In this nationwide cohort of recipients of over 400,000 solid organ transplants in the US, we found a modestly increased incidence of PC compared to the general population (SIR 1.40, 95% CI 1.29–1.52). This finding is similar to the SIR of 1.5 observed in our prior overview of cancer risk in the TCM Study, which was based on follow-up through 2008 and included a much smaller number of PC cases (n = 157).16 Of note, PC incidence was most elevated for cases arising in the head of the pancreas. Also, compared to other organ recipients, liver recipients had higher PC incidence, especially for local/regional stage PC. Demographic factors associated with increased incidence were consistent with those in the general population, including male sex, older age, blood type other than O, and history of diabetes mellitus. We also demonstrated that survival after PC detection was very poor among this study population.
In general, epidemiological studies have shown that cancer incidence is elevated in immunocompromised populations including SOT recipients exposed to long-term immunosuppressive therapy. Individuals with human immunodeficiency virus (HIV) infection have been studied as another immunocompromised population. A 2007 systematic review of cancer risk in people with HIV infection reported SIRs for PC ranging from 0.70 to 2.86.17 The most recent data from US population-based HIV registries demonstrated a slightly increased incidence of PC (SIR 1.13, 95% CI 1.01–1.26).22 Other recent registry-based studies of SOT recipients from Europe and Asia reported SIRs for PC that were similar to ours but with relatively wide confidence intervals (1.5, 1.0-2.1, and 1.58, 0.51–4.90, respectively).18,19
We observed the most elevated SIR in liver recipients, and PC incidence was higher in this group than other SOT recipients in multivariable analyses. Our result differs from those recently reported by Corral et al., who found a higher incidence of PC among heart and/or lung recipients than liver recipients.20 However, that study relied on cancer diagnoses reported by transplant centers, which may be inaccurate,23 and did not formally test whether these incidence estimates differed or adjust for other factors.
Because SOT recipients (especially liver recipients) frequently undergo hepatobiliary-related laboratory and radiology tests, we hypothesized that some of the PC cases in SOT recipients were incidentally detected, in which case they would tend to be diagnosed at an early stage. This hypothesis was supported by the following study findings: 1) the SIR appeared more strongly elevated for PCs arising in the head of the pancreas than in the body/tail, and this pattern was more evident in liver recipients than others; 2) there existed a shift in stage to more localized PC tumors among SOT recipients overall, with the greatest elevation of SIR for localized stage tumors (SIR 1.85, 95%CI 1.37–2.44) followed by regional stage tumors (1.57, 1.36–1.80) and distant stage tumors (1.17, 1.03–1.31); and 3) liver recipients had higher incidence of local/regional stage PC than recipients of other organs, but this association was not seen for distant stage PCs.
Since long-term use of immunosuppressive medication is an important clinical characteristic of SOT recipients, we also evaluated duration of immunosuppression and immunosuppression regimen as risk factors for PC. We did not see a progressive increase over time following transplantation (Table S2), arguing against a role for long-term immunosuppression. Instead, incidence increased after the first year post-SOT and then remained constant, which may be a result of pretransplant medical evaluation. Specifically, prior to being placed on the transplant waitlist, individuals who receive SOT have undergone rigorous medical evaluation, including cancer screening, laboratory measurements, and probably, cross-sectional abdominal imaging (especially for liver and other abdominal organ recipients). It is therefore likely that early asymptomatic PC cases would have been detected, which would have led to removal from the waitlist of individuals whose PC might have otherwise become clinically evident in the first year following transplant. Additionally, induction and common baseline maintenance medication combinations were not associated with PC risk. Those findings are consistent with our hypothesis that liver recipients, who are usually with the least exposure to immunosuppression,24 manifest the highest SIRs, again presumably due to the frequent laboratory and radiological tests performed posttransplant. Our analyses suggested that mTORis were associated with reduced PC incidence, which might be due to direct anticancer effects of mTORis25 or reduction in the use of calcineurin inhibitors. mTORis reduce the risk of skin cancer among SOT recipients and may be associated with reduced risk of other cancers.26,27
We also found that other established factors were associated with PC incidence in SOT recipients. Blood type O has been identified as a protective factor for PC, although the mechanism is unknown.28,29 Of note, the current prevalence of blood type O in SOT recipients is 44% (https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#, accessed on 12/7/2021), which is similar to the prevalence (38%) in the general population (American Red Cross; https://www.redcrossblood.org/donate-blood/blood-types/o-blood-type.html, accessed on 12/7/2021). Thus, it is unlikely that the blood type distribution in SOT recipients explains the elevated SIR for PC.
Diabetes mellitus is associated with development of PC in the general population30with a pooled relative risk of 2.1 reported in a 1995 meta-analysis.31 Diabetes at the time of transplantation was present in 28% of our cohort (data not shown). In comparison, approximately 13% of adults in the US general population have diabetes. Based on the prevalence of diabetes and its effect on PC risk, we would predict an SIR = [(1–0.28) + 2.1*0.28]/[(1–0.13) + 2.1*0.13] = 1.14, in the absence of other factors,32 which is smaller than what we observed. Thus, diabetes probably does not by itself explain the elevated SIR. Epidemiological studies also show a link between obesity and PC.33 In a cohort study conducted by the US National Institutes of Health, overweight or obese patients with a BMI ≥ 30 kg/m² were more likely to develop PC than those with a normal BMI (hazard ratios 1.15 to 1.53 for BMI measured at different ages).34 Indeed, the higher PC incidence in diabetic patients may be related to an increased prevalence of obesity, or vice versa. In our study, however, obesity was not associated with elevated PC incidence in a multivariable model (data not shown).
A recent study of patients with chronic hepatobiliary disease outside the SOT setting suggested the usefulness of early and incidental PC detection during surveillance imaging for hepatic disease.4 However, our analysis showed that survival after a PC diagnosis was very poor, regardless of stage at diagnosis, with a median survival of 4 months for the overall group. Survival was similarly poor for liver and other organ recipients. This seems no better than that of general population.3 Thus, our study failed to support the possibility that earlier PC detection in liver recipients would lead to improved survival.
A strength of this study is the evaluation of a large nationwide cohort representative of the SOT recipient population in the US. This allowed us to investigate PC in detail and to assess risk factors using multivariable analysis. One limitation is that the cohort lacked information on smoking, which is a risk factor for PC in the general population.6 However, the prevalence of cigarette smoking among SOT recipients seems unlikely to explain the elevated SIR of PC by itself, as kidney recipients, who comprise the majority of SOT recipients, have a smoking prevalence that is comparable to the US population.35 Also, only 15% of liver transplant recipients are active smokers.36 Heart and/or lung transplantation is usually not considered for active smokers, although up to a third of thoracic organ recipients resume smoking after transplantation.37,38 Another important limitation is the lack of information on changes over time in maintenance immunosuppressive medications and medication dosages, which prevented us from fully assessing the impact of immunosuppression on the PC incidence post-SOT.
To conclude, our study demonstrates that PC incidence in SOT recipients is modestly higher than in the general population. Novel findings include the increased incidence among liver recipients and elevated risks for PC cases with local and regional stages and for those located in the head of the pancreas, suggesting that some cases may be diagnosed earlier due to incidental detection, related to frequent laboratory and radiological monitoring. However, survival after the diagnosis of PC in SOT recipients is poor even in patients diagnosed at a local or regional stage, and liver transplant recipients did not have improved survival. Consequently, our findings fail to support a potential benefit for systematic screening for PC following SOT.