer incidence rates are projected to further decrease by 22.2% in males and 17.5% in females from 2014 to 2025. Our study showed consistent results, and the observed incidence rate of liver cancer decreased  Chronic hepatitis B (HBV) and C virus (HCV) infections are major causes of liver cancer in Taiwan. Prevention and treatment of chronic HBV and HCV infections contribute greatly to the decreased trend of liver cancer incidence. Since 1984, the Taiwanese government had launched a nationwide HBV vaccination program for all infants born thereafter with an over 90% vaccination coverage in children. 9 The hepatitis B surface antigenpositive rate in children ≤5 years old has decreased to 0.47% after universal HBV immunization. 10 In addition, the HBV vaccination program has been reported to significantly reduce childhood liver cancer incidence in Taiwan. 11 Antiviral treatment of chronic HBV infection has been shown to decrease the risk of hepatocellular carcinoma (HCC) incidence, 12,13 especially if the treatment started at the earlier stages of chronic hepatitis B. 14,15 Previous prospective studies with interferon-based therapy for chronic HCV infection concluded that sustained virologic response was strongly associated with a reduction in HCC risk. 16 Nowadays, direct-acting antiviral (DAA) therapy has revolutionized the treatment of HCV infection due to its high efficacy and excellent safety profile. 17 Multiple large cohort studies have demonstrated that DAA-induced sustained virologic response is associated with a reduced risk of HCC occurrence. 18,19 The World Health Organization's goal to eradicate HCV might reduce the risk of HCC by preventing the advancement of cirrhosis and allowing fibrosis regression; thus, avoiding the carcinogenic effect of the virus. 20 Since 2003, a national viral hepatitis therapy program was launched by the National Health Insurance, which targets all patients infected with HBV and HCV in Taiwan, resulting in a remarkably reduced incidence of liver cancer. 21 Our study shows that in Taiwan, male to female ratio is approximately 2.5 to 2.7 in the past 10 years without significant changes over time. The results are consistent with previous epidemiological studies that reported gender disparity in liver cancer of male predominance with a two-to fivefold higher incidence, regardless of the etiology of liver cancer. 2,3 The gender disparity in liver cancer risk could be attributable to the difference in exposure to environmental risk factors and intrinsic sex hormones. Considering age-specific sex ratios, our study shows the sex ratio peak at age 40-49 years and gradually decreases with age. A previous study in the US reported similar findings and revealed that the sex ratio in liver cancer peaked up to 5.4 at the age of 50-54 years and declined thereafter, with similar age-specific patterns in the sex difference of liver cancer incidence across calendar periods. 22 These results of prominent male dominance in liver cancer incidence, particularly those aged <60 years old, imply that female sex hormones may play a protective role in liver cancer development.
Based on the several lines of evidence including animal and epidemiological studies, sex hormones have been recognized to play an important role in the hepatic carcinogenesis. 3 Estrogen is considered to have a protective effect against liver cancer. A case-control study in Taiwan found an increased HCC risk for women who underwent oophorectomy during premenopausal years and for those who had a natural menopause at ages <45 years old. In contrast, hormone replacement therapy was associated with a low risk of HCC. These findings in Taiwan imply that high exposure to estrogen may protect against HCC. 23 In an animal study on diethylnitrosamine-induced liver cancer in mice, the estrogen-mediated inhibition of interleukin-6 production by Kupffer cells reduces the risk of liver cancer in female animals. 24 In contrast to estrogen, androgen may increase the risk of liver cancer. In animal studies, chronic administration of testosterone to castrated male animals increased the risk of chemically induced liver cancer. 25,26 In an early nested case-control study in Taiwan, a significant association between elevated plasma testosterone levels and HCC risk was observed among male chronic HBV carriers. 27 In another cohort study of male patients with HCV-related liver cirrhosis in Japan, serum testosterone levels were significantly associated with the risk of HCC. 28 Two nested case-control studies among men in Taiwan further explored the association between polymorphisms of genes involved in androgen signaling pathways and HCC risk. Both studies found a significant rise in HBV-related HCC risk with increasing plasma testosterone levels. Polymorphisms of genes involved in androgen signaling pathways, including cytochrome P450c17α, steroid 5α-reductase type II, and androgen receptor, were also associated with the risk of HBV-related HCC. 29,30 An animal study using hepatocyte-specific androgen receptor knockout mice had showed that later and less HCC developed compared with their wild-type littermates. 31 Hepatic androgen receptor promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice. Hepatic androgen receptor increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. 32,33 A genetic study of HBVrelated HCC tissues showed that telomerase reverse transcriptase elevation by androgen receptor through integrated HBV and point mutation at the telomerase reverse transcriptase gene promoter region was identified as a mechanism for the male dominance of HBV-related HCCs. 34 Recent breakthrough studies elucidating the mechanisms of sexual dimorphism in liver cancer revealed that forkhead box protein A (Foxa) factors, Foxa1 and Foxa2, also known as pioneer transcription factors in liver specification, are essential for estrogen and androgen signaling by acting as central regulators of sexual dimorphism in liver cancer. 35,36 Our study showed that sex ratios at ages <50 years seemed mildly decreasing in the past 10 years. This phenomenon requires more attention, and long-term followup studies are warranted to confirm this trend. There is a possibility that sex-associated environmental risk factors have changed over the past decade. Increased exposure to environmental risk factors among younger females against the protective role of sex hormones may contribute to this decreasing trend in sex ratios.
Our study had some limitations. We used data from the Taiwan Cancer Registry Annual Report to analyze the time trend and age-specific gender differences in the incidence of liver cancer. The individual important risk factors for liver cancer, including HBV, HCV infection, and cirrhosis status, could not be determined from the data. Further analysis to understand the influence of etiology and environmental risk factors on the time trend and age-specific gender differences in the incidence of liver cancer could not be performed. Previous studies had demonstrated that the gender disparity in the development of HCC is different between HBV-and HCV-related HCC. The male-to-female ratio for HBV-related HCC is higher than HCV-related HCC. 3,37,38 . The reasons for this discrepancy remain unclear. Further study in the future to evaluate the age-specific gender difference between hepatitis B and C related HCC is needed. In our study, liver cancer cases were defined using the C22 code by ICD-O-3, including HCC, intrahepatic cholangiocarcinoma, and other liver malignancies. Detailed information on the incidence of these various liver cancers is not available. However, in Taiwan, HCC is the major component of liver cancer (accounting for approximately 89-90%). Therefore, the time trend and gender disparity observed in liver cancer in our study suggest HCC.