Abstract
Background:
Hispanics/Latinos are a growing yet understudied population in the United States (US). Despite lower socioeconomic status, Hispanics/Latinos tend to have similar or better health outcomes than Non-Hispanic Whites (NHWs). This phenomenon has not been conclusively studied for lung cancer.
Methods:
Using a cohort of patients at Montefiore Medical Center (MMC) in the Bronx, NY, we examined factors related to lung cancer survival by race/ethnicity with an emphasis on Hispanics/Latinos. Subjects were diagnosed with non-small cell lung cancer (NSCLC) between 2004–2017. Demographic and clinical data were obtained from MMC’s clinical systems and tumor-related information from MMC/Einstein’s Cancer Registry. Survival was assessed using Cox proportional hazards modeling adjusted for clinical and sociodemographic factors including smoking. Factors related to survival within each major racial/ethnic group were examined.
Results:
Hispanics/Latinos experienced decreased risk of death relative to NHWs [hazard ratio (HR)=0.70, 95% confidence interval (95%CI): 0.57–0.86] overall and by sex (males: HR=0.78, 95%CI: 0.59–1.03, females: HR=0.61, 95%CI: 0.44–0.86). Decreased risk among Hispanics/Latinos relative to NHWs was evident in never-smokers (HR=0.55, 95%CI: 0.29–1.01), ever-smokers (HR=0.72, 95%CI: 0.57–0.90), younger subjects (HR=0.73, 95%CI: 0.54–0.99), and older subjects (HR=0.72, 95%CI: 0.53–0.97). Surgery was associated with improved survival in Hispanics/Latinos (HR=0.60, 95%CI: 0.43–0.85), and smoking with worse survival (HR=1.56, 95%CI: 1.02–2.39). Survival did not differ between Non-Hispanic Blacks and NHWs.
Conclusions:
In a poor urban community, Hispanics/Latinos experience improved survival from NSCLC compared to NHWs, which is not entirely explained by smoking. Future research should investigate the drivers of this benefit and differences in survival by Hispanic/Latino origin.
Keywords: lung, epidemiology, race, ethnicity, mortality
Introduction
Hispanics/Latinos are the fastest growing major demographic group in the United States (US), comprising over 15% of the US population and projected to make up nearly one-third of the population by 2050[1]. While socioeconomic status (SES) is a known predictor of adverse health outcomes, Hispanics/Latinos often experience similar or better health outcomes compared to Non-Hispanic Whites (NHWs) despite a lower average SES[2, 3]. This growing body of literature was recently summarized in a meta-analysis of 58 studies (consisting of over 4 million participants), where Hispanic populations were found to have a 17.5% lower risk of mortality compared to those of other racial/ethnic groups[4]. Potential hypotheses to explain this survival advantage include differences in genetic, behavioral (e.g. diet, smoking), and social characteristics of Hispanics/Latinos compared to other racial/ethnic groups[5, 4, 6, 7].
Hispanics/Latinos have approximately 50% lower age-adjusted incidence and mortality rates of lung cancer compared to NHWs[8, 9]. Using the Surveillance, Epidemiology, and End Results (SEER) database, Saeed et al. showed that after adjustment for age, sex, stage and histology, Hispanics/Latinos with non-small cell lung cancer (NSCLC) have greater survival and Blacks worse survival than NHW patients[10]. However, there have been conflicting reports in the literature regarding the relationship between Hispanic/Latino ethnicity and NSCLC survival, including within SEER itself[11–13]. Our recent meta-analysis suggested an association between Hispanic/Latino ethnicity and reduced risk of death in lung cancer[14]. Notably, this analysis highlighted that there is a critical need to further understand survival in Hispanics/Latinos with NSCLC after adjustment for important clinical and demographic variables such as smoking.
The goal of the present study was to assess the roles of race and ethnicity in NSCLC survival and factors related to NSCLC survival, using a cohort of patients at Montefiore Medical Center (MMC) in the Bronx, NY. There are about 800,000 Hispanics/Latinos living in Bronx County, New York, comprising 55% of the county population[15]. The Bronx Hispanic/Latino population is diverse, with Puerto Ricans being the most represented (46%), followed by Dominicans (31%), and Mexicans (9%), with the remaining Hispanic/Latino nationalities combined at 14%[16]. MMC is an academic institution and serves as the University Hospital for Albert Einstein College of Medicine that provides healthcare to more than two million people living in one of the poorest urban counties in the United States[17, 18].
Materials and Methods
Cohort
The Lung Cancer Clinical Cohort at Montefiore Medical Center (LC3MMC) is comprised of 5,638 patients who were diagnosed with lung cancer from January 1, 2004 through February 2017. To be eligible for inclusion in the LC3MMC, subjects had to 1) be diagnosed with incident primary lung cancer (ICD-10 Site Codes C34.0-C34.9), 2) be at least 18 years old at diagnosis, 3) be diagnosed with any American Joint Committee on Cancer (AJCC) stage other than 0, 4) be diagnosed with ICD-O morphology indicating carcinoma, and 5) have no prior history of cancer other than non-melanoma skin cancer. There were no exclusion criteria based on sex, race, or ethnicity. Ultimately, LC3MMC consisted of 5,102 subjects. Study approval was obtained from the Institutional Review Board at Albert Einstein College of Medicine.
Data Sources and Harmonization
Demographic data were obtained from MMC’s electronic medical records (EMR), collected by the registrar. Demographic variables include sex, race, ethnicity, marital status, language preference, and SES. Race (White, Black, Asian, Native Hawaiian/Pacific Islander, Native American/Alaskan Native) and ethnicity (Non-Hispanic, Hispanic/Latino) were self-reported and harmonized into one variable with mutually exclusive categories [Non-Hispanic Whites, Non-Hispanic Blacks (NHBs), Non-Hispanic Asians, Non-Hispanic Native Hawaiian/Pacific Islanders, Non-Hispanic Native American/Alaskan Natives, and Hispanics/Latinos of any race]. In addition, Velos, a clinical research management software for patients enrolling in clinical trials, was cross-referenced with subjects of unknown race and/or ethnicity. This enabled us to re-classify subjects from an unknown race to a known race in 26 instances and from unknown ethnicity to known ethnicity in 20 instances. Marital status was dichotomized as not married (divorced, legally separated, single, widowed, or other) or married/significant other. Language preference was categorized as English or Not English for the main analyses and, for analyses of Hispanics/Latinos, English versus Spanish language preference. SES was based upon the patient’s census block group and is reported as a summary z-score relative to the New York State mean using 6 variables (more details in Online Resource 1) [19].
Tumor-related information was obtained from MMC/Einstein’s Cancer Registry. Clinical data include age at diagnosis, year of diagnosis, smoking status (never, former, current), cancer stage and histology, treatment history, and vital status at the time of last contact. To protect patients’ identities, dates of birth, diagnosis, treatment, and last contact were skewed negatively in a random interval of up to 365.25 days, with the skewing interval consistent for each set of dates per patient. Cancer stage was classified from AJCC stage into local (stage I and II), regional (stage III), distant (IV), and other/unknown. Histology was classified as non-small cell, small cell, and other/unspecified based on the subject’s ICD-O-3 morphology codes (Online Resource 2). NSCLC cases were further classified as squamous cell carcinoma, adenocarcinoma, and other/unspecified. The ICD-O-3 codes were cross-referenced with the histology variable and if the ICD code was listed as 99999 (“not listed in ICD-O-3”) but had a non-missing histology, it was subsequently reclassified based on the histology variable (n = 10). Treatment data were categorized as to whether or not the subject had received any chemotherapy, radiation, surgery, and/or palliative care for their lung cancer. These treatments were not mutually exclusive and could be from any course of treatment.
The study outcome was all-cause mortality. Vital status was ascertained by the Montefiore Cancer Registry, which is a Commission on Cancer-accredited program[20] that complies with the standards of the Facility Oncology Registry Data Standards (FORDS)[21]. Follow–up information was required by the Commission on Cancer to be obtained at least annually for all living patients who were administered any of the first treatment course within the Montefiore Health System. Follow-up data reflected the most recent information available to the registry that originated from reported patient hospitalizations, known patient readmissions, contact with the patient’s physician, and/or direct contact with the patient[21]. An additional 311 deaths (6% of all deaths) were noted from MMC’s EMR.
Analytic Dataset
We restricted our analytic cohort to those with known NSCLC (n = 3,554). Furthermore, as our variable of interest was race/ethnicity, we excluded those with unknown race/ethnicity (n = 1,155) and, due to small sample size, Non-Hispanic Native American/Alaskan natives (n = 2) and Non-Hispanic Native Hawaiian/Other Pacific Islanders (n = 2). Our analytic dataset contained 2,395 subjects with NSCLC and known race/ethnicity (Figure 1).
Fig. 1.
Flowchart presenting the selection of subjects for multivariable analysis related to race/ethnicity and survival in Bronx non-small cell lung cancer (NSCLC) patients
Statistical analysis
Associations between baseline demographic and tumor-related characteristics and race/ethnicity were tested using Pearson’s chi-square test for categorical variables and Student’s t test, Mann-Whitney U test, ANOVA or Kruskal-Wallis tests for continuous variables. Survival was computed from the date of diagnosis to the date of death. Subjects who were still alive were censored at the date of last contact. Univariate survival analyses utilized the Kaplan-Meier method, with comparisons made between groups by the log-rank test. Cox proportional hazards models were used to build a multivariable model for the association between the variables of interest and outcome. The Cox proportional hazards model using number of days from diagnosis to death or censoring as the time-scale initially included variables that were significant (p < 0.2) in univariate Cox models: race/ethnicity, age at diagnosis, sex, smoking, stage, receipt of surgery, receipt of chemotherapy, receipt of palliative care, adenocarcinoma histology, and marital status (Online Resource 3). We additionally included SES in our multivariable model as it has often been shown to confound the relationship between race/ethnicity and cancer outcomes[22, 23]. Because former and current smokers had similar univariate HRs and 95% CIs, smoking status was collapsed into never- and ever-smokers. Covariates were removed (other than age and sex, which were to be kept in the model regardless) if they were no longer significant in the multivariable model and did not appear to be a meaningful confounder of our variable of interest (change in beta > 15% in any of the race/ethnicity dummy variables). Then, variables that were not significant in univariate models were added back and kept if the likelihood ratio test was statistically significant and/or the variable was found to be a meaningful confounder. Of note, diagnosis year (5-year intervals) was tested in the model at this stage, but results were not significant and this variable did not confound the association between race/ethnicity and survival. Thus, period effect was not adjusted for in the final model. Cox proportional hazards assumptions were tested using log-log plots and Schoenfeld residuals. Stage, receipt of chemotherapy, and receipt of radiation were found to violate the assumptions, so models were built stratified on those covariates. In a stratified Cox proportional hazards model, we allow each stratum to have its own baseline hazards function; however, the beta coefficients for the variables adjusted for in the model is assumed to be the same across the strata[24]. Although a stratum-specific analysis (e.g. stage-specific results) would allow the exposure-disease association to vary by stratum, we did not have adequate number of events in each stratum. Our final model adjusted for age, sex, adenocarcinoma histology, receipt of surgery, receipt of palliative care, smoking, language preference, and marital status; and our model also accounted for stage, receipt of chemotherapy, and receipt of radiation through stratification. First-order interactions between race/ethnicity and the covariates in the final model were assessed via likelihood ratio tests comparing the model with the product term of the variable of interest and the covariate included and a model without the product term, and with p < 0.10 considered significant. Sub-group analyses were performed by restricting the model to ever-smokers, never-smokers, males, females, age at diagnosis less than the median (68 years), age at diagnosis greater than or equal to the median, adenocarcinomas, and non-adenocarcinomas. We also performed the multivariable model in each major racial/ethnic group (NHWs, Hispanics/Latinos, and NHBs). Sensitivity analyses excluded those censored at less than 1 year of follow-up, other/unknown stage cancers, and cases not required to have annual follow-up as designated by FORDS[21]. All statistical analyses were performed using STATA software, version 15.1. Statistical significance was assumed for a two-tailed p-value less than 0.05.
Results
Of the 2,395 subjects in LC3MMC, the average age at diagnosis was 67.5 (± 11.4) years, 50% were female, and 15% were never-smokers (Table 1). Subjects were most commonly diagnosed with disease of distant stage (37%). The most predominant histology was adenocarcinoma (56%). Chemotherapy was the most common treatment (48%) followed by radiation (44%) and surgery (37%). There were no differences between NHWs, NHBs, Non-Hispanic Asians and Hispanics/Latinos in sex, rates of surgery, and the proportions with adenocarcinoma. NHBs presented at the youngest age (65.5 ± 11.3 years) and NHWs (70.0 ± 11.1) presented at the oldest (p <0.0001). Hispanics/Latinos had the lowest median socioeconomic status (−3.8), followed by NHBs (−2.5), Non-Hispanic Asians (−1.1) and NHWs (−0.6) (p = 0.0001). NHWs were most likely to be diagnosed with disease at a local stage (26%), while 15% of Non-Hispanic Asians, 18% of NHBs and 21% of Hispanics/Latinos were diagnosed at a local stage (p = 0.001). NHBs were the most likely to receive radiation (48%) (p = 0.008). Non-Hispanic Asians were most likely to receive chemotherapy (62%) and palliative care (24%) (p = 0.002, p = 0.005). While proportions of never-smokers were similar among NHWs (13%), NHBs (14%) and Hispanics/Latinos (16%), the majority of Non-Hispanic Asian patients were never-smokers (p < 0.001). Only 18% of Hispanics/Latinos were diagnosed between 2004–2008, compared to 33% of NHWs, 26% of NHBs, and 23% of Non-Hispanic Asians (p < 0.0001). In 43% of Hispanics/Latinos, Spanish was the preferred language. Hispanics/Latinos who preferred Spanish were older (mean 69.2 years versus 64.4, p < 0.0001) and had lower socioeconomic status (median score −4.5 versus −3.4, p=0.006) than Hispanics/Latinos who preferred English.
Table 1.
Characteristics of subjects with non-small cell lung cancer in the analytic cohort within the Lung Cancer Clinical Cohort at Montefiore Medical Center
| All subjectsa (n=2395) | Non-Hispanic Whites (n=871) | Hispanics/Latinos (n=583) | Non-Hispanic Blacks (n=894) | Non-Hispanic Asians (n=47) | p | |
|---|---|---|---|---|---|---|
| Mean (SD) or Median (IQR) | ||||||
| Age at diagnosis (years) | 67.5 (11.4) | 70.0 (11.1) | 66.8 (11.2) | 65.5 (11.3) | 66.7 (11.9) | <0.0001 |
| Socioeconomic statusbc | −1.8 (−5.5, −0.5) | −0.6 (−1.4, −0.5) | −3.8 (−6.6, −1.7) | −2.5 (−6.2, −1.1) | −1.1 (−3.3, 0.0) | 0.0001 |
| N (%) | ||||||
| Sex | ||||||
| Female | 1200 (50) | 421 (48) | 282 (48) | 475 (53) | 22 (47) | 0.15 |
| Male | 1195 (50) | 450 (52) | 301 (52) | 419 (47) | 25 (53) | |
| Stage | 0.001 | |||||
| Local (1 or 2) | 521 (22) | 229 (26) | 123 (21) | 162 (18) | 7 (15) | |
| Regional (3) | 573 (24) | 188 (22) | 140 (24) | 237 (27) | 8 (17) | |
| Distant (4) | 893 (37) | 311 (36) | 210 (36) | 353 (39) | 19 (40) | |
| Other/unstaged | 408 (17) | 143 (16) | 110 (19) | 142 (16) | 13 (28) | |
| Histology | 0.50 | |||||
| Adenocarcinoma | 1334 (56) | 490 (56) | 332 (57) | 482 (54) | 30 (64) | |
| Squamous cell carcinoma | 602 (25) | 213 (24) | 153 (26) | 227 (25) | 9 (19) | |
| Treatmentd | ||||||
| Surgery | 880 (37) | 325 (38) | 234 (40) | 303 (34) | 18 (40) | 0.13 |
| Radiation | 1046 (44) | 340 (40) | 265 (46) | 421 (48) | 20 (44) | 0.008 |
| Chemotherapy | 1141 (48) | 372 (44) | 291 (50) | 450 (51) | 28 (62) | 0.002 |
| Palliative Care | 436 (19) | 126 (15) | 120 (21) | 179 (20) | 11 (24) | 0.005 |
| Smoking Statuse | <0.001 | |||||
| Never-smoker | 348 (15) | 113 (13) | 89 (16) | 124(14) | 22 (52) | |
| Ever-smoker | 1975 (85) | 725 (87) | 484 (84) | 746 (86) | 20 (48) | |
| Languagef | <0.001 | |||||
| English | 2047 (88) | 1213 (96) | 441 (57) | 1205 (99) | 37 (64) | |
| Spanish | 236 (10) | 3 (<1) | 337 (43) | 5 (<1) | 0 | |
| Other | 41 (2) | 54 (4) | 1 (<1) | 3 (<1) | 21 (36) | |
| Marital Statusg | <0.001 | |||||
| Married | 866 (41) | 405 (54) | 183 (36) | 249 (30) | 29 (66) | |
| Not married | 1243 (59) | 346 (46) | 325 (64) | 557 (69) | 15 (34) | |
| Diagnosis Year | <0.001 | |||||
| 2004–2008 | 636 (27) | 287 (33) | 103 (18) | 235 (26) | 11 (23) | |
| 2009–2013 | 1090 (46) | 378 (43) | 281 (48) | 411 (46) | 20 (43) | |
| 2014–2017 | 669 (28) | 206 (24) | 199 (34) | 248 (28) | 16 (34) | |
Race/ethnicity data missing for 1,155 subjects with NSCLC; 4 subjects with NSCLC who were Non-Hispanic Native Hawaiian/Other Pacific Islander or Non-Hispanic Native American/Alaskan Native excluded due to low sample size
Summary score of several variables calculated using census block data (See Online Resource 1)
Data missing for 113 subjects (5% of the sample)
For all treatment variables, data was missing for 38 subjects (2%)
Data missing for 72 subjects (3%)
Data missing for 62 subjects (3%)
Married/significant other versus single/divorced/separated/widowed/other; data missing for 286 subjects (12%)
Hispanic/Latino ethnicity compared to NHWs was associated with a 15% decreased risk of death [hazard ratio (HR) = 0.85, 95% confidence interval (CI): 0.74 – 0.98, p = 0.03] (Online Resource 3, Figure 2). When adjusted for clinical and social factors, Hispanic/Latino ethnicity compared to NHWs was associated with a 30% decreased risk of death (HR = 0.70, 95% CI: 0.57 – 0.86) (Table 2). Non-Hispanic Asian race/ethnicity was also associated with decreased risk of death relative to NHWs (HR = 0.58, 95% CI: 0.36 – 0.95). There were no survival differences between NHBs and NHWs (HR = 1.00, 95% CI: 0.86 – 1.16). Other factors associated with reduced risk of death were adenocarcinoma histology (HR = 0.86, 95% CI: 0.76 – 0.97) and receipt of surgery (HR = 0.55, 95% CI: 0.47 – 0.65). Receiving palliative care was associated with increased risk of death (HR = 1.19, 95% CI: 1.02 – 1.39). No significant interactions were observed.
Fig. 2.
Univariate analysis of survival in non-small cell lung cancer by racial/ethnic group in the Lung Cancer Clinical Cohort at Montefiore Medical Center
Table 2.
Risk of deatha in subjects with non-small cell lung cancer (NSCLC) in the Lung Cancer Clinical Cohort at Montefiore Medical Center
| Variable | N | HR | 95% CI | p-value |
|---|---|---|---|---|
| Race and ethnicity | ||||
| Non-Hispanic White | 634 | 1.00 | Ref | |
| Hispanic/Latino | 452 | 0.70 | 0.57–0.86 | 0.001 |
| Non-Hispanic Black | 752 | 1.00 | 0.86–1.16 | 0.95 |
| Non-Hispanic Asian | 38 | 0.58 | 0.36–0.95 | 0.03 |
| Sex | ||||
| Males | 956 | 1.00 | Ref | |
| Females | 920 | 0.89 | 0.78–1.01 | 0.07 |
| Adenocarcinoma | ||||
| No | 833 | 1.00 | Ref | |
| Yes | 1043 | 0.86 | 0.76–0.97 | 0.02 |
| Surgery | ||||
| No | 1177 | 1.00 | Ref | |
| Yes | 699 | 0.55 | 0.47–0.65 | <0.001 |
| Palliative Care | ||||
| No | 1534 | 1.00 | Ref | |
| Yes | 342 | 1.19 | 1.02–1.39 | 0.03 |
| Smoking status | ||||
| Never-smoker | 295 | 1.00 | Ref | |
| Ever-smoker | 1581 | 1.16 | 0.97–1.38 | 0.10 |
| Language preference | ||||
| English | 1641 | 1.00 | Ref | |
| Not English | 235 | 1.17 | 0.93–1.48 | 0.18 |
| Marital statusb | ||||
| Not married | 1107 | 1.00 | Ref | |
| Married | 769 | 0.90 | 0.79–1.03 | 0.13 |
| Socioeconomic Statusc | 1876 | 1.00 | 0.97–1.02 | 0.72 |
Multivariable model adjusted for age and the above variables in the table and stratified by chemotherapy, radiation, and stage in order to meet proportional hazards assumption.
Married/significant other versus single/divorced/separated/widowed/other
Summary score of several variables calculated using census block data (See Online Resource 1)
Hispanic/Latino ethnicity was associated with a 45% decreased risk of death in never-smokers (HR = 0.55, 95% CI: 0.29 – 1.01), 28% decreased risk in ever-smokers (HR = 0.72, 95% CI: 0.57 – 0.90), 39% decreased risk in females (HR = 0.61, 95% CI: 0.44 – 0.86), and 22% decreased risk in males (HR = 0.78, 95% CI: 0.59 – 1.03) (Table 3). In both younger and older subjects, Hispanic/Latino ethnicity was associated with improved survival (less than 68 years at diagnosis, HR = 0.73, 95% CI: 0.54 – 0.99; 68 years or greater, HR = 0.72, 95% CI: 0.53 – 0.97). In adenocarcinoma cases, Hispanic/Latino ethnicity was not associated with improved survival (HR = 0.85, 95% CI: 0.64 – 1.14). In non-adenocarcinoma cases, Hispanics/Latinos compared to NHWs experienced a 40% decreased risk of death (HR = 0.60, 95% CI: 0.44 – 0.82). Hispanic/Latino ethnicity was associated with a similar risk of death compared to NHWs when restricting to 5-year survival (HR = 0.68, 95% CI: 0.55 – 0.85) (Online Resource 4), as well as when excluding subjects censored at less than 1 year of follow-up (HR = 0.74, 95% CI: 0.60 – 0.92), those with other/unknown stage (HR = 0.71, 95% CI: 0.57 – 0.89), and those who were not required by the Commission on Cancer to have annual-follow up (HR = 0.68, 95% CI: 0.54 – 0.86)[21] (Online Resource 5). The survival advantage in Hispanics/Latinos remained when excluding subjects who had enrolled in a clinical trial (n = 1,706, HR = 0.68, 95% CI: 0.55–0.85). When smoking status (ever/never) was replaced in the multivariable model with a three level-variable (never/former/current), the risk of death for Hispanic/Latino ethnicity remained virtually identical (HR = 0.70, 95% CI: 0.57 – 0.86), and similar estimates of ever-smoking compared to never-smoking were observed (current: HR = 1.24, 95% CI: 1.02 – 1.51; former: HR = 1.11, 95% CI: 0.92–1.34). When categorizing Hispanic/Latino subjects into those who preferred to speak English versus Spanish, survival was similar between the groups, although only the former group experienced significantly improved survival relative to NHWs (Online Resource 6).
Table 3.
Risk of deatha in subjects with non-small cell lung cancer in the Lung Cancer Clinical Cohort at Montefiore Medical Center, stratified by smoking status, sex, age, and histology
| Never-smokers (n=295) | Ever-smokers (n=1581) | Males (n=956) | Females (n=920) | Age at diagnosis < 68 (n=966) | Age at diagnosis ≥ 68 (n=910) | Adeno-carcinoma (n=1043) | Non adenocarcinoma (n=833) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Race and ethnicity | HR | 95%CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI |
| Non-Hispanic White | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref |
| Hispanic/Latino | 0.55 | 0.29–1.01 | 0.72 | 0.57–0.90 | 0.78 | 0.59–1.03 | 0.61 | 0.44–0.86 | 0.73 | 0.54–0.99 | 0.72 | 0.53–0.97 | 0.85 | 0.64–1.14 | 0.60 | 0.44–0.82 |
| Non-Hispanic Black | 0.90 | 0.60–1.36 | 0.99 | 0.84–1.17 | 1.00 | 0.81–1.24 | 1.02 | 0.81–1.27 | 1.06 | 0.85–1.33 | 0.95 | 0.76–1.18 | 1.15 | 0.93–1.42 | 0.90 | 0.72–1.12 |
| Non-Hispanic Asian | 0.74 | 0.36–1.49 | 0.42 | 0.19–0.91 | 0.61 | 0.31–1.18 | 0.53 | 0.25–1.13 | 0.69 | 0.35–1.35 | 0.47 | 0.23–0.98 | 0.69 | 0.36–1.30 | 0.48 | 0.22–1.05 |
Multivariable models adjusted for age, sex, adenocarcinoma, surgery, palliative care, smoking status, language preference, marital status, and socioeconomic status and stratified by chemotherapy, radiation, and stage in order to meet proportional hazards assumption
Surgery was associated with improved survival among Hispanics/Latinos (HR = 0.60, 95% CI: 0.43 – 0.85), NHWs (HR = 0.55, 95% CI: 0.42 – 0.73), and NHBs (HR = 0.51, 95% CI: 0.40 – 0.65) (Table 4). In Hispanics/Latinos, ever-smoking status was associated with a 56% increased risk of death (HR = 1.56, 95% CI: 1.02 – 2.39). Preferring a language other than English (Spanish: n = 192; Other: n = 1), was associated with a 31% increased risk of death although not significant (HR = 1.31, 95% CI: 0.97 – 1.76). Among NHWs, adenocarcinoma histology was associated with improved survival and palliative care receipt with worse survival.
Table 4.
Risk of deatha in subjects with non-small cell lung cancer in the Lung Cancer Clinical Cohort at Montefiore Medical Center, stratified by racial/ethnic groupb
| Hispanic/Latino (n=452) | Non-Hispanic White (n=634) | Non-Hispanic Black (n=752) | ||||
|---|---|---|---|---|---|---|
| Variable | HR | 95% CI | HR | 95% CI | HR | 95% CI |
| Sex | ||||||
| Males | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref |
| Females | 0.83 | 0.61–1.12 | 0.90 | 0.72–1.12 | 0.88 | 0.72–1.07 |
| Adenocarcinoma | ||||||
| No | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref |
| Yes | 0.93 | 0.69–1.25 | 0.70 | 0.57–0.87 | 0.93 | 0.77–1.14 |
| Surgery | ||||||
| No | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref |
| Yes | 0.60 | 0.43–0.85 | 0.55 | 0.42–0.73 | 0.51 | 0.40–0.65 |
| Palliative Care | ||||||
| No | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref |
| Yes | 1.06 | 0.75–1.51 | 1.48 | 1.11–1.97 | 1.06 | 0.84–1.34 |
| Smoking | ||||||
| Never-smoker | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref |
| Ever-smoker | 1.56 | 1.02–2.39 | 1.04 | 0.76–1.42 | 1.19 | 0.89–1.58 |
| Language preference | ||||||
| English | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref |
| Not English | 1.31 | 0.97–1.76 | 0.76 | 0.42–1.36 | 1.80 | 0.43–7.48 |
| Marital statusc | ||||||
| Not married | 1.00 | Ref | 1.00 | Ref | 1.00 | Ref |
| Married | 0.79 | 0.57–1.09 | 0.98 | 0.78–1.22 | 0.86 | 0.70–1.06 |
| Socioeconomic statusd | 1.00 | 0.95–1.05 | 1.01 | 0.97–1.06 | 0.99 | 0.96–1.03 |
Multivariable models adjusted for age and the other variables in the table and stratified by chemotherapy, radiation, and stage in order to meet proportional hazards assumption
Non-Hispanic Asians were not modeled due to limited sample size
Married/significant other versus single/divorced/separated/widowed/other
Summary score of several variables calculated using census block data (See Online Resource 1)
Discussion
We conducted a study of race and ethnicity in relation to non-small cell lung cancer survival in the Bronx, which is an ideal study population for this research given that it is comprised of predominantly minority groups[18]. We demonstrated that Hispanics/Latinos had improved overall survival in NSCLC compared to NHWs. This remained after accounting for important clinical and demographic variables, including smoking status. Interestingly, the association was evident in never-smokers, ever-smokers, females, males, younger, and older patients. In addition, our large sample size of Hispanics/Latinos with NSCLC enabled us to examine factors related to survival within the US Hispanic/Latino population. While the Bronx is home to some of the poorest populations in the US[25], the low variation in socioeconomic status in this patient population suggest that the improved survival in Hispanics/Latinos may not be solely driven by differences in access to care. Factors associated with improved survival in our population of Hispanics/Latinos included receiving surgery and never-smoking status
The drivers behind the observations of better health outcomes in US Hispanics/Latinos compared to NHWs[26, 27, 4] are still not fully elucidated. Initially, it was thought that the increased life expectancy was secondary to misclassification of Hispanics/Latinos on death certificates, healthy immigrant effects, and a tendency for sick Hispanics/Latinos to return to their home country when near death; however, these theories have not been shown to fully explain the mortality benefit[28–31]. It has been proposed that the majority of the Hispanic mortality advantage may be due to lower rates of smoking[5]. It has also been shown that the effects of familismo, a strong attitude towards family and an important part of Hispanic culture, may be a major contributor to the phenomenon of better-than-expected health outcomes in Hispanic/Latinos[32]. Importantly, there is marked heterogeneity of mortality by Hispanic background, which may explain why it has been difficult to conclusively understand the mechanisms of the generally improved survival in Hispanics/Latinos[33]. Others have put forth the notion that greater length of stay in the United States may be associated with an adoption of a lifestyle that is associated with worse health outcomes [34]. However, in a study of Mexican-Americans, those who lived in high-density Mexican-American neighborhoods had decreased mortality and reduced risk of stroke, cancer, and hip fracture[6], suggesting that community factors may play an important role in health outcomes and should be further studied in Hispanics/Latinos.
For NSCLC in particular, the improved survival in Hispanics/Latinos may be due to differences in environmental exposures, culture, tumor genetics, and/or lung cancer therapy. Hispanics/Latinos have differences in smoking patterns compared to NHWs, including greater likelihood of non-daily smoking and decreased pack-year history[35]. However, we found the protective association of Hispanic/Latino ethnicity with survival even among never-smokers, suggesting that differences in smoking do not fully explain the survival benefit. As previously mentioned as a theory for improved outcomes generally in Hispanics/Latinos, increased social support has been proposed to contribute to a survival advantage in NSCLC[36]. Furthermore, Hispanics/Latinos may have differences in lung cancer molecular profiles, including actionable targets (i.e., EGFR[37]). An analysis of Hispanic/Latino lung adenocarcinoma tissue samples (mix of US and Latin American patients) demonstrated higher rates of EGFR, lower rates of KRAS, and similar rates of TP53 mutations compared to NHWs[38]. Arrieta et al. also found higher rates of EGFR mutations in Hispanics/Latinos in Latin America compared to those reported in Caucasians[39]. On the other hand, a study of 40 US Hispanics/Latinos and 43 NHWs showed similar EGFR frequencies[40]. The difference in findings may be related to proportion of indigenous ancestry. Gimbrone et al. suggested that EGFR mutation rates in Hispanics/Latinos are elevated in those with indigenous ancestry but are similar in Hispanics/Latinos with European and African backgrounds[38]. Alternatively, it has been suggested that epigenetic changes, influenced by environmental exposures and community-level factors, may explain survival differences despite similar somatic mutation profiles [41]. In our study, Hispanics/Latinos with adenocarcinoma had similar survival compared to NHWs. This may suggest that EGFR mutations are not the major driver of improved survival. There may be other molecular drivers of survival more common to Hispanics/Latinos to investigate, particularly within non-adenocarcinoma NSCLCs. The drivers of survival within Hispanics/Latinos could serve as important targets for future healthcare interventions.
Our findings add to the literature assessing the role of Hispanic/Latino ethnicity in survival in lung cancer. These findings are in agreement with a recent meta-analysis showing improved survival in US Hispanics/Latinos with lung cancer relative to NHWs[14]. Similar to our findings, Tannenbaum et al. found a 6 percent improved survival in Hispanics/Latinos compared to Non-Hispanics in Florida when adjusting for clinical and demographic covariates such as smoking[13]. On the other hand, Brzezniak found no survival differences between Hispanics/Latinos and NHWs in a US military cohort[12]. Differences in the patient population at MMC compared to a military population may explain the heterogeneous findings. Unlike studies comparing Hispanics/Latinos to NHWs, of which there are few, our findings of similar survival in NHBs and NHWs, after accounting for clinical and access to care-related factors, has been well-documented[12, 13, 42–47]. Importantly, as was the case in this cohort, many of the studies analyzing the risk of death in NHBs versus NHWs utilized patient populations with low heterogeneity in socioeconomic status or health insurance type[12, 42, 45]. Similar to a meta-analysis of factors related to survival in lung cancer [14], we found that surgery was associated with improved survival. We also found that palliative care was associated with worse survival. A recent study in the Veterans Affairs health care system noted palliative care to be associated with worse survival if received 0 to 30 days after diagnosis, better survival 31 to 365 days, and similar survival more than 365 days after diagnosis[48]. This suggests that time of treatment receipt may be an important contributor to the relationship between palliative care and survival in lung cancer. In addition, the association between palliative care and survival could be explained by individual differences in specific treatment regimens. Among Hispanics/Latinos, language preference was not associated with differences in survival.
Our study has a number of strengths and limitations. The major strength of our is study is that it was conducted in a large and diverse sample of subjects with NSCLC in the Bronx, a poor, underserved community that is comprised predominantly of minorities[18, 25]. In the present analysis, while the SES of the NHW population was greater than that of the Hispanic/Latino population, the SES was still low among the entire patient population. As such, our population may be generalizable to NHWs, NHBs, and Hispanics receiving care in US urban underserved communities. Furthermore, the prospective study design limits temporality bias and the use of self-reported race/ethnicity reduces misclassification bias. We assessed the robustness of our findings with sensitivity analyses which demonstrated that our main results held when restricting to those with a minimum follow-up of at least 1 year, stage I-IV cases, and those with vital status ascertainment at least annually. Shortcomings in LC3MMC include the lack of detailed Hispanic/Latino background, pack-year smoking history, and medical comorbidities. Another limitation in our study is the large group of subjects with unknown race and/or ethnicity. While those with unknown race/ethnicity tended to be diagnosed with disease at a later stage (early: 22% in knowns versus 16% in unknowns, regional: 24 vs. 25%, distant: 37 versus 45%), we found no differences between those with known and those with unknown race/ethnicity in age at diagnosis (p = 0.59), sex (p = 0.64), smoking status (p = 0.34), marital status (p = 0.22) and SES (p = 0.29). As such, our findings may be influenced by subjects who present at an earlier stage and therefore have a more favorable prognosis. We also found a large difference in the percentage of subjects diagnosed in the earliest diagnosis year interval (2004–2008): 27% of subjects with known race/ethnicity were diagnosed at this time, whereas 57% with unknown race/ethnicity were diagnosed during this interval. To assess this discrepancy, we performed a sensitivity analysis where we restricted our multivariable model to only those diagnosed after 2008. We found a similar estimate of the protective association of Hispanic/Latino ethnicity with survival from NSCLC (HR = 0.73, 95% CI: 0.58 – 0.92).
This report demonstrates that Hispanic/Latino ethnicity is associated with survival from lung cancer, after accounting for clinical and sociodemographic factors. It is critical to characterize drivers of survival in each racial/ethnic group to inform future interventions. Future studies should assess the roles of comorbidities, more detailed smoking history, and health insurance status in survival from NSCLC. Given that we have demonstrated survival differences in lung cancer survival, there is additional justification that future research should utilize patient samples to investigate genetic and molecular factors related to survival in diverse populations. Ideally, future work would involve assessing the underlying genomic architecture of Hispanic/Latino patients using blood or tumor samples. While most of the research on the mortality advantage in Hispanics/Latinos has focused mainly on foreign-born Mexican-Americans[49, 50], Hispanics/Latinos demonstrate substantial heterogeneity with regards to genetic ancestry[38] and lifestyle behaviors such as smoking[51]. Considerable variation in mortality rate ratios by Hispanic ethnic groups has been demonstrated for lung cancer, with Cubans having the highest ratio and Mexicans and Central Americans with the lowest ratios for women and men, respectively[52]. Studies that incorporate genetic ancestry (i.e. European, indigenous, African, and Asian) may be helpful for discerning differences in risk within Hispanic/Latino populations[38, 39]. Finally, given that differences in mutational profiles may be an important contributor to risk of mortality, it is crucial to study the prevalence of specific driver mutations in Hispanic/Latino ethnic groups. Similarly, as targeted therapies based on molecular profiling, such as tyrosine kinase inhibitors and immunotherapy, have been shown to significantly improve survival and are becoming more widely available, future research should determine rates of targeted therapy receipt by race and ethnicity as well as its effects on survival.
Supplementary Material
Acknowledgements
We would like to thank Dr. Aileen McGinn, who provided insight on data analysis that greatly assisted the research
Funding
This work was supported in part by NIH/National Center for Advancing Translational Science (NCATS) Einstein-Montefiore CTSA Grant Number UL1TR001073. The funder had no direct role in the conduct of this study.
Footnotes
Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.
Conflict of Interest: Authors MK, XX, MG, HC, TR, and HDH declare that they have no conflict of interest.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Institutional Review Board at Albert Einstein College of Medicine, reference number 043574) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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