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.