Hispanic vs. Caucasian Race/Ethnicity in Adrenocortical Carcinoma Patients
ANDREA PANUNZIO1,2, STEFANO TAPPERO2,3,4, CRISTINA CANO GARCIA2,5, MATTIA PICCINELLI2,6, FRANCESCO BARLETTA2,7, REHA-BARIS INCESU2,8, ZHE TIAN2, ALESSANDRO TAFURI1, DERYA TILKI8,9,10, ALBERTO BRIGANTI7, OTTAVIO DE COBELLI6, FELIX K.H. CHUN5,
CARLO TERRONE3,4, FRED SAAD2, SHAHROKH F. SHARIAT11,12,13,14, ISABELLE BOURDEAU15, MARIA ANGELA CERRUTO1, ALESSANDRO ANTONELLI1 and PIERRE I. KARAKIEWICZ2
1 Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy;
2Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montreal, QC, Canada;
3Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genova, Genoa, Italy; 4Department of Urology, IRCCS Policlinico San Martino, Genoa, Italy;
5 Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany;
6 Department of Urology, IEO European Institute of Oncology, IRCCS, Milan, Italy;
7Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy;
8Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 9Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
10Department of Urology, Koc University Hospital, Istanbul, Turkey;
11 Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;
12 Department of Urology, Weill Cornell Medical College, New York, NY, U.S.A .;
13 Department of Urology, University of Texas Southwestern, Dallas, TX, U.S.A .;
14Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan; 15 Division of Endocrinology, Department of Medicine and Research Center,
Centre Hospitalier de l’Université de Montreal (CHUM), Montreal, QC, Canada
Abstract. Background/Aim: In primaries other than adrenocortical carcinoma (ACC), Hispanic race/ethnicity may predispose to higher stage at initial diagnosis and may result in worse survival. We tested the association between Hispanic race/ethnicity and cancer specific mortality (CSM) in ACC patients in addition to testing for differences in other-cause mortality (OCM) rates between Hispanics and Caucasians. Patients and Methods: Within Surveillance, Epidemiology, and End Results database (2004-2018), we identified 1,060 ACC patients: 167 (15.8%) Hispanics vs. 893 (84.2%) Caucasians. Propensity score matching (age, sex, grade, T, N and M stages,
Correspondence to: Andrea Panunzio, MD, Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata di Verona, Piazzale A. Stefani 1, 37126, Verona, Italy. Tel: +1 4385089432, +39 0458127702, email: panunzioandrea@virgilio.it
Key Words: Adrenocortical carcinoma, ACC, hispanics, race.
treatment types), cumulative incidence plots Poisson-smoothing and competing risk regression (CRR) were used. Results: Compared to Caucasians, Hispanics were younger (51 vs. 57 years, p<0.001) and presented higher rates of T3-4 primary tumor stage (52.7% vs. 42.8%, p=0.007). No other statistically significant differences were observed for grade, lymph node invasion, distant metastases, European Network for the Study of Adrenal Tumors (ENSAT) stage and treatment type (p>0.05 in all cases). After matching (1:3), 167 Hispanics and 501 Caucasians remained and were included in CRR analyses. In Hispanics, five-year CSM rates were 38.0% and 78.8% in respectively ENSAT stages I-II and III-IV vs. 34.1% and 74.4% in Caucasians. Overall, five-year OCM rates were 10.7% vs. 9.0% in Hispanics and Caucasians, respectively. In multivariable CRR models, Hispanic race/ethnicity was not an independent predictor for higher CSM (hazard ratio=1.18, p=0.2). Conclusion: In ACC, relative to Caucasians, Hispanic race/ethnicity is associated with lower age at initial diagnosis, but not with higher tumor stage or survival disadvantage.
Hispanics are the largest, youngest, and most rapidly growing ethnic minority in the United States (US) (1, 2). Hispanic race/ethnicity represents an established risk factor for cancer inequalities due to worse socio-economic status, higher percentage of uninsured and other barriers to optimal quality of care (1-4). For example, in several primaries Hispanics are less likely to be diagnosed at early stages, when treatment is usually less intensive and most successful. This relationship applies to melanoma (5), breast cancer (6), as well as to renal cell carcinoma (7) and prostate cancer (8). However, cancer incidence and mortality rates among Hispanics are generally lower or at least highly comparable with those recorded among Caucasians (9). This phenomenon is well-known as the Hispanic paradox (10, 11).
To date, no large-scale contemporary analyses have specifically focused on the association between Hispanic race/ethnicity and stage at presentation and/or mortality in adrenocortical carcinoma (ACC). We addressed this knowledge gap and tested whether Hispanic race/ethnicity is an independent predictor of higher cancer specific mortality (CSM) in ACC patients. We hypothesized that Hispanics may present with worse tumor stage and grade, not receive the same treatment intensity and experience higher CSM than their Caucasian counterparts. Additionally, to address the effect of non-cancer related mortality, we also quantified the contribution of other-cause mortality (OCM), according to Hispanic vs. Caucasian race/ethnicity. All comparisons were performed in the entire cohort, as well as in stage- specific fashion: ENSAT (European Network for the Study of the Adrenal Tumors (12)) stage I-II vs. III-IV. All analyses relied on data from the Surveillance, Epidemiology and End Results (SEER) database (2004-2018) (13).
Patients and Methods
Study population. The SEER database samples 48% of the US and approximates the US in terms of its demographic composition, as well as its cancer incidence (13). Within the SEER database (2004-2018), we identified patients with histologically confirmed ACC [International Classification of Disease for Oncology (ICD-O-3) site code C74.0/C74.9; histologic code: “8370/3: Adrenal cortical carcinoma”, “8010/3: Carcinoma, NOS”, and “8140/3: Adenocarcinoma, NOS”]. Patients aged <18 years, with unknown vital status, as well as autopsy only cases or race/ethnicity other than Hispanic or Caucasian were excluded. These selection criteria resulted in an overall cohort of 1,060 assessable patients: 167 Hispanics vs. 893 Caucasians.
Statistical analyses. Descriptive statistics included frequencies and proportions for categorical variables. Medians and interquartile ranges (IQR) were reported for continuously coded variables. Wilcoxon rank sum test, Pearson’s Chi-squared test and Fisher’s exact test examined the statistical significance of differences in medians and proportions, respectively. We relied on propensity score matching (PSM) to nearest neighbor between Hispanics and Caucasians, reducing the effect of selection bias. Here, PSM was applied for age at diagnosis, sex, grade, T, N and M stage, and type of treatment. A threshold of <0.1 in
standardized mean difference, which is indicative of clinically insignificant variability, was used (14). Subsequently, cumulative incidence plots and competing risk regression (CRR) models were fitted and tested for differences in CSM between Hispanics and Caucasians. Adjustment was made for OCM in addition to all available covariates. Finally, we relied on Poisson smoothed cumulative incidence plots to depict CSM relative to OCM within the entire cohort, as well as according to two specifics ENSAT stage groupings: I-II vs. III-IV. All tests were two-sided with a level of significance set at p<0.05. R software environment for statistical computing and graphics (version 4.1.2) was used for all analyses (15).
Results
Descriptive characteristics of the study population. Compared to Caucasians, Hispanics were younger [51 (IQR=40-62) vs. 57 (IQR=47-67) years, p<0.001] and harbored higher rates of more advanced primary tumor stage at initial diagnosis (52.7% vs. 42.8% T3-4, p=0.007; Table I). No statistically significant or clinically meaningful differences were recorded for sex, marital status, tumor grade, lymph node invasion, distant metastases, ENSAT stage, and type of treatment. All 167 Hispanics patients were matched in 1:3 fashion with 501 Caucasian patients. After PSM no statistically significant differences remained (Table I).
The effect of Hispanic vs. Caucasian race/ethnicity on CSM across all stages prior to and after propensity score matching. Prior to PSM, five-year CSM rates were 62.4% vs. 59.0% in Hispanics and Caucasians, respectively (p=0.3). After PSM, five-year CSM rates were 62.4% vs. 59.4% in Hispanics and Caucasians, respectively (p=0.3; Figure 1). After matching, multivariable CRR models addressing CSM that additionally adjusted for age, sex, marital status, tumor grade, T and N stages, ENSAT stage, type of treatment and adjuvant radiotherapy administration, showed no statistically significant differences between Hispanics vs. Caucasians: HR=1.18 [95% confidence interval (CI) 0.92-1.53, p=0.2].
The effect of Hispanic vs. Caucasian race/ethnicity on CSM and OCM according to stage after propensity score matching. Poisson smoothed cumulative incidence plots quantified the relative contribution of CSM vs. OCM, in Hispanics and subsequently in Caucasians. In both race/ethnicities data were stratified according to ENSAT I-II vs. ENSAT III-IV stages (Figure 2). In Hispanics, five-year CSM rates were 38.0% and 78.8% in respectively ENSAT stages I-II and III-IV. Similarly, in Caucasians five-year CSM rates were 34.1% and 74.4% in ENSAT stages I-II and III-IV, respectively. In multivariable CRR models addressing CSM according to stage, Hispanic race/ethnicity was associated with a HR of 1.20 (95% CI=0.71- 2.04; p=0.5) and 1.26 (95% CI=0.95-1.67; p=0.1) in respectively ENSAT stage I-II and III-IV, relative to Caucasians. In Hispanics, five-year OCM rates were 12.0% and 8.3% in
| Characteristic | Prior to propensity score matching | After propensity score matching | |||
|---|---|---|---|---|---|
| Overall cohort (n=1,060) | Overall cohort (n=668) | ||||
| Hispanics n=167 (15.8)1 | Caucasians n=893 (84.2)1 | p-Value2 | Hispanics n=167 (25.0)1 | Caucasians n=501 (75.0)1 | |
| Age at diagnosis (years) | 51 (40, 62) | 57 (47,67) | <0.001 | 51 (40, 62) | 51 (42, 621) |
| Sex | 0.07 | ||||
| Female | 112 (67.1) | 531 (59.5) | 112 (67.1) | 340 (67.9) | |
| Male | 55 (32.9) | 362 (40.5) | 55 (32.9) | 161 (32.1) | |
| Marital status | 0.2 | ||||
| Married | 90 (53.9) | 546 (61.1) | 90 (53.9) | 299 (59.7) | |
| Unmarried | 70 (41.9) | 317(35.5) | 70 (41.9) | 186 (37.1) | |
| Unknown | 7 (4.2) | 30 (3.4) | 7 (4.2) | 16 (3.2) | |
| Grade | 0.2 | ||||
| G1-2 | 8 (4.8) | 69 (7.7) | 8 (4.8) | 28 (5.6) | |
| G3-4 | 33 (19.8) | 139 (15.6) | 33 (19.8) | 101 (20.2) | |
| GX | 125 (75.4) | 685 (76.7) | 125 (75.4) | 372 (74.2) | |
| T stage | 0.007 | ||||
| T1 | 9 (5.4) | 52 (5.8) | 9 (5.4) | 29 (5.8) | |
| T2 | 58 (34.7) | 356 (39.9) | 58 (34.7) | 183 (36.5) | |
| T3 | 31 (18.6) | 192 (21.5) | 31 (18.6) | 92 (18.4) | |
| T4 | 57 (34.1) | 190 (21.3) | 57 (34.1) | 159 (31.7) | |
| TX | 12 (7.2) | 103 (11.5) | 12 (7.2) | 38 (7.6) | |
| Lymph node invasion | 25 (15.0) | 103 (11.5) | 0.4 | 25 (15.0) | 73 (14.6) |
| Distant metastasis | 67 (40.1) | 328 (36.7) | 0.4 | 67 (40.1) | 183 (36.5) |
| ENSAT stage | 0.8 | ||||
| Stage I | 8 (4.8) | 37 (4.1) | 8 (4.8) | 20 (4.4) | |
| Stage II | 42 (25.1) | 264 (29.6) | 42 (25.1) | 135 (26.9) | |
| Stage III | 43 (26.9) | 219 (24.5) | 43 (26.9) | 141 (28.1) | |
| Stage IV | 67 (40.1) | 328 (36.7) | 67 (40.1) | 183 (36.5) | |
| Unknown | 7 (3.1) | 45 (5.1) | 7 (3.1) | 22 (4.1) | |
| Type of treatment | 0.7 | ||||
| None/unknown | 21 (12.6) | 125 (14.0) | 21 (12.6) | 56 (11.2) | |
| Systemic therapy only | 26 (15.6) | 117 (13.1) | 26 (15.6) | 70 (14.0) | |
| Adrenalectomy only | 69 (41.3) | 395 (44.2) | 69 (41.3) | 222 (44.3) | |
| Adrenalectomy + systemic therapy | 51 (30.5) | 256 (28.7) | 51 (30.5) | 153 (30.5) | |
| Adjuvant radiotherapy | 19 (11.4) | 104 (11.6) | 0.9 | 19 (11.4) | 49 (9.7) |
1Median (IQR); n (%) 2Wilcoxon rank sum test; Pearson’s Chi-square test; Fisher’s exact test. ENSAT, European Network for the Study of Adrenal Tumors.
respectively ENSAT stages I-II and III-IV. Similarly, in Caucasians five-year OCM rates were 5.6% and 10.4% in ENSAT stages I-II and III-IV, respectively. In multivariable CRR models addressing OCM according to stage, Hispanic race/ethnicity was associated with a HR of 1.29 (95% CI=0.45- 3.75; p=0.6) and 0.67 (95% CI=0.30-1.53; p=0.4) in respectively ENSAT stage I-II and III-IV, relative to Caucasians.
Discussion
Hispanic race/ethnicity represents a determinant of disparities in access to care, as well as a risk factor for less favorable tumor stage at presentation, without apparently
affecting survival (1, 2). However, whether these relationships are also applicable to ACC is unknown. We hypothesized that Hispanics with ACC present with higher tumor stage and grade, do not receive the same treatment intensity and experience higher mortality than their Caucasian counterparts. We tested these hypotheses within SEER. Our observations are as follows.
First, we identified 167 (15.8%) Hispanics and 893 (84.2%) Caucasians within SEER. These individuals account for the vast majority of ACC patients. In previous north American based-population studies addressing ACC demographics, African Americans and Asians only represented 7-9% and 3- 7% of all ACC patients, respectively (16-19). Therefore, these
1.000
5 year CSM in Caucasians: 59.4%
5 year CSM in Hispanics: 62.4%
5 year OCM in Caucasians: 9.0%
0.750
5 year OCM in Hispanics: 10.7%
HR=1.13 (0.90-1.43), p=0.3
Probability
0.500
0.250
HR=0.98 (0.55-1.75), p=0.9
0.000
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
Caucasians
501
301
213
156
131
110
90
76
67
53
40
31
23
12
4
0
Hispanics
167
86
55
37
26
24
19
14
10
9
8
7
4
0
0
0
findings indicate that Hispanic race/ethnicity, that is the second largest ethnic minority in US after Caucasian, is also associated with the second highest ACC prevalence rate after Caucasian. These observations highlight the importance of Hispanic race/ethnicity as a potential independent risk factor for unfavorable cancer control outcomes. Instead, in more historical ACC reports Hispanic patients were unaccounted for and distributed in an unknown fashion between Caucasians and African Americans (20). To the best of our knowledge, the current manuscript represents the first formal attempt to test this hypothesis relying on the most unbiased methodology, within a very large study cohort.
Second, compared to Caucasians, Hispanics were younger (51 vs. 57 years, p<0.001). This observation regarding Hispanics also applies to several malignancies other than ACC, such as renal cell carcinoma (7), bladder cancer (21), colorectal cancer (22) and breast cancer (23) and could led to important considerations regarding cancer prevention and control. However, it is unlikely that this observation truly reflects earlier disease onset or diagnosis. Instead, some postulated that this phenomenon is mainly related to the younger age structure of Hispanic population (24).
Third, Hispanics present with more advanced primary tumor stage at initial diagnosis than their Caucasian
counterparts (52.7% vs. 42.8% T3-4, p=0.007). Conversely, Hispanics do not exhibit differences in tumor grade, lymph node invasion or distant metastases rates relative to Caucasians. In consequence, ENSAT stage groupings between Hispanics and Caucasians are highly comparable since they are based on input from these variables.
Fourth, the distribution of treatment modalities among Hispanics virtually perfectly corresponded to that recorded in Caucasians. Specifically, no statistically significant differences were observed for adrenalectomy only, systemic therapy only, combination of both adrenalectomy and systemic therapy and adjuvant radiotherapy rates. Therefore, the current findings rejected the original hypothesis that Hispanics with ACC may not benefit of the same treatment modalities and intensity as Caucasians. These observations cannot be directly compared with previous analyses addressing ACC, since no such analyses exist. However, in other primaries, Hispanic race/ethnicity independently predicted lower rates of surgical management or longer delays to active treatment (25, 26). For example, Obrochta et al. demonstrated that Hispanics with colorectal cancer were at increased risk of undertreatment [odds ratio (OR)=1.17] or treatment delay (OR=1.50) than their Caucasian counterparts (25). Similarly, Buac et al. found that
a
Stage I-II
Stage III-IV
0.0
0.0
0.2
0.2
Rates
0.4
Rates
0.4
0.6
0.6
0.8
0.8
1.0
CSM: 38%
OCM: 12%
1.0
CSM: 78.8%
OCM: 8.3%
0
12
24
36
48
60
0
12
24
36
48
60
Time (months)
Time (months)
b
Stage I-II
Stage III-IV
0.0
0.0
0.2
0.2
Rates
0.4
Rates
0.4
0.6
0.6
0.8
0.8
1.0
CSM: 34.1%
OCM: 5.6%
1.0
CSM: 74.4%
OCM: 10.4%
0
12
24
36
48
60
0
12
24
36
48
60
Time (months)
Time (months)
relative to Caucasians, Hispanics experienced a 30% higher rate of treatment delay in muscle invasive bladder cancer (26). Taken together, observations made with the current ACC data indicate no differences in treatment type or intensity between Hispanics vs. Caucasians.
Fifth, in analyses addressing the entire ACC cohort regardless of stage, five-year CSM was 62.4% in Hispanics vs. 59.4% in Caucasians. Despite this apparent rate difference favoring better survival in Caucasians, multivariable adjustment resulted in no CSM differences
between Hispanics and Caucasians either in analyses within the entire cohort across all stages, and in comparisons made in stage specific fashion. Taken together, these findings indicate the absence of a survival disadvantage in Hispanic ACC patients relative to Caucasians. Our data cannot be directly compared to previous ACC specific analyses since no such analyses have been performed. Other studies with different primary objectives occasionally included Hispanic race/ethnicity as a covariate. In those non-dedicated analyses Hispanic race/ethnicity was not clearly associated with worse
outcomes relative to not Hispanic patients (19). Finally, the observations of the current study are different from analyses addressing CSM in other primaries than ACC where a CSM disadvantage in Hispanics was recorded (1, 2).
Last but not least, we also examined OCM rates according to Hispanic vs. Caucasian race/ethnicity. Here, no differences in OCM rates were identified in univariable, as well as in multivariable analyses that either addressed the entire population or specific ENSAT stage groupings. To the best of our knowledge, the current study represents the first attempt to analyze OCM in ACC in a race/ethnicity specific fashion, as well as in a stage specific fashion. These OCM observations indicate that younger age at diagnosis in Hispanic patients vs. Caucasians does not result in unreconcilable differences between these two race/ethnicity groups, when OCM represents an endpoint. In consequence, future analyses addressing Hispanic vs. Caucasian population differences that focused on CSM do not invariably need to rely on CRR methodology where OCM is accounted for intead, such analyses may rely on less methodologically complex and challenging Cox regression model.
Despite the novelty of this study, several limitations needs to be acknowledged. First, despite the large scale of the SEER database, the overall recorded number of ACC patients was relatively small. To compensate for sample size limitations, oversampling of race/ethnicities minorities might allow better powered future comparisons. Based on sample size limitations, stratification of outcomes according to ENSAT I vs. II and ENSAT III vs. IV stages groupings was not possible. Second, grade assignment in the SEER database does not reflect the World Health Organization grade assignment recommendations for ACC (27). Nonetheless, in the current analysis grade exhibited the expected association in both univariable and multivariable CRR analyses predicting CSM. In consequence, SEER grade was included in all multivariable models in the current study. Third, no data regarding comorbidities or environmental risk factors (28), as well as socioeconomic status, insurance type, education level, and residential urbanicity (19) that might have potentially affected health care access or quality of care within different race/ethnicity groups was available within SEER. Other limitations related to the retrospective nature of the SEER apply to the current study, as well as to other analyses based on similar large-scale databases.
Conclusion
The current study represents the first formal analysis to address the importance of Hispanic race/ethnicity as a potential risk factor for worse cancer control outcome in ACC. Specifically, we demonstrated that in ACC relative to Caucasian, Hispanic race/ethnicity is associated with lower age at initial diagnosis, but not with higher tumor stage, treatment disparities or survival disadvantage.
Conflicts of Interest
The Authors declare that there are no conflicts of interest.
Authors’ Contributions
AP - conceptualization, methodology, formal analysis, writing original draft, writing review, editing and visualization. ST - writing review, editing and visualization. CCG - writing review, editing and visualization. MP - writing review, editing and visualization. FB - writing review, editing and visualization. RBI - writing review, editing and visualization. ZT - methodology, software, validation, formal analysis, and resources. AT - writing review, editing and visualization. DT - writing review, editing and supervision. AB - writing review, editing and supervision. ODC - writing review, editing and supervision. FC - writing review, editing and supervision. CT - writing review, editing and supervision. FS - writing review, editing and supervision. SS - writing review, editing and supervision. IB - writing review, editing and supervision. MAC - writing review, editing and supervision. AA - writing review, editing and supervision. PK - writing review, editing, supervision, project administration and conceptualization. All Authors contributed to the article and approved the submitted version.
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Received August 24, 2022 Revised September 5, 2022 Accepted September 6, 2022