
==== Front
JNCI Cancer Spectr
JNCI Cancer Spectr
jncics
JNCI Cancer Spectrum
2515-5091
Oxford University Press

39186009
10.1093/jncics/pkae072
pkae072
Article
AcademicSubjects/MED00010
Racial and ethnic differences in second primary lung cancer risk among lung cancer survivors
https://orcid.org/0000-0003-1315-1433
Choi Eunji PhD Conceptualization Data curation Formal analysis Investigation Methodology Project administration Software Validation Visualization Writing - original draft Writing - review & editing Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA

https://orcid.org/0000-0003-3406-7046
Hua Yue MS Formal analysis Investigation Software Validation Visualization Writing - original draft Writing - review & editing Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA, USA
Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA

https://orcid.org/0000-0002-2204-3314
Su Chloe C PhD Writing - review & editing Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA, USA
Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA

Wu Julie T MD, PhD Writing - review & editing Department of Veterans Affairs, Veterans Affairs Palo Alto Health Care, Palo Alto, CA, USA

https://orcid.org/0000-0003-3119-9334
Neal Joel W MD Writing - review & editing Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

Leung Ann N MD Writing - review & editing Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA

https://orcid.org/0000-0002-4553-1003
Backhus Leah M MD Writing - review & editing Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA

https://orcid.org/0000-0002-0097-9971
Haiman Christopher ScD Writing - review & editing Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA

https://orcid.org/0000-0001-5013-980X
Le Marchand Loïc MD, PhD Writing - review & editing Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

https://orcid.org/0000-0002-6616-5970
Liang Su-Ying PhD Writing - review & editing Palo Alto Medical Foundation Research Institute, Sutter Health, Palo Alto, CA, USA

https://orcid.org/0000-0003-1136-980X
Wakelee Heather A MD Writing - review & editing Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

https://orcid.org/0000-0003-4132-2893
Cheng Iona PhD Writing - review & editing Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

https://orcid.org/0000-0002-2013-6883
Han Summer S PhD Conceptualization Investigation Methodology Project administration Resources Supervision Validation Writing - review & editing Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA, USA
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

Correspondence to: Summer S. Han, PhD, Quantitative Sciences Unit, Department of Medicine, Department of Neurosurgery, and Department of Epidemiology and Population Health, Stanford University School of Medicine, 3180 Porter Drive, Office 118, Stanford, CA 94304, USA (e-mail: summer.han@stanford.edu).
Eunji Choi and Yue Hua authors contributed equally to this work.

10 2024
26 8 2024
26 8 2024
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18 9 2024
© The Author(s) 2024. Published by Oxford University Press.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Background

Recent therapeutic advances have improved survival among lung cancer (LC) patients, who are now at high risk of second primary lung cancer (SPLC). Hispanics comprise the largest minority in the United States, who have shown a lower LC incidence and mortality than other races, and yet their SPLC risk is poorly understood. We quantified the SPLC incidence patterns among Hispanics vs other races.

Methods

We used data from the Multiethnic Cohort, a population-based cohort of 5 races (African American, Japanese American, Hispanic, Native Hawaiian, and White), recruited between 1993 and 1996 and followed through 2017. We identified patients diagnosed with initial primary lung cancer (IPLC) and SPLC via linkage to Surveillance, Epidemiology, and End Results registries. We estimated the 10-year cumulative incidence of IPLC (in the entire cohort) and SPLC (among IPLC patients). A standardized incidence ratio (SIR) was calculated as the ratio of SPLC-to-IPLC incidence by race and ethnicity.

Results

Among 202 692 participants, 6788 (3.3%) developed IPLC over 3 871  417 person-years. The 10-year cumulative IPLC incidence was lower among Hispanics (0.80%, 0.72 to 0.88) vs Whites (1.67%, 1.56 to 1.78) or Blacks (2.44%, 2.28 to 2.60). However, the 10-year SPLC incidence following IPLC was higher among Hispanics (3.11%, 1.62 to 4.61) vs Whites (2.80%, 1.94 to 3.66) or Blacks (2.29%, 1.48 to 3.10), resulting in a significantly higher SIR for Hispanics (SIR = 8.27, 5.05 to 12.78) vs Whites (SIR = 5.60, 4.11 to 7.45) or Blacks (SIR = 3.48, 2.42 to 4.84; P < .001).

Conclusion

Hispanics have a higher SPLC incidence following IPLC than other races, which may be potentially due to better survival after IPLC and extended duration for SPLC development. Continuing surveillance is warranted to reduce racial disparities among LC survivors.

National Institutes of Health 10.13039/100000002 1R01CA282793
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pmcLung cancer is the leading cause of cancer mortality worldwide (1). Prior studies have shown racial and ethnic disparities in the incidence and mortality of lung cancer. For instance, Hispanics, the largest minority group in the United States, have the lowest incidence of lung cancer, whereas African Americans have the highest incidence, which may be partly explained by the differences in smoking prevalence (2), with Hispanics having the lowest smoking rate and cumulative pack-year exposure (3). Furthermore, Hispanic lung cancer patients have shown distinctive patterns in disease prognosis. The phenomenon, known as the Hispanic Paradox, has shown that despite having a higher likelihood of being diagnosed at an advanced stage and having a lower socioeconomic status, Hispanics have a lower lung cancer mortality than Whites by 50% (4).

Concurrently, recent advances in therapy and screening have significantly increased lung cancer survival. However, prior studies have shown that lung cancer survivors have a high risk of developing second primary lung cancer (SPLC), with an incidence of 4-6 times greater than that of developing initial primary lung cancer (IPLC) in the general population (5). Importantly, lung cancer survivors diagnosed with SPLC have shown to have significantly worse overall survival compared with those who remain with a single diagnosis of primary lung cancer (hazard ratio = 2.12, P < .001) (6). In an effort to identify high-risk survivors to be screened for SPLC, prior studies have examined and identified several factors associated with SPLC risk, including smoking history (7), IPLC tumor characteristics (8), and prior medical conditions (eg, prior history of cancer) (9). However, potential differences in SPLC risk by racial and ethnic groups are still poorly understood. Thakur et al. (10) evaluated SPLC risk by race using national cancer registries but used only a broad race category—White, Black, and all other races merged into a single group, showing some intriguing high SPLC incidence among “other” racial group in women patients with a history of IPLC. Fisher et al. (11), also examined SPLC risk by several factors, including race and ethnicity, but the study suffered from potential biases because of small sample sizes for racial and ethnic minorities and being based on a single institution. To the best of our knowledge, no existing study has comprehensively examined SPLC incidence stratified by distinct racial and ethnic groups in the United States in a large prospective cohort with a long follow-up.

In this study, we used a population-based cohort, the Multiethnic Cohort Study (MEC), that includes 5 major racial and ethnic groups in the United States to quantify and compare the cumulative incidence of SPLC among Hispanics vs other race groups (African Americans, Japanese Americans, Native Hawaiians, and Whites). To characterize patterns of SPLC incidence and disease burden, we used the standardized incidence ratio (SIR) to compare the incidence of SPLC to the incidence of IPLC by race and ethnicity.

Methods

Study cohort

The MEC is a prospective population-based cohort of more than 215 000 healthy residents in California and Hawaii. Designed to discover key factors associated with cancer risk across 5 racial and ethnic groups, the MEC enrolled participants 45-75 years old in 1993-1996. In this study, based on the number of participants enrolled at baseline (n = 214 862), we excluded those (n = 12 170, 5.6%) who did not identify themselves as 1 of the 5 racial categories in MEC (African American, Japanese American, Hispanic, Native Hawaiian, and White) (Supplementary Figure 1, available online). The definition of race and ethnicity is as follows: individuals with Hispanic ethnicity were first classified as “Hispanic,” which included “White Hispanic” and “Black Hispanic.” Then the remaining races in non-Hispanic individuals were categorized as (non-Hispanic) African American, (non-Hispanic) Japanese American, (non-Hispanic) Native Hawaiian, and (non-Hispanic) White. Demographic (age at cohort enrollment, sex), clinical (personal history of cancer before cohort enrollment, family history of lung cancer), and smoking data (smoking status, smoking pack-year) was collected by a self-reported survey at cohort enrollment.

Incident cancers, including IPLC and SPLC, were identified via linkage through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Hawaii and California for 1993-2017. The cohort members who have left the state are still being followed up on via follow-up surveys as well as linkages to Medicare, the National Death Index, and the cancer registries in other states through the SEER programs. SPLC was defined according to the most widely accepted criteria by Martini and Melamed (12) with a modification to further reduce the potential misclassification from recurrence (6,8,13): SPLC should meet at least 1 of the following conditions: (1) have different histology from that of the IPLC or (2) have at least 2 years of a disease-free interval from the time of IPLC diagnosis. The SEER summary stage variable was used to categorize IPLC diagnosis stages as early (localized and regional) or advanced (distant). IPLC histology was classified into adenocarcinoma, squamous cell carcinoma, large cell, small-cell lung cancer, and other (not belonging to non-small cell lung cancer or small-cell lung cancer).

Study outcome

The primary study outcome was the cumulative incidence by race (African Americans, Japanese Americans, Hispanics, Native Hawaiians, and Whites), which captures the following 2 components: cumulative incidence of IPLC in the general population, and the cumulative incidence of SPLC in lung cancer survivors.

The secondary study outcome was the standardized incidence ratio (SIR) by race, calculated as the SPLC incidence divided by the IPLC incidence. To calculate the SIR, the SPLC incidence rate was calculated as observed SPLC cases over the person-years of patients with IPLC; the IPLC incidence rate is as observed IPLC cases over the person-years of the entire cohort as shown below. SIR=SPLC incidence rateIPLC incidence rates+Observed SPLC casesPerson - years of IPLC patientsObserved IPLC casesPerson - years of the entire cohort

This SIR can be interpreted as the relative level of incidence for new primary lung cancers among patients previously diagnosed with IPLC vs those without IPLC in the general population. The SPLC (numerator) and IPLC incidence rates (denominator) to calculate the SIR for overall cohort and by race are provided in Supplementary Table 3 (available online).

Statistical analysis

To compute the cumulative incidence of IPLC (in the general population) and SPLC (in lung cancer survivors) by race and ethnicity while accounting for the competing risk of death, we applied the Aalen-Johansen estimator (14-16).

We estimated SIRs using the National Cancer Institute’s (NCI’s) approach for multiple primary-SIR (MP-SIR) (17), which quantifies the ratio of the incidence of a new primary malignancy (in a group of patients consisting of those already diagnosed with an initial primary malignancy) vs the incidence of initial primary malignancy in the general population at risk. In applying the MP-SIR method to our study, our SIR is interpreted as the ratio of SPLC cases (among patients previously diagnosed with IPLC) to the cases of IPLC in the general population (18). The 95% confidence interval (CI) of the MP-SIR is calculated using the Byar approximation (19). To test the statistical significance in differences in SIRs by race/ethnicity (Whites as a reference group), we conducted additional Poisson regression analyses (18) on the aggregated count data for SPLC incidence and IPLC incidence by racial and ethnic groups. We used the Bonferroni method to adjust for multiple testing, with a significance threshold of alpha at 0.0125 (0.05/4) for the 4 comparisons (African Americans, Hispanics, Japanese Americans, and Native Hawaiians) made to Whites as the reference. To assess the robustness of the finding, we conducted subgroup analyses for estimating the SIR differences by race and ethnicity in each subgroup defined by smoking status (never vs ever smokers), sex (male vs female), and stage of IPLC (early-stage vs advanced stage).

Given the consistent observation of the Hispanic paradox in lung cancer survival in prior literature (4), we hypothesized that the Hispanic lung cancer survivors’ longer survival time might lead to extended duration for SPLC development. Thus, we examined whether Hispanic lung cancer patients have longer lung cancer–specific or overall survival compared with those of other races and ethnicities. Overall survival in lung cancer patients was defined as the time from IPLC diagnosis to all-cause death (or censored date). Lung cancer–specific survival time was defined as the time from IPLC diagnosis to either lung cancer–specific death or censored date due to last follow-up or death from other causes, whichever occurred first. We applied multivariable Cox regression to evaluate the difference in survival among Hispanics vs other race groups, adjusting for sex, age, and smoking status; IPLC tumor characteristics (histology and stage); and first course treatment (surgery, radiotherapy, and chemotherapy). The proportional hazard assumptions were tested by examining the plot of the estimate of time-dependent coefficients over time; if the proportional hazard assumption holds, the true β(t) function would appear as a horizontal line. For variables that did not meet the proportional hazard assumption (ie, those with a time-dependent coefficient), we transformed these variables by incorporating their interaction with time. For a pairwise comparison between Hispanics and each of the other racial and ethnic groups, we used Hispanics as a reference and applied the Bonferroni correction with a significance level adjusted to account for multiple comparisons, applying the significance threshold of alpha at 0.0125 (0.05/4). Additionally, we conducted a sensitivity analysis to examine survival differences within subgroups known for their favorable prognosis among lung cancer patients, including those in early-stage, never-smokers, and female patients. The same multiple testing adjustment method was used for each of the subgroup analyses (ie, alpha = 0.0125).

All analyses were performed using R, version 4.3.1, statistical software (R Project for Statistical Computing) with the prodlim R package for computing cumulative incidence in the presence of competing events.

Results

Of 202 692 participants enrolled in MEC, 6788 (3.3%) developed IPLC over 3 871 417 person-years (Table 1). The entire cohort (ie, 202 692 healthy participants at baseline) consisted of 28.0% Japanese American, 24.3% White, 23.4% Hispanic, 17.1% African American, and 7.1% Native Hawaiian. A self-reported never-smoking history at baseline was high among Japanese Americans (49.6%) and Hispanics (47.1%), followed by Whites and Native Hawaiians (38.5%) and African Americans (37.1%) (Supplementary Table 1, available online).

Table 1. Characteristics of study participants in the Multiethnic Cohort Study

Variables	Total (N = 202 692)	IPLC cases (N = 6788)	SPLC cases (N = 156)	
Baseline characteristics a				
Age at study enrollment, mean (SD)	60.0 (±8.8)	63.8 (±7.7)	62.9 (±7.2)	
Race and ethnicity				
 African American	34 706 (17.1%)	1850 (27.3%)	35 (22.4%)	
 Japanese American	56 818 (28.0%)	1645 (24.2%)	40 (25.6%)	
 Hispanic	47 388 (23.4%)	990 (14.6%)	20 (12.8%)	
 Native Hawaiian	14 441 (7.1%)	584 (8.6%)	13 (8.3%)	
 White	49 339 (24.3%)	1719 (25.3%)	14 (9.0%)	
Sex, n (%)				
 Male	111 273 (54.9%)	3835 (56.5%)	74 (47.4%)	
 Female	91 419 (45.1%)	2953 (43.5%)	82 (52.6%)	
Smoking status, n (%)				
 Never	87 976 (43.4%)	745 (11.0%)	15 (9.6%)	
 Former	79 149 (39.0%)	2835 (41.8%)	65 (41.7%)	
 Current	32 302 (15.9%)	3140 (46.3%)	75 (48.1%)	
Packyears (0 for never-smokers)				
 Mean (SD)	10.1 (±14.9)	26.2 (±18.9)	29.8 (±19.5)	
Personal history of cancer, n (%)				
 Yes	17 266 (8.5%)	1775 (26.1%)	51 (32.7%)	
 No	185 424 (91.5%)	5013 (73.9%)	105 (67.3%)	
Family history of lung cancer, n (%)				
 Yes	12 397 (6.1%)	612 (9.0%)	13 (8.3%)	
 No	190 295 (93.9%)	6176 (91.0%)	143 (91.7%)	
IPLC characteristics b				
Age at IPLC diagnosis, mean (SD)		74.3 (±8.3)	72.2 (±8.1)	
IPLC SEER Summary stage				
 Early (Localized + Regional)		2685 (39.6%)	139 (89.1)	
 Advanced (Distant)		3670 (54.1%)	15 (9.6)	
 Unknown		433 (6.4%)	2 (1.3)	
IPLC histology				
 Adenocarcinoma		2676 (39.4%)	92 (59.0%)	
 Squamous cell carcinoma		1355 (20.0%)	34 (21.8%)	
 Large cell carcinoma		196 (2.9%)	8 (5.1%)	
 Small cell lung adenocarcinoma		693 (10.2%)	3 (1.9%)	
 Other		1323 (19.5%)	14 (9.0%)	
a Collected through a self-reported survey at cohort enrollment. IPLC = initial primary lung cancer; SPLC = second primary lung cancer; SD = standard deviation.

b Identified via linkage to the Surveillance, Epidemiology, and End Results (SEER) cancer registries.

Of the 6788 patients who developed IPLC, 156 (2.3%) subsequently developed SPLC (Table 1). The mean smoking pack-years in this IPLC cohort (n = 6788) was 26.2 (interquartile range [IQR] = 10.2 to 39.5), with Hispanics having the lowest mean smoking pack-years of 19.9 (IQR = 2.0 to 31.8), followed by African American (21.6; IQR = 10.2 to 31.8]), Japanese American (26.3; IQR = 10.2 to 45.3]), Native Hawaiian (28.8; IQR = 14.2 to 45.3), and White (33.4; IQR = 19.8 to 2.3) (Supplementary Table 2, available online). In the IPLC cohort, about 39.4% of IPLC was adenocarcinoma (Table 1). Japanese Americans (44.1%) had the highest proportion of adenocarcinoma, followed by Whites (39.1%), Hispanics (38.0%), African Americans (37.4%), and Native Hawaiians (36.1%) (Supplementary Table 2, available online).

The 10-year cumulative IPLC incidence in the entire cohort was 1.47% (95% CI = 0.51% to 2.01%). Notably, Hispanics had the lowest 10-year IPLC incidence (0.80%, 0.72% to 0.88%), which was 2-3 times lower than other groups, including African Americans (2.44%, 2.28% to 2.60%) and Whites (1.67%, 1.56% to 1.78%) (Figure 1C). However, the 10-year SPLC cumulative incidence after IPLC diagnosis was the highest among Hispanics (3.11%, 1.62% to 4.61%), followed by Japanese Americans (3.00%, 2.01% to 4.00%), Whites (2.80%, 1.94% to 3.66%), Native Hawaiians (2.47%, 1.04% to 3.89%), and Blacks (2.29%, 1.48% to 3.10%) (Figure 1D). This observation was consistent by smoking status and sex (Supplementary Figures 2 and 3, available online).

Figure 1. Race-specific cumulative incidence of IPLC and SPLC in the Multiethnic Cohort Study (MEC). Race-specific cumulative incidence of IPLC in the entire MEC cohort (N = 202 692) in (A) and SPLC among LC patients (N=6788) in (B). The 10-year point estimate of cumulative incidence of IPLC in (C) and SPLC in (D). Dotted line in Panels A and B indicates 10 years from the time of cohort enrollment (A) and 10 years from the time of IPLC diagnosis (B). IPLC = initial primary lung cancer; SPLC = second primary lung cancer.

The overall SIR (ie, the ratio of SPLC to IPLC incidence) was 5.62 (95% CI = 4.78 to 6.58) in the entire cohort (Table 2). Hispanics, who had the highest point estimate of SPLC incidence—despite the lowest IPLC incidence (Figure 1)—had a substantially higher SIR (8.27, 5.05 to 12.78), surpassing SIRs of other racial groups, which ranged from 3.48 to 6.37. Based on the additional Poisson regression analysis to test the statistical difference in SIRs by race, with Whites serving as the reference group, Hispanics demonstrated a statistically significant difference in SIR (8.27, 5.05 to 12.78) compared with Whites (5.60, 4.11 to 7.45, P < .0125) (Table 2). The consistent results were observed across different subgroups by smoking history, sex, and IPLC stage (Table 2) with a particularly high SIR among Hispanics, especially in subgroups of never-smokers, women, and early-stage IPLC patients, owing primarily to the small denominators (ie, lower IPLC incidence) (Supplementary Table 3, available online).

Table 2. Standardized incidence ratio of SPLC to IPLC in the entire cohort and by subgroups in the Multiethnic Cohort Study

	Standardized Incidence Ratio (95% CIa)	
Entire cohort	By smoking history	By sex	IPLC stage	
Ever	Never	Men	Women	Early-stagec	
Total	5.62 (4.78 to 6.58)	3.63 (3.05 to 4.28)	14.21 (7.95 to 23.43)	4.91 (3.91 to 6.08)	6.36 (4.98 to 7.99)	15.22 (12.79 to 17.97)	
African American	3.48 (2.42 to 4.84)b	2.42 (1.68 to 3.36)b	0.00 (0.00 to 0.00)	2.98 (1.79 to 4.65)b	3.65 (2.08 to 5.93)b	9.98 (6.73 to 14.24)b	
Hispanic	8.27 (5.05 to 12.78)b	5.28 (2.95 to 8.71)b	21.15 (6.82 to 49.37)	5.79 (2.77 to 10.65)b	12.42 (5.95 to 22.85)b	23.78 (13.84 to 38.08)	
Japanese American	6.37 (4.55 to 8.67)b	3.96 (2.74 to 5.54)	11.98 (3.86 to 27.96)b	6.42 (4.44 to 8.97)b	3.59 (1.31 to 7.81)b	16.98 (11.95 to 23.40)	
Native Hawaiian	4.47 (2.44 to 7.49)b	2.98 (1.58 to 5.09)b	16.34 (0.21 to 90.89)b	3.37 (1.23 to 7.34)b	5.68 (2.45 to 11.19)b	9.28 (4.23 to 17.61)b	
White	5.60 (4.11 to 7.45)	3.75 (2.72 to 5.05)	20.92 (5.63 to 53.55)	3.89 (2.12 to 6.53)	6.98 (4.80 to 9.80)	14.90 (10.91 to 19.88)	
a The 95% confidence interval (CI) is calculated using the Byar approximation. IPLC = initial primary lung cancer; SPLC = second primary lung cancer.

b P < .0125; Bonferroni corrected alpha = 0.0125 (0.05/4) was used for testing the difference in SIRs between Whites (reference group) and the other racial and ethnic group via Poisson regression.

c Early-stage was defined using SEER summary stage (localized and regional).

Given that extended survival can potentially affect SPLC incidence, we further examined survival after IPLC diagnosis by race. Hispanics showed relatively high median survival rates for both overall and lung cancer-specific survival compared with the other race groups in MEC (Supplementary Figures 4 and 5, available online), but the differences did not reach statistical significance. In the subgroup of survivors diagnosed with early-stage IPLC, Hispanics showed better median overall survival (2.75, 95% CI = 2.17 to 3.59) compared with the other races (Japanese American = 2.58, 95% CI = 2.17 to 3.17; White: 2.42, 95% CI = 1.92 to 2.91; African American: 1.75, 95% CI = 1.66 to 2.00), but this difference was not statistically significant after adjusting for confounders (Supplementary Figure 4 and Supplementary Table 4, available online). Similar findings were observed for lung cancer-specific survival between Hispanic patients with early-stage IPLC (median survival = 4.33, 95% CI = 3.17 to 6.00) vs the other races (Japanese American = 4.58, 95% CI = 3.58 to 5.92; White = 3.75, 95% CI = 3.09 to 4.91; African American = 2.59, 95% CI = 2.00 to 3.42), which also did not reach statistical significance (Supplementary Figure 5 and Supplementary Table 5, available online).

Discussion

In this study, we evaluated SPLC incidence among lung cancer survivors by race and ethnicity using a large, population-based cohort that represents 5 major racial and ethnic groups in the United States (African Americans, Japanese Americans, Hispanics, Native Hawaiians, and Whites). This study showed that although the 10-year cumulative IPLC incidence was substantially lower among Hispanics compared with the other races, the SPLC incidence after IPLC was as high among Hispanics as other racial groups, resulting in a significantly higher SIR for Hispanics than the other race groups.

Prior studies have identified several factors associated with SPLC risk, including personal history of cancer before IPLC diagnosis, histology of IPLC (7,8,13), and radiotherapy for IPLC (20). Furthermore, early-stage or surgically treatable IPLC were significant factors associated with SPLC risk because these patients have a potentially curable condition and lower competing risks, leading to a longer timeframe for SPLC development (6,8). However, currently there are no race-specific risk factors for SPLC, including those for Hispanics. Often referred to as a paradox, Hispanics in the United States tend to have better health outcomes compared with their non-Hispanic White counterparts, including all-cause mortality and cardiovascular disease despite facing inferior socioeconomic conditions (21-23). This trend is also evident in lung cancer, where Hispanic patients often survive longer than their White counterparts, even when diagnosed at more advanced stages and having lower socioeconomic status (4). Potential explanations for this better survival include lower smoking rates and a higher frequency of epidermal growth factor receptor (EGFR) mutations (24-26), although the survival difference between Hispanics vs the other race groups did not achieve statistical significance in MEC. Notably, a higher proportion of Hispanic lung cancer patients (18.1%) had no smoking history compared with Whites (7.4%) or African Americans (7.0%) in MEC. Potential differences in tumor biology between patients with vs without a smoking history or treatment response—such as to EGFR targeted therapy—could be related to the Hispanics’ higher SPLC risk (27). Hispanics also exhibit lower adherence to recommended therapy (28,29), resulting in varying exposure to treatment modalities, which could be potentially related to the greater SPLC risk observed in this population. Given the significant impact of SPLC diagnosis on the survival among lung cancer patients (6), it would be critical to further investigate race-specific SPLC risk factors to understand the drivers contributing to the higher incidence of SPLC among Hispanics and to optimize surveillance strategies by race.

Our study benefits from a large and racially diverse population from the MEC, enabling a comprehensive examination of racial disparities in SPLC incidence. Its longitudinal design spanning an extended period offered insights into SPLC incidence trends over time by the granular classification of racial groups. Also, the use of the Aalen-Johansen estimator helped minimize potential bias by accounting for competing risks of death to accurately capture the SPLC incidence and burden among lung cancer survivors who have a particularly high risk of competing death due to heavy smoking and the lethal prognosis of lung cancer. We conducted thorough subgroup analyses to evaluate the robustness of our main findings and to explore potential drivers of the observed racial disparities.

This study also has several limitations. Given that the data were collected via self-reported surveys in MEC, it is possible that there may be potential biases and inaccuracies based on self-reported smoking and demographic characteristics. Also, mixed Asian ethnicity may be found in Hispanics. In addition, Hispanics may return to their country of origin, which may cause loss of follow-up, but about 90% of the Hispanics in MEC were identified to remain in the United States through linkage to the system of Center for Medicare Services (30). A family history of any cancer is also a known risk factor for second or multiple primary cancers, including SPLC (31). However, we could not evaluate this relationship because our dataset does not include such information. Nonetheless, considering the similar distribution of family history of lung cancer across different racial and ethnic groups in the tables, we would expect the differential impact of a family history of any cancer by race to be relatively minimal. Our analysis faced challenges due to the small number of SPLC cases when stratified by race. However, all estimates were calculated using robust statistical methods, specifically the Byar approximation, and are presented with 95% confidence intervals, which supports the validity of these estimates and inferences. Despite the inclusion of a diverse racial and ethnic population in the present study, the generalizability of our study could be limited, given that the MEC cohort primarily recruited and followed participants in the regions of California and Hawaii. Further validation is warranted to examine the SPLC incidence patterns across different racial and ethnic groups using representative samples in the United States, inclusive of other states; this would require the use of a prospective cohort design that can provide the data on both initial and subsequent primary cancer diagnoses over an extended duration.

To conclude, Hispanic lung cancer survivors remain at high risk of developing SPLC. Tailored surveillance strategies are warranted to reduce potential health disparities among IPLC survivors by accounting for racial characteristics. Our results provide the basis for follow-up studies on racial disparities in post-IPLC surveillance and patient care to reduce disparities and mortality among lung cancer survivors.

Supplementary Material

pkae072_Supplementary_Data

Acknowledgments

Role of the funder: The funder has no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Data availability

The data underlying this analysis were provided by the Multiethnic Cohort Study (MEC) under data use agreement. Researchers interested in the MEC data may submit an inquiry online: https://www.uhcancercenter.org/for-researchers/mecdata-sharing.

Author contributions

Eunji Choi, PhD (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Software; Validation; Visualization; Writing—original draft; Writing—review & editing), Yue Hua, MS (Formal analysis; Investigation; Software; Validation; Visualization; Writing—original draft; Writing—review & editing), Chloe C. Su, PhD (Writing—review & editing), Julie T. Wu, MD, PhD (Writing—review & editing), Joel W. Neal, MD (Writing—review & editing), Ann N. Leung, MD (Writing—review & editing), Leah M. Backhus, MD (Writing—review & editing), Christopher Haiman, PhD (Writing—review & editing), Loïc Le Marchand, MD (Writing—review & editing), Su-Ying Liang, PhD (Writing—review & editing), Heather A. Wakelee, MD (Writing—review & editing), Iona Cheng, PhD (Writing—review & editing), Summer S. Han, PhD (Conceptualization; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Writing—review & editing).

Funding

This study is supported by a grant from the National Institutes of Health (1R01CA282793).

Conflicts of interest

Dr Backhus reports personal fees from Johnson & Johnson, outside the submitted work. Dr Neal reports grants from Genetech/Roche, grants from Merck, grants from Boehringer Ingelheim, grants from Exelixis, grants from Nektar Therapeutics, grants from Takeda Pharmaceuticals, grants from Adaptimmune, grants from GSK, grants from Janssen, grants from AbbVie, other from CME Matters, other from Clinical Care Options, other from Research to Practice, other from Medscape, other from Biomedical Learning Institute, other from MLI Peerview, other from Prime Oncology, other from Projects in Knowledge, other from Rockpointe, other from MJH Life Science, other from AstraZeneca, other from Genetech/Roche, other from Exelixis, other from Jounce Therapeutics, other from Takeda Pharmaceuticals, other from Eli Lilly and Company, other from Calithera BIosciences, other from Amgen, other from Iovance Biotherapeutics, other from Blueprint Pharmaceuticals, other from Regeneron Pharmaceuticals, other from Natera, outside the submitted work. Dr Wakelee reports grants from ACEA Biosciences, grants from Arrys Therapeutics, grants from BMS, grants from Celgene, grants from Clovis Oncology, grants from Exelixis, grants from Genetech/Roche, grants from Gilead, grants from Merck, grants from Novartis, grants from Pharmacyclics, grants from Sea Gen, grants from Xcovery, other from AstraZeneca, other from Xcovery, other from Janssen, other from Daiichi Sankyo, other from Blueprint, other from Mirati, other from Helsinn, other from Merch—Not compensated, other from Genetech/Roche—Not compensated, other from IASLC, other from ECOG-ACRIN, outside the submitted work. All remaining authors report no other disclosures.
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