A Path Forward for Understanding and Addressing Multifaceted Pancreatic Cancer Disparities

Globally, the incidence of pancreatic cancer and pancreatic ductal adenocarcinoma (PDAC) in particular has risen 2.3-fold since 1990, which has been partly attributed to the growing and aging population, improvements in diagnostic methods, and a higher prevalence of modifiable risk factors¹. With an estimated 62,210 new cases and 49, 830 deaths predicted in 2022, PDAC is projected to surpass colorectal cancer and become the 2^nd leading cause of cancer-related deaths in the United States (US) by 2040. ² In the US, the incidence of PDAC continues to rise, with notable disparities reported by race, ethnicity, gender, age, and socioeconomic factors³.

In this issue of Gastroenterology, Amirian and colleagues ⁴ analyzed the Surveillance, Epidemiology, and End Result (SEER) database to investigate trends in incidence, incidence-based mortality, and survival differences between Black and White patients diagnosed with PDAC between 1995 and 2018. They ⁴ found that while incidence rates increased for Black and White patients over this period, the increase was significantly greater among White patients than Black patients for incidence and incidence-based mortality. Furthermore, although the incidence rate has historically been lower in females compared to males in both racial groups, the incidence of PDAC in Black females significantly increased (with an annual percentage change (APC) of 0.6, P<0.001) and approached rates of male counterparts ⁴. When compared by decade (1995–2004 versus 2005–2014), survival improved for both racial groups and was attributed to advances in surgical techniques and chemotherapy. Despite this, Black patients continued to have a lower survival rate compared to White patients, with Black females having the poorest survival. Potential explanations for these racial and gender disparities mentioned by the authors include access to care, underrepresentation of Black patients in clinical trials, and socioeconomic, environmental, and genetic factors.

Also in this issue, Huang et al. ⁵ report on an analysis of 1995–2018 data from the North American Association of Central Cancer Registries (NAACCR) that compared incidence trends of early-onset pancreatic cancer (EOPC) (diagnosed ≤ age 54) and late-onset pancreatic cancer (LOPC) (age 55 and above) by gender and race/ethnicity in a larger, more generalizable population than that represented by SEER. Steady increases in EOPC and LOPC were observed over the study period, with the average APC being twice as high for LOPC compared to EOPC. For EOPC and LOPC, age-adjusted incidence rates were highest in non-Hispanic Black patients, though significant decreases in EOPC incidence were observed among Black males, in line with other studies ⁶. In the EOPC group, the largest increase over time was observed in females, especially non-Hispanic White and Hispanic patients, consistent with prior SEER-based studies ^{6, 7}. Possible reasons cited for the rise in EOPC among non-Hispanic White and Hispanic females include increases in body mass index, increased access to diagnostic imaging, detection of certain histologic subtypes (ie. cystic adenocarcinomas) that are more common in females^{5, 6}, and sex-based differences in exposure to known or unknown agents and risk factors, including estrogen^{7, 8}.

Using retrospective data from the National Cancer Data Base (NCDB), Saadat et al⁹ explored treatment patterns for patients with EOPC diagnosed from 2004–2016. The analysis revealed that nearly 20% of patients with EOPC did not receive any therapy, representing a significant missed opportunity for guideline-concordant care for this historically underrepresented group. The authors also found that patients with EOPC had almost 4-fold higher odds for receiving multimodal therapy than patients with LOPC after accounting for measured confounders. Data on the intensity, type, and duration of therapy are unavailable in the NCDB and therefore could not be evaluated.

Taken together, the registry-based studies in this issue ^{4, 5} suggest that PDAC incidence is rising at a rapid pace in specific subgroups, particularly non-Hispanic white, Hispanic, or non-Hispanic Black females <55 years of age. The data leveraged by these analyses ^{4, 5} provide a wealth of information on patient demographics, the primary tumor site and morphology, stage at diagnosis, first course of treatment, and follow-up. However, understanding the factors that contribute to health disparities is a complex and multifaceted problem that requires information beyond that routinely captured by such registries.

As summarized by Singhi and colleagues¹⁰, established PDAC risk factors include pathogenic germline variants, tobacco use, diabetes, obesity, pancreatitis, and mucinous pancreatic cysts, which are important conditions that are not accounted for in most registry-based studies. There is great value in augmenting registry data through linkage to additional sources with elements collected through longitudinal biorepositories such as the Florida Pancreas Collaborative, a statewide initiative collecting data from a racially and ethnically diverse PDAC population¹¹. Such data could include genetic, lifestyle, and socioeconomic factors, laboratory values, patient-reported outcomes, quantitative features from standard-of-care medical images, and molecular data. For example, several recent single-institutional studies^{12, 13} have reported on unique molecular characteristics of tumors from patients with EOPC, including actionable alterations (ie. mismatch repair deficiency, NTRK fusions) among RAS wild type tumors which may drive targeted treatment¹².

Importantly, data suggest that advances in practice patterns are sorely needed to ensure all eligible patients receive multimodal treatment regardless of age, race/ethnicity, and socioeconomic level.^{4, 5, 14, 15}. Additionally, there is an unmet need to increase minority recruitment to clinical trials through promotion of inclusivity in study eligibility, increasing diversity of providers and coordinators who conduct trials, increasing the conduct of trials in geographic locations accessible to racially and ethnically diverse populations, patient advocacy, and public policy. ¹⁶

In summary, factors that underlie the growing disparities in PDAC incidence and mortality are multifaceted and likely reflect the interplay of lifestyle, socioeconomic, and biological determinants as well as the need for improved health care access, coordination, and delivery. Future multi-center longitudinal studies that collect and integrate data related to these determinants will undoubtedly provide critical insight into factors that contribute to rising trends and disparate outcomes. Such insight will be instrumental for charting a path forward that will include designing effective strategies to minimize PDAC disparities and improve outcomes through personalized approaches for targeted prevention, early detection, and/or therapeutic intervention for high-risk populations.