CONCLUSIONS
In this study spanning three decades and nearly 50,000 heart transplant patients from the OPTN database, 18.3% of patients developed a post-transplant de novo malignancy (excluding non-melanoma skin cancers) an average of eight years after transplantation. While the most common malignancies were lung, PTLD, and prostate, the risk was most elevated for female genital, tongue/throat, renal, and esophageal cancer as compared to the general population. We found male gender, older age, smoking history, and impaired renal function to be risk factors for developing DNM, whereas the use of MMF for maintenance immunosuppression was protective. Cigarette use, increasing age, the use of ATG for induction and calcineurin inhibitors for maintenance were specifically risk factors for cancer-specific mortality. The development of a post-transplant malignancy increased the risk of death by 43%.
Our malignancy incidence rates of 18.3% over the entire follow-up period (median 6.9 years) and 10.2% at five years post-transplant largely agree with the published literature.2,7,15–17Youn et al. published the experience of 17,587 heart transplant patients from the International Society for Heart and Lung Transplantation (ISHLT) registry and found that 10.7% of patients developed a solid de novo malignancy by five years post-transplant.15Unique to our study is the large sample size and multi-institutional data, whereas many prior studies are from a single institution, and it is the first published report of DNM post-heart transplant in the OPTN database. Our median follow-up time was 6.9 years, yet malignancies were diagnosed, on average, eight years after transplantation. Hence, 18.3% may actually represent an underestimation of the true DNM rates with longer follow-up time.
Of the 9,150 DNMs diagnosed in patients followed in the OPTN database, the most common were lung in 22.3%, PTLD in 16.5%, and prostate in 16.4%. Notably, however, men formed the majority of this cohort (76.7%), increasing the prevalence of a male-specific malignancy like prostate cancer. Compared to the general population, post-heart transplant patients had a 5.3-times higher rate of developing lung cancer, whereas the IR of other common malignancies were not as elevated – 2.1 for prostate cancer (men only), 1.5 for breast cancer (women), and 1.6 for colorectal cancer. Kellerman et al., in a single-center study of 911 patients over 13 years, found similarly slightly increased SIRs for prostate, breast, and colorectal cancer (1.2, 2.4, and 1.0, respectively), but on the contrary also found a comparable risk of lung cancer (SIR 0.95).18 Engels et al., however, in a 20-year study of solid organ transplant recipients from the U.S. Scientific Registry of Transplant Recipients (SRTR) database, reported a SIR of 2.57 for heart transplant patients developing lung cancer compared to the general population.3
Malignancies that are rare in the general population were much more prevalent in the post-transplant population, including female genital (IR 11.2), tongue/throat (IR 7.4), renal (IR 6.5), esophagus (IR 6.2), and male breast cancer (IR 5.6). This points to the importance of not only routine cancer surveillance—such as colonoscopy, mammography, and skin checks—but also heightened awareness of the possibility for less common malignancies in the transplant population.
Not surprisingly, we found increasing age and smoking history to be risk factors for development of a DNM and cancer-specific mortality, in keeping with findings from prior studies.2,3,7,15,19,20 Age is a particularly important risk factor given that the average age of heart transplant recipients has been increasing for the past three decades, with median age at time of transplant now around 55 years.9 In our analysis, increasing GFR at the time of transplantation, representing better renal function, was associated with a decreased risk of DNM development and of all-cause mortality. Requiring dialysis post-transplant particularly increased risk. Increased cancer risk amongst end-stage renal disease (ESRD) patients has been previously described, attributed to dialysis-induced immune dysfunction and the ill effects of uremia such as impaired DNA repair.21–23 Some cohort studies have also suggested increased malignancy risk in chronic kidney disease (CKD) not requiring dialysis.24–26 Our current study confirms this risk in the post-heart transplant patient population and points to the need for particularly careful surveillance in heart transplant patients with CKD.
Much attention has been paid to immunosuppressive regimens and malignancy risk. In this patient cohort, 73.7% of patients received induction therapy. Induction therapy did not predict development of DNM, cancer-specific, or all-cause mortality, but there was increased all-cause mortality in patients who received basiliximab, and ATG increased the risk of cancer-specific mortality. Regarding maintenance immunosuppression, the use of MMF was associated with a lower risk of DNM and all-cause mortality but did not significantly decrease cancer-specific mortality. Taken together with evidence suggesting MMF has anti-tumor properties, these results support the preferential use of MMF for post-transplant immunosuppression with respect to DNM risk.12 Calcineurin inhibitors, on the other hand, have been implicated in increasing cancer risk.10,11While in our analysis we did not see significantly increased risk of developing a DNM or of all-cause mortality, cancer-specific mortality was higher, supporting a move away from or at least caution and attention to surveillance and screening with calcineurin inhibitors. mTOR inhibitors were not associated with increased risk of DNM, all-cause, or cancer-specific mortality and might serve as an alternative immunosuppressive strategy in appropriately selected patients at higher risk for DNM development. While there is limited data on mTOR inhibitor use and DNM development (and only 1.8% of our cohort were on them), Asleh et al. reported a decreased risk of all DNM, PTLD, and non-melanoma skin cancers in patients converted from a calcineurin inhibitor-based to a sirolimus-based immunosuppressive regimen.8
This study is limited by its lack of granular data and sometimes large number of unknown clinical variables. For instance, infectious disease serology, which has important implications for cancer risk, was particularly under-reported (e.g. EBV serologic status was reported in only 52.3% of patients). These variables with high rates of unknown values should, therefore, be interpreted with caution given potential sampling bias.
In conclusion, the development of a DNM in heart transplant patients from the OPTN database increased the risk of death by 43%. Recipients were at the highest risk for malignancies that are rarer in the general population, such as female genital cancer and tongue/throat cancer. The use of ATG for induction and calcineurin inhibitors for maintenance immunosuppression increased risk for cancer-specific mortality, whereas MMF reduced the risk of developing a DNM. This represents one of the largest studies to date examining trends and risk factors for DNM after heart transplantation and points to the critical importance of strict follow-up that includes optimizing immunosuppressive regimens, routine cancer surveillance, and particular attention to the risk of rarer cancers in these patients.