Unmasking Disparities in Gallbladder Cancer Outcomes in the Disaggregated Asian American Population

There were 45,070 patients identified with GBC from 2010 to 2019 (Fig. 1). In this dataset, 1,317 patients (5% of the total) of AsA heritage were identified. Of these patients, Chinese patients accounted for 15.49% (n = 204), Japanese 6.23% (n = 82), Filipino 11.6% (n = 147), Korean 9.72% (n = 128), Vietnamese 7.44% (n = 98), Indian 20.50% (n = 270), and other 29.46% (388), which included Native Hawaiian and Pacific Islander ethnic groups. Of the total patients, 1440 (3%) were excluded because of missing data or unknown ethnicities. These groups comprised less than 2% of the total cohort and were excluded from the survival curves and multivariate analysis. A specific breakdown of each ethnic group is located in Supplementary Table 1. First, a comparison of baseline demographic data was performed between the individual AsA, Caucasian, and African American groups, representing most of the U.S. patients. In general, more patients from AsA heritage were treated at academic/research hospitals versus Caucasian patients but similar to African American patients (AsA: n = 575 [44%] vs. Caucasian: n = 6905 [35%] vs. African American n = 1925 [45%]). More AsA patients had private insurance than the other groups (AsA: n = 446 [34%] vs. Caucasian: n = 5,216 [26%] vs. African American: 1278 [n = 30]). A greater proportion of AsA patients were in the highest income bracket of >$63,333 compared with other groups (AsA: n = 625 [n = 47%] vs. Caucasian n = 6366 [32%] vs. African American: n = 757 [18%]). In terms of distance traveled to the treatment facility, Caucasian patients traveled the furthest (median distance 9.4 mi [interquartile range (IQR) 4.2–23.7] vs. AsA: 6.1 [IQR 3.3–12.1] vs. African American 6.6 [IQR 3.1–13.4]) (Table 1).

There are approximately 22 million Asian Americans currently in the United States, comprising approximately 7% of the population.⁷ This highly heterogeneous demographic from more than 20 countries is the fastest-growing demographic in the United States, projected to surpass 46 million people by 2060. Gallbladder cancer is an aggressive form of cancer with poor outcomes. The current relative 5-year survival rate for Asian Americans with gallbladder cancer is 22.1%, which is slightly higher than the U.S. relative 5-year survival rate of 20.9%.¹³ Gallbladder cancer often starts with chronic inflammation of the area, which then disrupts normal cell growth. Major factors for gallbladder cancer include age, obesity, genetics, occupational exposure to mutagens, chronic infection, and gallstones. Chronic infections with Salmonella (e.g., S. typhi and S. paratyphi) or Helicobacter (H. pylori and H. bilis) have been associated with gallbladder cancer. Salmonella enterica serovar Typhi, which causes typhoid fever, also has been associated with gallbladder cancer. Areas where typhoid fever is more common, such as South Asia or Latin America, have seen a higher increase in gallbladder cancer.¹⁴ Gallstones are an important risk factor owing to their high correlation with GBC. Studies have found high rates of gallbladder cancer incidence and gallstone prevalence in Pima Indian females, East Indian females.^14,15

Historically, studies have aggregated the AsA population when investigating cancer diagnoses, treatments, and outcomes. However, an increasing body of evidence demonstrates that this heterogeneous group has numerous differences in cancer statistics when disaggregated in other cancer types.^8‐12 This paper builds on this body of evidence by looking at cancer outcomes in the disaggregated AsA population for gallbladder cancer, a type of cancer with generally poor outcomes. The data demonstrated that the aggregated AsA population had the most extended OS at 15.1 months compared with other ethnic demographics. However, when disaggregated, analysis showed a difference between the shortest OS of 12.6 months in Koreans and the longest of 19.1 months in Filipinos. To our knowledge, this is the first paper to look at gallbladder cancer in a disaggregated AsA population.

Previous studies have demonstrated the importance of socioeconomic barriers to access to care and financial status as predictive factors for survival with cancer.¹⁶ This study found that the AsA patient population tended to have the highest proportion of patients within the highest income bracket. While there is still generous heterogeneity in income between people within each ethnic grouping, these data may suggest that economic status is only part of the equation regarding patient outcomes. Specifically, with hepatobiliary cancers, increased travel distance is associated with poor survival.¹⁷ However, this analysis found that Filipino patients traveled the furthest median distance for treatment but had the highest OS.

High-quality care for GBC includes surgical resection and adjuvant therapies if feasible. For T1a disease, management is limited to cholecystectomy. Still, for more advanced tumors, surgical management extends to hepatic resection, including the gallbladder fossa, portal and retroperitoneal lymphadenectomy, and resection of the biliary ductal margin as indicated to achieve an R0 resection.^18,19 While the NDCB is limited in distinguishing the extent of surgery patients received, previous literature has demonstrated the benefit of receiving care at high-volume centers.²⁰ This paper’s data also shows that the Filipino population had the highest rate of surgical resection (67%) compared with other AsA groups. The Chinese and Korean populations had the lowest rates (55% and 60% respectively). This corresponded with lower OS in these groups.

It is not yet clear what role adjuvant chemotherapy plays in the treatment of gallbladder cancer. Two meta-analyses showed a nonsignificant survival benefit with adjuvant therapy and a significant survival benefit for R1 and node-positive disease.^21,22 Additionally, the BILCAP phase III trial showed an overall survival benefit for 223 biliary tract cancers, which included 79 cases of GBC in a per-protocol analysis but did not show a significant survival benefit to treat.²³ Overall, the current NCCN guidelines recommend adjuvant chemotherapy as part of the treatment algorithm for patients with GBC.²⁴ This paper demonstrated that the Korean population had the highest rate of adjuvant chemotherapy (20%), whereas the Filipino group had the lowest rate (7%).

Patients who had received multimodality therapy were expected to have the highest OS in the population, but interestingly, it was found that Filipino patients had the most increased OS even while having a lower rate of treatment in academic/research centers, further travel distance, and no apparent differences in financial status. These findings suggest that socioeconomic factors and access to care are only part of the answer, which differs from studies that looked at pancreatic cancer in a disaggregated AsA population.¹⁰ Instead, we hypothesize that genetic and epigenetic influence likely drives patient outcomes. Tumor biology ultimately mediates how patients respond to therapy but is challenging to capture in retrospective database studies. There is limited data on the impact of ethnic and genetic variability on patients with gallbladder cancer. However, there is growing literature surrounding the integral role that epigenetic and genetic factors play in cancer etiology and treatment targets.

Epigenetics refer to modifications in gene function and expression without alteration to DNA sequence. There are several mechanisms in which epigenetics affect gene expression, such methylation, acetylation, or phosphorylation of histones, among many others.²⁵ There are well-known examples of cancers associated with epigenetic changes in certain genes, such as hypermethylation of BRCA1 in breast cancer and hMLH1 in colon cancer.²⁶ One comprehensive review by Feinberg et al.²⁷ further advances a theory of epigenetic “landscapes” and its role in cancer etiology and potentially targeted therapies, such as tyrosine-kinase inhibitors. Furthermore, there is growing literature around the role of epigenetics in prognosis. Nagaraju et al.²⁸ review the association of degrees of methylation and hepatocellular carcinoma (HCC) etiology, metastatic transformation, and survival outcomes in HCC patients. Specifically, hypermethylated CGI methylator phenotypes were associated with poor survival in HCC.^29,30

While epigenetics in the propagation of cancer is well studied, the literature regarding differences in epigenetics between different ethnicities is still growing. There is a known racial disparity in breast cancer outcomes between African American women and Caucasian American women. Whereas robust literature surrounds the socioeconomic roots of these health disparities,¹⁶ epigenetic differences between races also is noted. One review discusses several genes that are differentially methylated in breast cancer between AA and CA women, e.g., methylation of CDH13, which is associated with triple negative breast cancers.^31‐33 Another systematic review of genetic and epigenetic differences in prostate cancer between African American patients and European American patients discussed differential methylation of multiple different gene promoters associated with prostate cancer.³⁴ However, the clinical utility of these promoters are not certain.

There is sparse literature on the genetic and epigenetic profiles of Asian patients compared with Western patients. One study did show several genetic differences in prostate cancer tumors between Asian and Western patients,³⁵ although they did not discuss epigenetic differences between races. Literature on epigenetic differences between races in regards to gallbladder cancer thus far has not been studied.

Further evidence of differential tumor biology based on race can be seen in gastric cancer. Gastric cancer has disproportionally affected Asian populations compared with Western populations. One study of SEER data showed that after adjusting for age, gender, tumor site, tumor grade, number of positive and total examined lymph nodes, and stage, Asian ethnicity was still a favorable prognostic factor for improved median and 5-year survival.³⁶ A single-center study in the 1990s showed that the clinical behavior of patients with gastric cancer for patients of Asian descent was markedly different than the general population, which was also demonstrated in a recent NCDB analysis.^37,38 Studies of the immune microenvironment for patients with gastric cancer have begun to suggest that specific tumor-infiltrating lymphocytes (TIL) are associated with differential survival. One study found that patients in the United States with increased survival had TIL profiles that were similar to those from Asian ancestry, which supports the notion that tumor biology is paramount.³⁹ Similar studies are needed in gallbladder cancer and other hepatobiliary malignancies to characterize better genetic and epigenetic differences that mediate variation in survival.

A recent review also showed significant variability between tumor biology (among other factors, such as age at diagnosis, stage at diagnosis, tumor biology, treatment, and survival rates) of breast cancer between disaggregated subgroups of the AsA population.⁹ When controlled for socioeconomic differences, one investigation found that among AsA subgroups, Japanese women had a relatively high rate of hormone receptor-positive (HR+) disease and lower frequency of HER2+ and triple-negative disease compared with Korean, Filipina, and Vietnamese women.⁴⁰ This growing body of literature demonstrating differences in tumor biology and pathology for other cancers based on disaggregated AsA subgroups independent of socioeconomic factors advances the notion of the important role genetic and epigenetic factors have on cancer outcomes.

Our study has limitations. The NCDB is a national retrospective database and is associated with limitations. Help is needed to understand specific patient tumor biology, surgical management, or specific chemotherapy regimens for individual patients in the dataset. Additionally, while this study attempted to control patient factors, it could not capture relevant cultural differences amongst patients, which are likely critical to explain differences in treatment utilization. Future institutional studies are needed to understand these populations’ patient decision-making better.

This study identified differences in overall survival for patients with gallbladder cancer with a disaggregated AsA study design. Factors, such as socioeconomic barriers, cultural differences, and genetic and epigenetic causes, may explain these differences. This investigation highlights the importance of conducting research in a more disaggregated fashion to reduce disparities in access to care for patients of all ethnic backgrounds.