The study population was derived from HT recipients and donors captured in the United Network for Organ Sharing (UNOS) registry. The UNOS registry represents a multicenter collaboration designed to capture waitlist, transplant, and post-transplant data, in order to improve future transplant outcomes. The registry has been capturing transplant outcomes since its inception in 1987 to current date. Northwestern University Institutional Review Board approval was obtained for this study.

Adults aged 18 years and older who underwent HT from 1987 to October 2019 were included in this analysis. Patients were categorized based on the presence of post-HT malignancy (“yes” or “no”), reported by the transplanting center. Individuals with post-HT malignancy were subcategorized to include de novo solid tumors, post-transplant lymphoproliferative disorder (PTLD), donor related tumors, recurrence of pretransplant malignancy, and “Malignancy but, Type unknown.” Patients with de novo solid tumors were classified by their solid-organ subtype. Solid-organ subtypes that comprised 1% or greater of all solid-organ malignancies were included in the analysis as discrete tumor sub-types.

Patients whose malignancy status was unknown or who had greater than 1 malignancy post-transplant were excluded from all analyses. Among patients with post-transplant malignancy, patients with donor related malignancies and recurrence of pretransplant malignancy were summarized, but not included in regression or time to event analyses due to low frequency. Patients with unknown malignancy types (“Malignancy but, Type unknown”) were also excluded from regression and time to event models given lack of differentiation of malignancy subtype.

The primary outcomes were overall incidence of and risk factors for de novo malignancy after HT. Secondary outcomes included overall incidence and risk factors for solid tumors, PTLD, and individual solid-organ tumor subtypes. Donor and transplant recipient characteristics were compared between patients with or without post-HT malignancy. Donor and recipient characteristics evaluated included age, sex, race, history of cigarette use, and EBV serostatus at time of transplantation. Additional recipient characteristics assessed included treatment for rejection, hospitalization for infection, and induction immunosuppression (including IL-2 receptor antagonist, polyclonal antibodies, and monoclonal antibodies) as documented in the UNOS registry. All available follow up data from the UNOS registry were used for time to event analyses. HT recipients who did not develop any malignancy were censored at the end of the data collection period (October 2019).

All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary NC). Baseline characteristics were summarized using counts and percentages, means and standard deviations. The differences between the malignancy free and post-HT malignancy were compared using the Chi-squared tests and Student’s t-tests for categorical and continuous variables, respectively. Multivariable analyses for de novo malignancy after transplant assessing covariates including recipients’ age, gender, race, history of cigarette use, primary insurance, time of transplant, EBV status at time of transplantation, induction immunosuppression, post-transplant hospitalization for infection, and treatment for rejection, as well as donors’ age, gender, race, and history of cigarette use were performed using logistic regressions. Additionally, given immunosuppressive regimens have changed greatly over the decades with mycophenolate, tacrolimus, and everolimus being introduced and popularized in the late 1990s and early 2000s, we included an early era (1987-2003) and current era (2004-current) in the multivariable analysis. ^,, Time to post-transplant malignancy were assessed using the Fine-Gray regressions after consideration of the events of death and graft failure. Multicollinearity was assessed. Statistical significance was established at the 2-sided 5% level, and no multiplicity adjustments were made.

Of 63,947 patients who underwent HT in the study period, 50,370 had reported post-HT malignancy status and were included in the study. A total of 12,212 (24.2%) developed malignancies including 9,910 (19.7%) patients with de novo solid tumors and 971 (1.9%) patients with PTLDs ( Figure 1 ). Baseline clinical and demographic characteristics of 12,212 patients who developed de novo malignancies and 38,158 patients without malignancy after HT are shown in Table 1 . There were 1,186 patients with malignancies in which the underlying pathology was unknown, 129 patients with recurrence of pretransplant malignancies, and 16 patients with donor related malignancies; these patients were excluded from further analysis. Patients who developed malignancies after HT treatment were older (mean 55.9 years [standard deviation 9.3] vs 50.8 [12.7], P <.001), more likely to be male (85% vs 73%, P <.001), more likely to be white (90% vs 68%, P <.001), and less likely to not have used cigarettes (32% vs 16%, P <.001) compared to patients with no malignancy. Significant differences were also observed in the proportion of patients with induction immunosuppression, hospitalization for infection, and treatment for rejection between the 2 groups (all P -values <.001). De novo malignancy types post-HT are depicted in Table 2 . Nonmelanoma skin cancer (NMSC) (58%) was the most common malignancy overall, while lung (10%) and prostate (9%) cancer were the most common solid organ tumors.

Consort flow diagram. The inclusion and exclusion criteria of this study yielded 63,947 individuals who underwent heart transplantation, of which 50,370 had known post-HT malignancy status.

Among patients with malignancies, 10,743 had a documented date of diagnosis; the overall incidence of de novo malignancies among this patient population was 7.6%, 43.4%, and 75.4% at 1, 5, and 10 years, respectively ( Figure 2 ). The 10-year cumulative incidences of PTLD (73.6%) and de novo solid organ tumors (73.3%) were similar ( Figure 2 ).

KM Curve of Time to Malignancy Cumulative Incidence Among All De Novo Malignancy.

In a multivariable analysis, recipients with older age (OR, 1.052; 95% CI, 1.049-1.06), male gender (female vs male; OR, 0.63; 95% CI, 0.58-0.68), history of cigarette use (OR, 1.19; 95% CI, 1.11-1.27), private insurance (OR, 1.21; 95%CI, 1.14-1.30), induction immunosuppression with OKT3 (OR, 1.47; 95%CI, 1.23-1.76) or >1 induction agent (OR, 1.44; 95%CI, 1.14-1.82), and hospitalization for infection (OR, 1.25; 95% CI, 1.18-1.33) were more likely to develop de novo malignancy. White recipient race led to increased risk when compared to all other races and ethnicities. Additionally, younger donor age (OR, 0.99; 95% CI, 0.99-1.00) and induction immunosuppression with IL-2 receptor antagonist (OR, 0.90; 95% CI, 0.84-0.97) were associated with decreased risk of de novo malignancy. Treatment for rejection was not associated with an increased likelihood for malignancy ( Table 3 ). The incidence of de novo malignancy at 10 years post-transplant was greater in the current era compared to the early era (22.55% vs. 18.33%, P <.001) ( Figure 2 ).

PTLD accounted for 7.9% of all de novo malignancies after HT. In multivariable analysis, male gender (female vs male; OR, 0.64; 95% CI, 0.49-0.83) and female donor (OR, 1.39; 95% CI, 1.11-1.74) was associated with increased risk of PTLD ( Table 3 ). Pretransplant EBV seropositivity (OR, 0.39; 95% CI, 0.30-0.5) and self-identified Black (OR, 0.42; 95% CI, 0.30-0.59) as well as Hispanic (OR, 0.60; 95% CI, 0.40-0.91) recipient race was associated with a decreased risk of PTLD ( Table 3 ).

Solid tumors accounted for 81.1% of all de novo malignancies after HT. Of these, 58% were NMSC. In multivariable analysis, recipient characteristics including age (OR, 1.06; 95% CI, 1.05-1.06), male gender (female vs male; OR, 0.62; 95% CI, 0.57-0.68), induction immunosuppression with OTK3 (OR, 1.51; 95% CI, 1.26-1.81) or >1 induction agent (OR, 1.41; 95% CI, 1.10-1.81), hospitalization for infection (OR, 1.22; 95% CI, 1.14-1.30), and private recipient insurance (OR, 1.23; 95%CI, 1.16-1.31) were associated with increased risk. Younger donor age (OR, 0.994; 95% CI, 0.991-0.996) and induction immunosuppression with IL-2 receptor antagonist (OR, 0.91; 95% CI, 0.84-0.98) were associated with decreased risk ( Table 3 ).

Risk factors for individual solid-organ tumors are shown in Table 4 . Recipient age was associated with increased risks for bladder, breast, colorectal, lung, melanoma, pancreatic, prostate, and NMSC. Female recipient gender was associated with increased risk for breast and thyroid and decreased risk for bladder, renal, and melanoma. Recipient hospitalization for infection was associated with increased risk for lung, prostate, renal cancer, and NMSC. Induction immunosuppression with OKT3 was associated with increased risk of bladder, colorectal, and NMSC. Induction immunosuppression with >1 immunosuppressive drug was associated with increased risk of breast and lung cancer. Induction immunosuppression with IL-2 receptor antagonist alone was associated with decreased risk of prostate cancer. Treatment for rejection was not associated with any solid-organ malignancy subtypes. There were higher rates of colorectal, lung, pancreatic, prostate, renal cell, and thyroid in the current era compared to early era. ( Table 5 ).

Table 4

Risk factors for solid-organ malignancy subtypes after heart transplantation.

	Bladder ( n = 189)			Breast § ( n = 226)			Colorectal ( n = 219)			Lung ( n = 1,008)			Melanoma ( n = 307)
	OR (95% CI)		P- value	OR (95% CI)		P- value	OR (95% CI)		P- value	OR (95% CI)		P- value	OR (95% CI)		P- value
Recipient
Age, y	1.07	(1.04, 1.1)	<.001	1.05	(1.03, 1.07)	<.001	1.05	(1.03, 1.08)	<.001	1.07	(1.05, 1.08)	<.001	1.04	(1.03, 1.06)	<.001
Female	0.48	(0.25, 0.92)	.027	36.69	(18.5, 72.76)	<.001	1.22	(0.77, 1.93)	.39	1.21	(0.97, 1.51)	.084	0.44	(0.28, 0.7)	<.001
Race (Ref = White) *
Black	0.56	(0.29, 1.08)	.08	0.69	(0.44, 1.09)	.11	1.40	(0.88, 2.24)	.16	0.72	(0.56, 0.93)	.011	Not estimable
Other	0.58	(0.27, 1.27)	.18	0.66	(0.34, 1.3)	.23	0.36	(0.13, 0.99)	.047	0.35	(0.23, 0.54)	<.001	0.12	(0.05, 0.34)	<.001
History of cigarette use (Ref = No)
Yes	2.63	(1.44, 4.8)	.002	1.22	(0.79, 1.9)	.37	1.57	(0.91, 2.69)	.10	6.74	(4.79, 9.49)	<.001	1.00	(0.71, 1.42)	.99
Unknown	3.85	(1.76, 8.46)	<.001	2.68	(1.42, 5.06)	.003	0.78	(0.36, 1.66)	.51	2.31	(1.49, 3.59)	<.001	1.86	(1.07, 3.24)	.028
EBV status (Ref = Negative)
Positive	0.75	(0.39, 1.44)	.39	1.174	(0.64, 2.17)	.61	0.70	(0.39, 1.25)	.23	0.93	(0.69, 1.24)	.60	0.88	(0.56, 1.39)	.59
Not done	1.56	(0.77, 3.19)	.22	1.01	(0.49, 2.09)	.98	0.61	(0.3, 1.24)	.17	1.15	(0.82, 1.6)	.43	0.91	(0.51, 1.6)	.73
Hospitalization for infection	1.42	(0.95, 2.13)	.09	1.24	(0.86, 1.78)	.25	1.08	(0.72, 1.62)	.69	1.22	(1.02, 1.45)	.032	1.14	(0.83, 1.55)	.42
Treated for rejection	0.72	(0.36, 1.45)	.35	0.80	(0.43, 1.48)	.47	0.88	(0.48, 1.6)	.67	1.15	(0.87, 1.53)	.32	0.84	(0.46, 1.52)	.57
Induction immunosuppression (Ref = Steroids/None) †
IL2 R antagonist	1.02	(0.58, 1.79)	.95	0.93	(0.59, 1.45)	.74	0.86	(0.51, 1.45)	.57	0.97	(0.78, 1.2)	.76	0.96	(0.66, 1.4)	.83
Antithymoglobulin	1.09	(0.66, 1.82)	.73	0.84	(0.52, 1.36)	.48	1.08	(0.65, 1.81)	.76	0.86	(0.67, 1.09)	.20	1.28	(0.88, 1.86)	.19
OKT3	2.39	(1.01, 5.69)	.048	1.22	(0.46, 3.21)	.69	3.03	(1.39, 6.57)	.005	1.25	(0.77, 2.02)	.37	1.47	(0.65, 3.35)	.36
>1 Immunosuppressive	2.67	(0.81, 8.78)	.11	2.99	(1.14, 7.82)	.026	0.77	(0.11, 5.65)	.80	2.28	(1.31, 3.95)	.004	1.69	(0.61, 4.69)	.31
Other	1.18	(0.55, 2.55)	.67	1.01	(0.5, 2.04)	.98	1.06	(0.51, 2.2)	.89	0.86	(0.61, 1.21)	.38	0.93	(0.46, 1.88)	.84
Primary insurance (Ref = Public) ‡
Private insurance	1.36	(0.9, 2.04)	.14	1.50	(1.04, 2.17)	.031	1.30	(0.88, 1.94)	.19	1.10	(0.4, 3.05)	.86	0.99	(0.14, 7.26)	.99
Other	Not estimable			Not estimable			Not estimable			1.00	(0.84, 1.19)	.97	1.30	(0.96, 1.76)	.10
Transplant Era (1987-2003 vs 2004-2019)	1.23	(0.69, 2.19)	.49	1.30	(0.71, 2.39)	.39	4.02	(2.32, 6.98)	<.001	2.44	(1.93, 3.09)	<.001	1.14	(0.7, 1.88)	.60
Donor
Age, y	1.00	(0.98, 1.02)	.78	0.98	(0.97, 1)	.023	0.99	(0.98, 1.01)	.34	0.99	(0.99, 1)	.055	1.00	(0.99, 1.01)	.72
Female	0.75	(0.45, 1.24)	.26	0.90	(0.62, 1.31)	.59	1.30	(0.84, 2.02)	.24	1.00	(0.81, 1.23)	.999	1.11	(0.79, 1.58)	.55
History of cigarette use (Ref = No)
Yes	1.39	(0.87, 2.21)	.17	1.40	(0.9, 2.18)	.13	0.97	(0.6, 1.58)	.91	1.07	(0.86, 1.33)	.55	0.68	(0.45, 1.04)	.08
Unknown	2.02	(0.49, 8.42)	.33	0.90	(0.12, 6.69)	.92	Not estimable			1.30	(0.6, 2.82)	0.51	0.46	(0.06, 3.3)	.43

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