- Email: [email protected]
Interstitial Lung Abnormalities and Lung Cancer Risk in the National Lung Screening Trial
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Interstitial Lung Abnormalities and Lung Cancer Risk in the National Lung Screening Trial
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Stacey-Ann Whittaker Brown, MD, MPH; Maria Padilla, MD; Grace Mhango, MPH; Charles Powell, MD; Mary Salvatore, MD; Claudia Henschke, PhD, MD; David Yankelevitz, MD; Keith Sigel, MD, PhD; Juan P. de-Torres, MD;
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and Juan Wisnivesky, MD, DrPH
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Some interstitial lung diseases are associated with lung cancer. However, it is unclear whether asymptomatic interstitial lung abnormalities convey an independent risk.
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OBJECTIVES:
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The goal of this study was to assess whether interstitial lung abnormalities are associated with an increased risk of lung cancer.
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METHODS:
Data from all participants in the National Lung Cancer Trial were analyzed, except for subjects with preexisting interstitial lung disease or prevalent lung cancers. The primary analysis included those who underwent low-dose CT imaging; those undergoing chest radiography were included in a confirmatory analysis. Participants with evidence of reticular/ reticulonodular opacities, honeycombing, fibrosis, or scarring were classified as having interstitial lung abnormalities. Lung cancer incidence and mortality in participants with and without interstitial lung abnormalities were compared by using Poisson and Cox regression, respectively.
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BACKGROUND:
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Of the 25,041 participants undergoing low-dose CT imaging included in the primary analysis, 20.2% had interstitial lung abnormalities. Participants with interstitial lung abnormalities had a higher incidence of lung cancer (incidence rate ratio, 1.61; 95% CI, 1.301.99). Interstitial lung abnormalities were associated with higher lung cancer incidence on adjusted analyses (incidence rate ratio, 1.33; 95% CI, 1.07-1.65). Lung cancer-specific mortality was also greater in participants with interstitial lung abnormalities. Similar findings were obtained in the analysis of participants undergoing chest radiography. RESULTS:
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Asymptomatic interstitial lung abnormalities are an independent risk factor for lung cancer that can be incorporated into risk score models. CHEST 2019; -(-):--CONCLUSIONS:
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KEY WORDS:
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interstitial lung abnormalities; lung cancer screening
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ABBREVIATIONS:
CXR = chest radiography; HR = hazard ratio; ILA = interstitial lung abnormality; IRR = incidence rate ratio; LDCT = lowdose chest CT AFFILIATIONS: From the Division of Pulmonary, Critical Care, and Sleep Medicine (Drs Whittaker Brown, Padilla, Powell, and Wisnivesky), Division of General Internal Medicine (Ms Mhango and Drs Sigel and Wisnivesky), and Division of Radiology (Drs Salvatore, Henschke, and Yankelevitz), Icahn School of Medicine at Mount Sinai, New York, NY; and Division of Respiratory Medicine (Dr de-Torres), Clínica Universidad de Navarra, Pamplona, Spain.
FUNDING/SUPPORT: This study was partially supported by the Stony Wold Herbert Inc. Foundation Fellowship Award. Q4 CORRESPONDENCE TO: Stacey-Ann Whittaker Brown, MD, MPH, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1232, New York, NY 10029; e-mail: [email protected] Q5 Copyright Ó 2019 Published by Elsevier Inc under license from the American College of Chest Physicians. DOI: https://doi.org/10.1016/j.chest.2019.06.041
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Interstitial lung diseases are associated with an increased risk of lung cancer.1-5 In particular, idiopathic pulmonary fibrosis (the most common interstitial lung disease) conveys a sixfold increased risk of lung cancer after adjusting for smoking.4,5 Preclinical or asymptomatic interstitial lung abnormalities (ILAs) are frequently detected in chest imaging studies conducted as part of routine care or for lung cancer screening.6-8 These abnormalities are associated with a lower exercise tolerance, a restrictive pattern on spirometry testing, a higher risk of developing clinically significant interstitial lung disease, and increased overall mortality.6,8-10 However, there is conflicting data as to whether ILAs are associated with an increased risk of lung cancer. An analysis of a cohort from the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study found
no association between ILA and overall risk of mortality from any cancer, although lung cancer mortality was not individually assessed.10 Hoyer et al11 reported that ILAs were associated with an increased risk of death from all cancers (both pulmonary and extrapulmonary) in a Danish lung cancer-screening population after adjusting for smoking exposure and FEV1. Further studies are therefore needed to clarify the significance of ILA on cancer risk.
Patients and Methods
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Study Population
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The National Lung Screening Trial protocol has previously been described.12 Overall, 53,452 participants from 33 medical centers in the United States were enrolled between April 2002 and April 2004 and randomized to three annual lung cancer screenings with either low-dose chest CT (LDCT) scans or chest radiography (CXR). Eligibility criteria included age 55 to 74 years with at least a 30 pack-year smoking history; former smokers were required to have quit smoking within the past 15 years. Participants with previous lung cancer, a CT scan in the past 18 months, or who had unexplained weight loss or hemoptysis were excluded. All lung cancer cases and deaths were recorded until December 31, 2009. For the current study, we included participants in both arms of the NLST, with participants from the LDCT arm included in the primary analysis and those in the CXR arm included in a secondary analysis. To assess prospective associations, participants with a positive baseline screen (ie, with findings suspicious for lung cancer) who developed lung cancer during the follow-up period were excluded. We also excluded participants with a history of interstitial lung diseases (pulmonary fibrosis, sarcoidosis, asbestosis, TB, or silicosis), which are known to be associated with lung cancer risk.
135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165
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The current study used data from the National Lung Cancer Screening Trial (NLST), the largest randomized controlled trial of lung cancer screening to date, to determine whether participants with ILA on baseline screening were at increased risk of developing lung cancer after controlling for other established risk factors.
177 178 179 180 181 182 183 184
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NLST radiologists were required to be certified by national accreditation boards, and all images were evaluated according to their institutions’ practice standards. Screening reports were recorded on standardized data forms and included both an isolated interpretation of the study examination and a reading following review of historical images, if available. Screening examinations were considered positive if they had findings concerning for lung cancer: noncalcified nodules that were $ 4 mm in diameter or were otherwise enlarging compared with historical examinations, concerning adenopathy, or pleural effusions. Study radiologists also reported whether radiographic emphysema or other abnormalities were present on chest imaging. In our analysis, participants with evidence of reticular/reticulonodular opacities, honeycombing, fibrosis, or scarring on their baseline screening test were classified as having ILA. Self-reported demographic information (age, sex, ethnicity, marital status, and education level) was obtained from study data. BMI was
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calculated from self-reported height and weight. Participants completed detailed questionnaires on smoking history (quantity and duration) and asbestos and other occupational exposures exceeding 1 year of duration. The Bach probability model was used as a summary measure of other lung cancer risk factors.13 This index assesses 10-year risk of lung cancer based on age, sex, smoking history, and asbestos exposure; it was derived from the b-Carotene and Retinol Efficacy Trial (CARET), a multicenter, randomized controlled trial comparing b-carotene and vitamin A supplementation in smokers.13,14 The Bach index has been validated in multiple screening cohorts15,16 and is extensively used to estimate lung cancer risk in epidemiologic and screening studies. The study’s primary end points were lung cancer incidence and mortality. Lung cancer cases were ascertained through standardized data collection forms and confirmed by review of the medical records and pathology reports. Lung cancer stage was determined Q8 according to American Joint Commission on Cancer, 7th edition.17 Lung cancer histology was determined according to the third edition of the International Classification of Diseases for Oncology,18 and morphology codes were abstracted from the medical record. Vital status information was collected through semi-annually or annually distributed data collection forms and/or from the National Death Index for those lost to follow-up. Death certificates were obtained for those known to have died, and lung cancer as the cause of death was determined via an end point verification team.
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The study was deemed exempt by the Institutional Review Board of the Icahn School of Medicine at Mount Sinai.
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Statistical Analysis
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The prevalence of ILA among participants in the LDCT and CXR arms was estimated with 95% CIs based on the binomial distribution. We compared baseline sociodemographic and lung cancer risk factors of NLST participants with and without ILA by using the c2 test for categorical variables and the Wilcoxon rank sum test for continuous variables. Unadjusted lung cancer incidence and the incidence rate ratio (IRR) in participants with and without ILA were calculated assuming a Poisson distribution; person-years were determined from time of baseline screening to diagnosis of lung cancer or last follow-up. Characteristics of lung tumors (location, stage, and histology)
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diagnosed in those with and without ILA were compared by using c2 tests. Poisson regression was used to assess the association of ILA with lung cancer risk after adjusting for the presence of radiographic emphysema and other lung cancer risk factors as summarized by using the Bach index. In a separate model, the analysis was repeated adjusting for age, sex, race, ethnicity, marital status, socioeconomic status, BMI, lung cancer family history, smoking history, history of COPD, presence of radiographic emphysema, asbestos exposure, and
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other occupational exposures entered as individual covariates. Lung cancer mortality in participants with and without ILA on baseline screening was compared by using Cox regression after adjusting for the covariates listed here. Analyses were conducted separately according to study arm (LDCT or CXR). All analyses were conducted by using SAS version 9.4 (SAS Institute, Inc.) using two-sided P values.
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Results
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A total of 53,452 subjects were enrolled in the NLST trial, and 50,206 participants were included in the analyses (Fig 1). There were 25,041 participants in the LDCT arm included in the primary analysis; ILAs were present in 5,053 (20.2%; 95% CI, 19.7-20.7) baseline LDCT images. Participants with ILAs were older (P < .01), more likely to be female (P < .01), and to have lower BMI (P < .01) (Table 1). In addition, ILAs were associated with more extensive smoking history (P ¼ .01) and higher rates of COPD and radiographic emphysema (P < .01). There was no significant difference in the frequency of asbestos exposure (P ¼ .28) or nonasbestos occupational exposures (P ¼ .57).
231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250
53,452 enrolled in the trial
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3,246 participants excluded:
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906 participants with lung cancer during follow-up were excluded (654 in LDCT scan arm, 252 in CXR arm): -20 diagnosed prior to the trial -852 had a positive baseline screen -34 did not complete baseline screen.
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2,340 participants without lung cancer were excluded: -1,300 had preexisting ILD -7 died prior to the trial -1,033 did not complete baseline imaging
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Participants with ILAs had reduced lung function relative to those without ILAs; a greater proportion were both restricted (40% vs 34%; P < .01) and obstructed (36% vs 31%; P < .01) (Table 2).
Figure 1 – Flow diagram of the study population. CXR ¼ chest radiograph; ILD ¼ interstitial lung disease; LDCT ¼ low-dose CT.
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The median follow-up time from baseline screening test was 6.6 years (interquartile range, 6.2-6.9 years). The cumulative incidence of lung cancer in the ILA group was higher relative to the non-ILA group (Fig 2). In the LDCT arm, there were 121 (2.4%) lung cancer cases (398 per 100,000 person-years) in the ILA group compared with 304 (1.5%) cases (249 per 100,000 person-years) in the non-ILA group (IRR, 1.61; 95% CI, 1.30-1.99) (Table 3). No significant differences were seen in tumor stage, location, or histology based on the presence of ILA (Table 4). Adjusted analyses also showed a higher lung cancer incidence in the ILA group (Table 5). The model adjusting for the presence of radiographic emphysema and Bach index yielded an IRR of 1.33 (95% CI, 1.071.65). Analyses adjusting for individual risk factors showed similar results.
There was a higher rate of lung cancer deaths in the ILA group vs the non-ILA group in the LDCT arm; there were 68 (1.3%) lung cancer deaths in the ILA group compared with 151 (0.8%) deaths in the non-ILA group (270 vs 187 per 100,000 person-years; hazard ratio [HR], 1.82; 95% CI, 1.37-2.42) (Table 3). Cox regression analysis adjusted for the presence of radiographic emphysema, and the Bach index showed increased lung cancer-specific mortality in participants with ILA (HR, 1.51; 95% CI, 1.13-2.03). Similar results were obtained in analyses adjusting for individual risk factors (Table 5). There was no difference in proportionate mortality in the ILA group vs the nonILA group (e-Table 1). Secondary Analysis in Participants Undergoing CXR
ILAs were present in 1,652 of the 25,146 participants undergoing CXR included in the analysis. Participants were older (P < .01) and more likely to be male
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Lung Cancer Mortality
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Lung Cancer Incidence
50,206 included in the final analysis • 25,041 in the LDCT scan arm • 25,146 in the CXR armC
285 286
310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330
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TABLE 1
] Characteristics of Participants With and Without ILAs on Baseline Screening, Low-Dose CT Scan No Baseline ILA (n ¼ 19,988)
Characteristic
334
Age, median (IQR), y
335
Female, No. (%)
336
Race/ethnicity, No. (%)
337
White
338
Black
339 340 341 342
60 (57-64)
4,552 (90)
< .01
392
391
352 (2)
398
334 (7)
.01
400
399
High school degree
4,577 (24)
Some college
401
2,780 (14)
701 (14)
402
4,676 (24)
1,178 (24)
3,505 (20)
796 (16)
Graduate school
2,881 (12)
730 (15)
14,571 (73)
3,284 (65)
BMI category, overweight or obese, No. (%)
353
Occupational exposure, No. (%)
354
Asbestos
355
Other
358
1,219 (25)
College degree
352
357
397 .03
346
Post-high school
79 (2) 3,324 (66)
1,165 (6)
348
395 396
13,465 (68)
Did not complete high school
356
393 394
74 (2)
345
351
191 (4)
368 (2)
347
Current smokers, No. (%)
403 404 405
826 (4)
192 (4)
.28
409
5,244 (26)
1,306 (26)
.57
410
9,503 (48)
2,505 (50)
.01
Total pack-years, median (IQR)
48 (39-66)
48 (39-66) 1,076 (22)
.49
360
COPD, No. (%)
3,216 (16)
1,039 (21)
< .01
361
Radiographic emphysema, No. (%)
5,406 (27)
2,262 (45)
< .01
365 366 367 368 369 370
375 376 377 378
415 416 417 418
(P < .01) (e-Table 2). There was a higher proportion of those with nonasbestos occupational exposure in the ILA group (P < .01), with more extensive smoking (P < .01), COPD, and radiographic emphysema (P < .01). ILAs were also associated with reduced lung TABLE 2
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function (e-Table 3). Lung cancer incidence was greater in the ILA group on unadjusted analysis (IRR, 1.69; 95% CI, 1.32-2.16) (e-Table 4) and following adjustment for the Bach index and radiographic emphysema (adjusted IRR, 1.47; 95% CI, 1.15-1.88) (e-Table 5). ILAs
No Baseline ILA (n ¼ 5,175)
Characteristic FVC, L
3.44 (2.80-4.20)
FVC, % predicted
86 (75-97)
FEV1, L
2.48 (2.00-3.08)
Baseline ILA (n ¼ 1,415) 3.26 (2.69-4.06) 84 (71-96) 2.36 (1.88-2.96)
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] Spirometric Values of Patients With and Without ILAs on Baseline Screening, Low-Dose CT Scan
373 374
413 414
ILA ¼ interstitial lung abnormality; IQR ¼ interquartile range.
371 372
411 412
.83
4,367 (23)
364
407 408
Family history of lung cancer, No. (%)
363
406
< .01
359
362
389
18,006 (90)
Latino
Education, No. (%)
< .01
390
154 (2)
344
388
< .01
358 (2)
Other
387
P Value
2,311 (46)
Asian
343
350
61 (58-66)
386
8,035 (40)
881 (4)
Married, No. (%)
349
Baseline ILA (n ¼ 5,053)
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427 428 429
P Value
430
< .01
431
< .01
432
< .01
433
< .01
379
FEV1, % predicted
380
Ratio of FEV1 to FVC
381
Proportion with restriction, FVC % predicted < 80%, No. (%)
1,774 (34)
560 (40)
< .01
436
Proportion with obstruction, ratio of FEV1 to FVC < 0.7, No. (%)
1,606 (31)
510 (36)
< .01
438
382 383 384 385
83 (68-96) 0.74 (0.67-0.79)
80 (64-93) 0.73 (0.66-0.79)
434
< .01
435 437 439 440
Data are presented as the median (IQR) unless otherwise indicated. See Table 1 legend for expansion of abbreviations.
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Cumulative Incidence of Lung Cancer
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0.020 0.015 0.010 0.005 0.000
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0.025
0
2
ILA
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present
Figure 2 – Cumulative lung cancer incidence based on the presence of ILAs on baseline screening LDCT scan. ILAs ¼ interstitial lung abnormalities. See Figure 1 legend for expansion of other abbreviation.
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were also associated with increased lung cancer mortality (adjusted HR, 1.53; 95% CI, 1.11-2.09). There was no difference in the lung cancer characteristics between the two groups (e-Table 6). A greater proportion of deaths in the ILA group were related to respiratory causes (15% vs 8%; P ¼ .02) (e-Table 1).
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Discussion
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In this study, we found that ILAs were independently associated with lung cancer incidence and mortality among high-risk smokers after controlling for other established risk factors. Our study extends previous results showing an association of clinically evident interstitial lung disease with lung cancer risk and provides new evidence regarding the prognostic significance of asymptomatic, radiologically detected ILA.
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Interstitial lung disease represents a heterogeneous designation of pathologic states diffusely affecting the lung parenchyma. Of the interstitial lung diseases of known etiology, pulmonary asbestosis conveys the
highest lung cancer risk, with a more than sevenfold increased incidence in nonsmokers and an even greater synergistically increased risk in smokers.19-21 Similarly, some connective tissue disease-associated interstitial lung diseases are also associated with an increased incidence of lung cancer.22-24 In a large retrospective observational study of US veterans, the adjusted OR for lung cancer in patients with rheumatoid arthritis was 1.43 (95% CI, 1.23-1.65).24 Likewise, a Danish population-based study of scleroderma reported a standardized lung cancer incidence ratio of 1.6 (95% CI, 1.2-2.0).23 Of the interstitial lung diseases of unknown origin, idiopathic pulmonary fibrosis is the most strongly associated with lung cancer,3-5,25-27 with adjusted lung cancer IRRs ranging from 4.96 (95% CI, 3.0-8.18) to 8.25 (95% CI, 4.70-11.48).4,5 This literature shows evidence of the relation between more severe parenchymal abnormalities and carcinogenesis. The current study assessed whether asymptomatic interstitial abnormalities, incidentally detected on screening LDCT imaging, are an independent risk factor for subsequent lung cancer. A secondary analysis of the Danish Lung Cancer Screening Trial found an association of ILA with lung cancer incidence (OR, 5.4; P < .01) that varied according to ILA subtype: centrilobular nodules (OR, 2.5; P < .01), ground-glass opacities (OR, 5.4; P < .01), reticulation (OR, 4.3; P < .01), and honeycombing (OR, 14; P < .01).28 However, these analyses were unadjusted and did not account for smoking exposure, concomitant presence of COPD, or radiographic emphysema, all major confounders of the association of ILA with lung cancer risk.9,29-34 Nishino et al35 assessed the relationship between ILA and lung cancer mortality in a cohort of 120 patients with treatment-naive, advanced lung cancer and showed that ILA was associated with worse survival (HR, 2.09; P ¼ .03) after adjusting for age, smoking
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537
483
538
484
TABLE 3
] Unadjusted Lung Cancer Incidence and Mortality in Participants With and Without ILAs on Baseline
486
541 P Value
Lung Cancer Incident Cases per 100,000 Person-Years (95% CI)
ILA
121 (2.4)
< .01
398 (333-476)
1.61 (1.30-1.99)
543
No ILA
304 (1.5)
248 (221-227)
Reference
544
Variable
488 489 490
Lung Cancer Deaths, No. (%)
491 493
ILA
494
No ILA
495
540
Lung Cancer Cases, No. (%)
487
492
539
Screening, Low-Dose CT Scan
485
68 (1.3) 151 (0.8)
Unadjusted IRR (95% CI)
542
545 546
P Value
Lung Cancer Deaths per 100,000 Person-Years (95% CI)
< .01
217 (171-275))
1.82 (1.37-2.42)
548
120 (103-141
Reference
549
Unadjusted HR (95% CI)
550
HR ¼ hazard ratio; IRR ¼ incidence rate ratio. See Table 1 legend for expansion of other abbreviation.
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TABLE 4
] Lung Cancer Characteristics According to Presence of ILAs on Baseline Screening, Low-Dose CT Scan
Characteristic
No Baseline ILA (n ¼ 300)
Baseline ILA (n ¼ 120)
606 607
P Value
608
Stage, No. (%)
609
555
I
122 (42)
39 (33)
556
II
24 (8)
16 (14)
611
557
III
59 (20)
20 (17)
612
558
IV
89 (31)
43 (36)
559 560 561
Upper lobe
158 (55) 24 (8)
563
Lower lobe
79 (28)
Other
25 (9)
566
Small cell carcinoma
616
3 (3)
617
40 (36)
618
8 (7)
52 (17)
Squamous cell carcinoma Adenocarcinoma
571
615
.11
619 620
568 570
61 (55)
Histology, No. (%)
567 569
613
Location, No. (%)
Middle lobe
565
610
614
562 564
.14
Other
28 (23)
85 (28)
37 (31)
108 (36)
37 (31)
55 (18)
15 (15)
621
.55
622 623 624 625 626
See Table 1 legend for expansion of other abbreviation.
572
627
573
628
574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596
exposure, and type of first-line systemic therapy. Hoyer et al11 determined that ILA was associated with lung cancer mortality in the Danish screening population (HR, 3.2; 95% CI, 1.7-6.2) after adjusting for age, sex, BMI, smoking exposure, and FEV1. However, FEV1 alone does not adequately capture cases of COPD or radiographic emphysema, and thus residual confounding by COPD/emphysema may explain why their reported estimate was higher than reported in our study. In the current study, we found that asymptomatic ILA was independently associated with lung cancer incidence and mortality even following careful adjustment for confounders, suggesting that ILAs are an independent risk factor for lung cancer. There are several potential explanations for the relationship between ILAs and lung cancer. First, some individuals with ILA develop clinically significant pulmonary fibrosis, an established risk factor for lung cancer.6 However, the small percentage of those with ILA who are expected to develop clinically significant interstitial lung disease within the follow-up period
597 598
TABLE 5
suggests that the severity and progression of ILA alone are unlikely to explain our findings. Second, some histopathologic features associated with ILAs may play a role in lung cancer risk. Miller et al36 reported increased odds of atypical adenomatous hyperplasia, fibroblast foci, and subpleural fibrosis in biopsy specimens of subjects with preclinical ILA. Atypical adenomatous hyperplasia is recognized as a preinvasive adenocarcinoma, potentially explaining our findings.37 In addition, fibroblast foci, a pathologic hallmark of pulmonary fibrosis that arises in the setting of myofibroblast activation, may be important for supporting tumorigenesis.38 Third, ILAs are associated with genetic changes that may predispose to lung cancer development. MUC5B is a glycoprotein required for optimal mucociliary clearance; a promoter variant (rs35705950) is associated with MUC5B overexpression, ILAs, and pulmonary fibrosis.39-42 Although no studies have reported a direct relationship with lung cancer incidence, MUC5B expression in lung tumors has been associated with worse prognosis,43-45 suggesting a
633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653
Dose CT Scan
600 601
Study Arm
602
ILA vs no ILA
654 Model 1 Adjusted IRR (95% CI)
Model 2 Adjusted IRR (95% CI)
Model 3 Adjusted HR (95% CI)
Model 4 Adjusted HR (95% CI)
1.33 (1.07-1.65)
1.39 (1.11-1.74)
1.51 (1.13-2.03)
1.58 (1.17-2.15)
655 656 657
603 605
631 632
] Adjusted Lung Cancer Incidence and Mortality based on Presence of ILAs on Baseline Screening, Low-
599
604
629 630
Models 1 and 3 were adjusted for the presence of radiographic emphysema and the Bach index. Models 2 and 4 were adjusted for age, race, sex, marital status, socioeconomic status, BMI, lung cancer family history, smoking history, COPD, presence of radiographic emphysema, asbestos exposure, and other occupational exposures. See Table 1 and 3 legends for expansion of other abbreviations.
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658 659 660
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potential role in cancer biology. Similarly, galectin-3, a lecithin involved in tumor angiogenesis and metastases,46-51 has also been implicated in the development of ILA.52 However, the detailed pathways underlying the relationship between ILA and lung cancer remain unclear. Further research in this area may unveil unknown mechanisms, potentially offering new therapeutic targets for these conditions. There are strengths and limitations of our study that should be noted. We analyzed data from a large, wellcharacterized multisite study with uniform and comprehensive ascertainment of lung cancer incidence and long-term follow-up of study participants. In addition, there was standardization in the collection and reporting of radiographic findings and detailed information regarding confounding risk factors that allowed for careful adjustment in our models. Our results should be generalizable to most screening populations. However, our data cannot be extrapolated to nonsmokers with ILAs who did not meet selection criteria for the NLST trial. Although the NLST provided a detailed description of lung nodules, a relatively heterogeneous group of interstitial radiologic findings was reported as a single ILA category. Thus, we were unable to determine if certain ILA subtypes or whether the extent of abnormalities have a differential effect on lung cancer risk. Our reported prevalence of ILA in the LDCT arm was 20% compared with a prevalence of 5% to 10% for definitive ILA and 20% to 36% for indeterminate ILA reported in the literature.6,9,10,53-55 However, if a proportion of NLST participants with equivocal changes were classified as having ILAs, our results would be biased toward the null. Regarding ILA subtypes, Hoyer
et al11 reported that all subtypes (honeycombing, ground-glass opacities, nodular, and reticular changes) were associated with lung cancer risk, with the highest risk conveyed by honeycomb changes. We were unable to test these relationships due to the heterogeneous designation used by radiologists. In addition, although the study radiologists used standardized forms, there was no standardized process in defining an ILA. A larger problem is that there is currently no standardized definition of ILA in the literature. Therefore, further study into lung cancer risk in ILA subtypes ascertained by validated quantitative and qualitative methods, accounting for radiographic emphysema, should be conducted. Only a subset of participants in the NLST trial underwent spirometry; thus, we were unable to fully assess whether spirometric data acted as a mediator between the relationship between ILA and lung cancer. Because our study used data from a screening trial, some of the lung cancers may be overdiagnosed cases. However, ILA was also associated with increased lung cancer mortality, suggesting that differences in the incidence of lung cancer could not be explained by a higher prevalence of nonaggressive cancers among participants with ILAs.
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The current study found that ILA is an independent risk factor for lung cancer in smokers. These results suggest the need for additional research to unveil the mechanisms linking pulmonary fibrosis and lung carcinogenesis. In addition, the presence of ILA could be used to further stratify lung cancer risk following baseline screening LDCT to select the best subsequent screening regimen.
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Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. P. has served as a consultant to Boehringer Ingelheim. She has also served as faculty presenter on lectures supported by Genentech and the France Foundation; and has been an investigator on several multisite clinical trials on idiopathic pulmonary fibrosis sponsored by various pharmaceutical companies. M. S. has been a speaker for Genentech, Boehringer Ingelheim, and Eastern Pulmonary Conference; and a consultant for Genentech and Boehringer Ingelheim. C. H. is a named inventor on a number of patents and patent applications relating to the evaluation of pulmonary nodules on CT scans of the chest which are owned by Cornell Research Foundation. Since 2009, she does not accept any financial benefit from these patents, including royalties and any other proceeds related to the patents or patent applications owned by Cornell Research Foundation. She is President and serves on the board of the Early Diagnosis and Treatment Research Foundation and receives no compensation from the Foundation. The Foundation is established to provide grants for projects, conferences, and public databases for research on early diagnosis and treatment of diseases. Recipients include the International Early Lung Cancer Action Program, among others. The funding comes from a variety of sources, including philanthropic donations, grants and contracts with agencies (federal and nonfederal), imaging, and pharmaceutical companies relating to image processing assessments. The various sources of funding exclude any funding from tobacco companies or tobacco-related sources. D. Y. is an equity owner in Accumetra, a privately held technology company committed to improving the science and practice of imagebased decision-making. He also serves on the advisory board of GRAIL. In addition, he is a named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest, including measurement of nodules. Some of these, which are owned by Cornell Research Foundation, are nonexclusively licensed to General Electric. As an inventor of these patents, he is entitled to a share of any compensation that Cornell Research Foundation may receive from its commercialization of these patents. J. W. has received consulting honorarium from Sanofi and Banook and research grants from Sanofi and Quorum. None declared (S.-A. W. B., G. M., C. P., K. S., J. P. d.-T.).
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Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
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Author contributions: All authors contributed to conception and design; manuscript writing; and collection, assembly, analysis, and interpretation of data. All authors gave final approval of the manuscript as submitted.
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Other contributions: The authors are grateful to the National Cancer Institute for providing access to data from the NLST. The analysis and manuscript are solely the responsibility of the authors. Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.
References 1. Lee T, Park JY, Lee HY, et al. Lung cancer in patients with idiopathic pulmonary fibrosis: clinical characteristics and impact on survival. Respir Med. 2014;108(10): 1549-1555. 2. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J. 2015;46(4):11131130. 3. Tomassetti S, Gurioli C, Ryu JH, et al. The impact of lung cancer on survival of idiopathic pulmonary fibrosis. Chest. 2015;147(1):157-164. 4. Le Jeune I, Gribbin J, West J, Smith C, Cullinan P, Hubbard R. The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med. 2007;101(12):2534-2540. 5. Hubbard R, Venn A, Lewis S, Britton J. Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med. 2000;161(1):5-8. 6. Jin GY, Lynch D, Chawla A, et al. Interstitial lung abnormalities in a CT lung cancer screening population: prevalence and progression rate. Radiology. 2013;268(2):563-571. 7. Washko GR, Lynch DA, Matsuoka S, et al. Identification of early interstitial lung disease in smokers from the COPDGene Study. Acad Radiol. 2010;17(1):48-53. 8. Doyle TJ, Washko GR, Fernandez IE, et al. Interstitial lung abnormalities and reduced exercise capacity. Am J Respir Crit Care Med. 2012;185(7):756-762. 9. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med. 2011;364(10):897-906. 10. Putman RK, Hatabu H, Araki T, et al. Association between interstitial lung abnormalities and all-cause mortality. JAMA. 2016;315(7):672-681. 11. Hoyer N, Wille MMW, Thomsen LH, et al. Interstitial lung abnormalities are associated with increased mortality in smokers. Respir Med. 2018;136:77-82. 12. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with lowdose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.
combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):11501155. 15. Li K, Husing A, Sookthai D, et al. Selecting high-risk individuals for lung cancer screening: a prospective evaluation of existing risk models and eligibility criteria in the German EPIC cohort. Cancer Prev Res (Phila). 2015;8(9):777-785.
826 827 828 829 830 831 832 833
16. Ten Haaf K, Jeon J, Tammemagi MC, et al. Risk prediction models for selection of lung cancer screening candidates: a retrospective validation study. PLoS Med. 2017;14(4):e1002277.
834
17. Edge SBBD, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. 2010. New York, NY.
838
18. Fritz AG. International Classification of Diseases for Oncology: ICD-O. 3rd ed. Geneva, Switzerland: World Health Organization; 2000.
840
843 844 845 846 847 848 849
21. Erren TC, Jacobsen M, Piekarski C. Synergy between asbestos and smoking on lung cancer risks. Epidemiology. 1999;10(4):405-411. 22. Enomoto Y, Inui N, Yoshimura K, et al. Lung cancer development in patients with connective tissue disease-related interstitial lung disease: a retrospective observational study. Medicine (Baltimore). 2016;95(50):e5716. 23. Olesen AB, Svaerke C, Farkas DK, Sorensen HT. Systemic sclerosis and the risk of cancer: a nationwide populationbased cohort study. Br J Dermatol. 2010;163(4):800-806. 24. Khurana R, Wolf R, Berney S, Caldito G, Hayat S, Berney SM. Risk of development of lung cancer is increased in patients with rheumatoid arthritis: a large case control study in US veterans. J Rheumatol. 2008;35(9):1704-1708. 25. Ozawa Y, Suda T, Naito T, et al. Cumulative incidence of and predictive factors for lung cancer in IPF. Respirology. 2009;14(5):723-728. 26. Harris JM, Johnston ID, Rudd R, Taylor AJ, Cullinan P. Cryptogenic fibrosing alveolitis and lung cancer: the BTS study. Thorax. 2010;65(1):70-76.
850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872
27. Park J, Kim DS, Shim TS, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2001;17(6):1216-1219.
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13. Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst. 2003;95(6): 470-478.
28. Wille MM, Thomsen LH, Petersen J, et al. Visual assessment of early emphysema and interstitial abnormalities on CT is useful in lung cancer risk analysis. Eur Radiol. 2016;26(2):487-494.
14. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a
29. Lederer DJ, Enright PL, Kawut SM, et al. Cigarette smoking is associated with
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20. Weiss W. Asbestosis: a marker for the increased risk of lung cancer among workers exposed to asbestos. Chest. 1999;115(2):536-549.
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19. Markowitz SB, Levin SM, Miller A, Morabia A. Asbestos, asbestosis, smoking, and lung cancer. New findings from the North American insulator cohort. Am J Respir Crit Care Med. 2013;188(1):90-96.
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subclinical parenchymal lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA)-lung study. Am J Respir Crit Care Med. 2009;180(5):407-414.
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30. Araki T, Nishino M, Zazueta OE, et al. Paraseptal emphysema: prevalence and distribution on CT and association with interstitial lung abnormalities. Eur J Radiol. 2015;84(7):1413-1418.
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31. Denholm R, Schuz J, Straif K, et al. Is previous respiratory disease a risk factor for lung cancer? Am J Respir Crit Care Med. 2014;190(5):549-559.
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32. Henschke CI, Yip R, Boffetta P, et al. CT screening for lung cancer: importance of emphysema for never smokers and smokers. Lung Cancer. 2015;88(1):42-47.
892 893 894
33. de Torres JP, Bastarrika G, Wisnivesky JP, et al. Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest. 2007;132(6):1932-1938.
895 896 897 898
34. Smith BM, Pinto L, Ezer N, Sverzellati N, Muro S, Schwartzman K. Emphysema detected on computed tomography and risk of lung cancer: a systematic review and meta-analysis. Lung Cancer. 2012;77(1):58-63.
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35. Nishino M, Cardarella S, Dahlberg SE, et al. Interstitial lung abnormalities in treatment-naive advanced non-small-cell lung cancer patients are associated with shorter survival. Eur J Radiol. 2015;84(5): 998-1004.
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36. Miller ER, Putman RK, Vivero M, et al. Histopathology of interstitial lung abnormalities in the context of lung nodule resections. Am J Respir Crit Care Med. 2018;197(7):955-958.
Q14
37. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Fourth edition. IARC; 2015.
908 909 910 911 912 913 914
38. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582-598. 39. Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503-1512. 40. Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med. 2011;364(16):1576-1577. 41. Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med. 2013;368(23):2192-2200. 42. Putman RK, Gudmundsson G, Araki T, et al. The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes. Eur Respir J. 2017;50(3). 43. Kim YK, Shin DH, Kim KB, et al. MUC5AC and MUC5B enhance the characterization of mucinous adenocarcinomas of the lung and predict poor prognosis. Histopathology. 2015;67(4):520-528. 44. Yu CJ, Yang PC, Shun CT, Lee YC, Kuo SH, Luh KT. Overexpression of MUC5 genes is associated with early postoperative metastasis in non-small-cell lung cancer. Int J Cancer. 1996;69(6):457465. 45. Nagashio R, Ueda J, Ryuge S, et al. Diagnostic and prognostic significances of MUC5B and TTF-1 expressions in resected non-small cell lung cancer. Sci Rep. 2015;5:8649. 46. Chung LY, Tang SJ, Wu YC, Sun GH, Liu HY, Sun KH. Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with beta-catenin. Oncotarget. 2015;6(7):4936-4952.
47. Kosacka M, Piesiak P, Kowal A, Golecki M, Jankowska R. Galectin-3 and cyclin D1 expression in non-small cell lung cancer. J Exp Clin Cancer Res. 2011;30:101.
936 937 938 939
48. Szoke T, Kayser K, Baumhakel JD, et al. Prognostic significance of endogenous adhesion/growth-regulatory lectins in lung cancer. Oncology. 2005;69(2):167174.
940
49. Nangia-Makker P, Balan V, Raz A. Galectin-3 binding and metastasis. Methods Mol Biol. 2012;878:251-266.
944
941 942 943 945
50. Nishi Y, Sano H, Kawashima T, et al. Role of galectin-3 in human pulmonary fibrosis. Allergol Int. 2007;56(1):57-65. 51. Mackinnon AC, Gibbons MA, Farnworth SL, et al. Regulation of transforming growth factor-beta1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012;185(5):537-546. 52. Ho JE, Gao W, Levy D, et al. Galectin-3 is associated with restrictive lung disease and interstitial lung abnormalities. Am J Respir Crit Care Med. 2016;194(1):77-83.
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53. Araki T, Putman RK, Hatabu H, et al. Development and progression of interstitial lung abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med. 2016;194(12):1514-1522.
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54. Shah RD, Hutchison PJ, Nicholson TT. Risk factors for development of acute lung injury, physicians’ decision-making roles in critical illness, and prevalence of interstitial lung abnormalities in lung cancer screening populations. Am J Respir Crit Care Med. 2014;189(10):12731274.
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55. Salvatore M, Henschke CI, Yip R, et al. JOURNAL CLUB: evidence of interstitial lung disease on low-dose chest CT images: prevalence, patterns, and progression. AJR Am J Roentgenol. 2016;206(3):487-494.
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Interstitial Lung Abnormalities and Lung Cancer Risk in the National Lung Screening Trial
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Stacey-Ann Whittaker Brown, MD, MPH; Maria Padilla, MD; Grace Mhango, MPH; Charles Powell, MD; Mary Salvatore, MD; Claudia Henschke, PhD, MD; David Yankelevitz, MD; Keith Sigel, MD, PhD; Juan P. de-Torres, MD;
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Some interstitial lung diseases are associated with lung cancer. However, it is unclear whether asymptomatic interstitial lung abnormalities convey an independent risk.
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OBJECTIVES:
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The goal of this study was to assess whether interstitial lung abnormalities are associated with an increased risk of lung cancer.
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Data from all participants in the National Lung Cancer Trial were analyzed, except for subjects with preexisting interstitial lung disease or prevalent lung cancers. The primary analysis included those who underwent low-dose CT imaging; those undergoing chest radiography were included in a confirmatory analysis. Participants with evidence of reticular/ reticulonodular opacities, honeycombing, fibrosis, or scarring were classified as having interstitial lung abnormalities. Lung cancer incidence and mortality in participants with and without interstitial lung abnormalities were compared by using Poisson and Cox regression, respectively.
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Of the 25,041 participants undergoing low-dose CT imaging included in the primary analysis, 20.2% had interstitial lung abnormalities. Participants with interstitial lung abnormalities had a higher incidence of lung cancer (incidence rate ratio, 1.61; 95% CI, 1.301.99). Interstitial lung abnormalities were associated with higher lung cancer incidence on adjusted analyses (incidence rate ratio, 1.33; 95% CI, 1.07-1.65). Lung cancer-specific mortality was also greater in participants with interstitial lung abnormalities. Similar findings were obtained in the analysis of participants undergoing chest radiography. RESULTS:
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Asymptomatic interstitial lung abnormalities are an independent risk factor for lung cancer that can be incorporated into risk score models. CHEST 2019; -(-):--CONCLUSIONS:
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KEY WORDS:
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interstitial lung abnormalities; lung cancer screening
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ABBREVIATIONS:
CXR = chest radiography; HR = hazard ratio; ILA = interstitial lung abnormality; IRR = incidence rate ratio; LDCT = lowdose chest CT AFFILIATIONS: From the Division of Pulmonary, Critical Care, and Sleep Medicine (Drs Whittaker Brown, Padilla, Powell, and Wisnivesky), Division of General Internal Medicine (Ms Mhango and Drs Sigel and Wisnivesky), and Division of Radiology (Drs Salvatore, Henschke, and Yankelevitz), Icahn School of Medicine at Mount Sinai, New York, NY; and Division of Respiratory Medicine (Dr de-Torres), Clínica Universidad de Navarra, Pamplona, Spain.
FUNDING/SUPPORT: This study was partially supported by the Stony Wold Herbert Inc. Foundation Fellowship Award. Q4 CORRESPONDENCE TO: Stacey-Ann Whittaker Brown, MD, MPH, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1232, New York, NY 10029; e-mail: [email protected] Q5 Copyright Ó 2019 Published by Elsevier Inc under license from the American College of Chest Physicians. DOI: https://doi.org/10.1016/j.chest.2019.06.041
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Interstitial lung diseases are associated with an increased risk of lung cancer.1-5 In particular, idiopathic pulmonary fibrosis (the most common interstitial lung disease) conveys a sixfold increased risk of lung cancer after adjusting for smoking.4,5 Preclinical or asymptomatic interstitial lung abnormalities (ILAs) are frequently detected in chest imaging studies conducted as part of routine care or for lung cancer screening.6-8 These abnormalities are associated with a lower exercise tolerance, a restrictive pattern on spirometry testing, a higher risk of developing clinically significant interstitial lung disease, and increased overall mortality.6,8-10 However, there is conflicting data as to whether ILAs are associated with an increased risk of lung cancer. An analysis of a cohort from the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study found
no association between ILA and overall risk of mortality from any cancer, although lung cancer mortality was not individually assessed.10 Hoyer et al11 reported that ILAs were associated with an increased risk of death from all cancers (both pulmonary and extrapulmonary) in a Danish lung cancer-screening population after adjusting for smoking exposure and FEV1. Further studies are therefore needed to clarify the significance of ILA on cancer risk.
Patients and Methods
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The National Lung Screening Trial protocol has previously been described.12 Overall, 53,452 participants from 33 medical centers in the United States were enrolled between April 2002 and April 2004 and randomized to three annual lung cancer screenings with either low-dose chest CT (LDCT) scans or chest radiography (CXR). Eligibility criteria included age 55 to 74 years with at least a 30 pack-year smoking history; former smokers were required to have quit smoking within the past 15 years. Participants with previous lung cancer, a CT scan in the past 18 months, or who had unexplained weight loss or hemoptysis were excluded. All lung cancer cases and deaths were recorded until December 31, 2009. For the current study, we included participants in both arms of the NLST, with participants from the LDCT arm included in the primary analysis and those in the CXR arm included in a secondary analysis. To assess prospective associations, participants with a positive baseline screen (ie, with findings suspicious for lung cancer) who developed lung cancer during the follow-up period were excluded. We also excluded participants with a history of interstitial lung diseases (pulmonary fibrosis, sarcoidosis, asbestosis, TB, or silicosis), which are known to be associated with lung cancer risk.
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The current study used data from the National Lung Cancer Screening Trial (NLST), the largest randomized controlled trial of lung cancer screening to date, to determine whether participants with ILA on baseline screening were at increased risk of developing lung cancer after controlling for other established risk factors.
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NLST radiologists were required to be certified by national accreditation boards, and all images were evaluated according to their institutions’ practice standards. Screening reports were recorded on standardized data forms and included both an isolated interpretation of the study examination and a reading following review of historical images, if available. Screening examinations were considered positive if they had findings concerning for lung cancer: noncalcified nodules that were $ 4 mm in diameter or were otherwise enlarging compared with historical examinations, concerning adenopathy, or pleural effusions. Study radiologists also reported whether radiographic emphysema or other abnormalities were present on chest imaging. In our analysis, participants with evidence of reticular/reticulonodular opacities, honeycombing, fibrosis, or scarring on their baseline screening test were classified as having ILA. Self-reported demographic information (age, sex, ethnicity, marital status, and education level) was obtained from study data. BMI was
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calculated from self-reported height and weight. Participants completed detailed questionnaires on smoking history (quantity and duration) and asbestos and other occupational exposures exceeding 1 year of duration. The Bach probability model was used as a summary measure of other lung cancer risk factors.13 This index assesses 10-year risk of lung cancer based on age, sex, smoking history, and asbestos exposure; it was derived from the b-Carotene and Retinol Efficacy Trial (CARET), a multicenter, randomized controlled trial comparing b-carotene and vitamin A supplementation in smokers.13,14 The Bach index has been validated in multiple screening cohorts15,16 and is extensively used to estimate lung cancer risk in epidemiologic and screening studies. The study’s primary end points were lung cancer incidence and mortality. Lung cancer cases were ascertained through standardized data collection forms and confirmed by review of the medical records and pathology reports. Lung cancer stage was determined Q8 according to American Joint Commission on Cancer, 7th edition.17 Lung cancer histology was determined according to the third edition of the International Classification of Diseases for Oncology,18 and morphology codes were abstracted from the medical record. Vital status information was collected through semi-annually or annually distributed data collection forms and/or from the National Death Index for those lost to follow-up. Death certificates were obtained for those known to have died, and lung cancer as the cause of death was determined via an end point verification team.
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The study was deemed exempt by the Institutional Review Board of the Icahn School of Medicine at Mount Sinai.
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Statistical Analysis
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The prevalence of ILA among participants in the LDCT and CXR arms was estimated with 95% CIs based on the binomial distribution. We compared baseline sociodemographic and lung cancer risk factors of NLST participants with and without ILA by using the c2 test for categorical variables and the Wilcoxon rank sum test for continuous variables. Unadjusted lung cancer incidence and the incidence rate ratio (IRR) in participants with and without ILA were calculated assuming a Poisson distribution; person-years were determined from time of baseline screening to diagnosis of lung cancer or last follow-up. Characteristics of lung tumors (location, stage, and histology)
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diagnosed in those with and without ILA were compared by using c2 tests. Poisson regression was used to assess the association of ILA with lung cancer risk after adjusting for the presence of radiographic emphysema and other lung cancer risk factors as summarized by using the Bach index. In a separate model, the analysis was repeated adjusting for age, sex, race, ethnicity, marital status, socioeconomic status, BMI, lung cancer family history, smoking history, history of COPD, presence of radiographic emphysema, asbestos exposure, and
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other occupational exposures entered as individual covariates. Lung cancer mortality in participants with and without ILA on baseline screening was compared by using Cox regression after adjusting for the covariates listed here. Analyses were conducted separately according to study arm (LDCT or CXR). All analyses were conducted by using SAS version 9.4 (SAS Institute, Inc.) using two-sided P values.
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A total of 53,452 subjects were enrolled in the NLST trial, and 50,206 participants were included in the analyses (Fig 1). There were 25,041 participants in the LDCT arm included in the primary analysis; ILAs were present in 5,053 (20.2%; 95% CI, 19.7-20.7) baseline LDCT images. Participants with ILAs were older (P < .01), more likely to be female (P < .01), and to have lower BMI (P < .01) (Table 1). In addition, ILAs were associated with more extensive smoking history (P ¼ .01) and higher rates of COPD and radiographic emphysema (P < .01). There was no significant difference in the frequency of asbestos exposure (P ¼ .28) or nonasbestos occupational exposures (P ¼ .57).
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906 participants with lung cancer during follow-up were excluded (654 in LDCT scan arm, 252 in CXR arm): -20 diagnosed prior to the trial -852 had a positive baseline screen -34 did not complete baseline screen.
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2,340 participants without lung cancer were excluded: -1,300 had preexisting ILD -7 died prior to the trial -1,033 did not complete baseline imaging
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Participants with ILAs had reduced lung function relative to those without ILAs; a greater proportion were both restricted (40% vs 34%; P < .01) and obstructed (36% vs 31%; P < .01) (Table 2).
Figure 1 – Flow diagram of the study population. CXR ¼ chest radiograph; ILD ¼ interstitial lung disease; LDCT ¼ low-dose CT.
290
The median follow-up time from baseline screening test was 6.6 years (interquartile range, 6.2-6.9 years). The cumulative incidence of lung cancer in the ILA group was higher relative to the non-ILA group (Fig 2). In the LDCT arm, there were 121 (2.4%) lung cancer cases (398 per 100,000 person-years) in the ILA group compared with 304 (1.5%) cases (249 per 100,000 person-years) in the non-ILA group (IRR, 1.61; 95% CI, 1.30-1.99) (Table 3). No significant differences were seen in tumor stage, location, or histology based on the presence of ILA (Table 4). Adjusted analyses also showed a higher lung cancer incidence in the ILA group (Table 5). The model adjusting for the presence of radiographic emphysema and Bach index yielded an IRR of 1.33 (95% CI, 1.071.65). Analyses adjusting for individual risk factors showed similar results.
There was a higher rate of lung cancer deaths in the ILA group vs the non-ILA group in the LDCT arm; there were 68 (1.3%) lung cancer deaths in the ILA group compared with 151 (0.8%) deaths in the non-ILA group (270 vs 187 per 100,000 person-years; hazard ratio [HR], 1.82; 95% CI, 1.37-2.42) (Table 3). Cox regression analysis adjusted for the presence of radiographic emphysema, and the Bach index showed increased lung cancer-specific mortality in participants with ILA (HR, 1.51; 95% CI, 1.13-2.03). Similar results were obtained in analyses adjusting for individual risk factors (Table 5). There was no difference in proportionate mortality in the ILA group vs the nonILA group (e-Table 1). Secondary Analysis in Participants Undergoing CXR
ILAs were present in 1,652 of the 25,146 participants undergoing CXR included in the analysis. Participants were older (P < .01) and more likely to be male
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Lung Cancer Mortality
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287 288 289
Lung Cancer Incidence
50,206 included in the final analysis • 25,041 in the LDCT scan arm • 25,146 in the CXR armC
285 286
310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330
331 332 333
TABLE 1
] Characteristics of Participants With and Without ILAs on Baseline Screening, Low-Dose CT Scan No Baseline ILA (n ¼ 19,988)
Characteristic
334
Age, median (IQR), y
335
Female, No. (%)
336
Race/ethnicity, No. (%)
337
White
338
Black
339 340 341 342
60 (57-64)
4,552 (90)
< .01
392
391
352 (2)
398
334 (7)
.01
400
399
High school degree
4,577 (24)
Some college
401
2,780 (14)
701 (14)
402
4,676 (24)
1,178 (24)
3,505 (20)
796 (16)
Graduate school
2,881 (12)
730 (15)
14,571 (73)
3,284 (65)
BMI category, overweight or obese, No. (%)
353
Occupational exposure, No. (%)
354
Asbestos
355
Other
358
1,219 (25)
College degree
352
357
397 .03
346
Post-high school
79 (2) 3,324 (66)
1,165 (6)
348
395 396
13,465 (68)
Did not complete high school
356
393 394
74 (2)
345
351
191 (4)
368 (2)
347
Current smokers, No. (%)
403 404 405
826 (4)
192 (4)
.28
409
5,244 (26)
1,306 (26)
.57
410
9,503 (48)
2,505 (50)
.01
Total pack-years, median (IQR)
48 (39-66)
48 (39-66) 1,076 (22)
.49
360
COPD, No. (%)
3,216 (16)
1,039 (21)
< .01
361
Radiographic emphysema, No. (%)
5,406 (27)
2,262 (45)
< .01
365 366 367 368 369 370
375 376 377 378
415 416 417 418
(P < .01) (e-Table 2). There was a higher proportion of those with nonasbestos occupational exposure in the ILA group (P < .01), with more extensive smoking (P < .01), COPD, and radiographic emphysema (P < .01). ILAs were also associated with reduced lung TABLE 2
419
function (e-Table 3). Lung cancer incidence was greater in the ILA group on unadjusted analysis (IRR, 1.69; 95% CI, 1.32-2.16) (e-Table 4) and following adjustment for the Bach index and radiographic emphysema (adjusted IRR, 1.47; 95% CI, 1.15-1.88) (e-Table 5). ILAs
No Baseline ILA (n ¼ 5,175)
Characteristic FVC, L
3.44 (2.80-4.20)
FVC, % predicted
86 (75-97)
FEV1, L
2.48 (2.00-3.08)
Baseline ILA (n ¼ 1,415) 3.26 (2.69-4.06) 84 (71-96) 2.36 (1.88-2.96)
420 421 422 423 424 425 426
] Spirometric Values of Patients With and Without ILAs on Baseline Screening, Low-Dose CT Scan
373 374
413 414
ILA ¼ interstitial lung abnormality; IQR ¼ interquartile range.
371 372
411 412
.83
4,367 (23)
364
407 408
Family history of lung cancer, No. (%)
363
406
< .01
359
362
389
18,006 (90)
Latino
Education, No. (%)
< .01
390
154 (2)
344
388
< .01
358 (2)
Other
387
P Value
2,311 (46)
Asian
343
350
61 (58-66)
386
8,035 (40)
881 (4)
Married, No. (%)
349
Baseline ILA (n ¼ 5,053)
Q15
427 428 429
P Value
430
< .01
431
< .01
432
< .01
433
< .01
379
FEV1, % predicted
380
Ratio of FEV1 to FVC
381
Proportion with restriction, FVC % predicted < 80%, No. (%)
1,774 (34)
560 (40)
< .01
436
Proportion with obstruction, ratio of FEV1 to FVC < 0.7, No. (%)
1,606 (31)
510 (36)
< .01
438
382 383 384 385
83 (68-96) 0.74 (0.67-0.79)
80 (64-93) 0.73 (0.66-0.79)
434
< .01
435 437 439 440
Data are presented as the median (IQR) unless otherwise indicated. See Table 1 legend for expansion of abbreviations.
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Cumulative Incidence of Lung Cancer
442 443 444 445 446 447 448 449 450 452 453 454 455 456 457
0.020 0.015 0.010 0.005 0.000
print & web 4C=FPO
451
0.025
0
2
ILA
4 Time (y) absent
6
present
Figure 2 – Cumulative lung cancer incidence based on the presence of ILAs on baseline screening LDCT scan. ILAs ¼ interstitial lung abnormalities. See Figure 1 legend for expansion of other abbreviation.
458 459 460 461 462 463 464 465
were also associated with increased lung cancer mortality (adjusted HR, 1.53; 95% CI, 1.11-2.09). There was no difference in the lung cancer characteristics between the two groups (e-Table 6). A greater proportion of deaths in the ILA group were related to respiratory causes (15% vs 8%; P ¼ .02) (e-Table 1).
466 467
Discussion
468
In this study, we found that ILAs were independently associated with lung cancer incidence and mortality among high-risk smokers after controlling for other established risk factors. Our study extends previous results showing an association of clinically evident interstitial lung disease with lung cancer risk and provides new evidence regarding the prognostic significance of asymptomatic, radiologically detected ILA.
469 470 471 472 473 474 475 476 477 478 479 480 481
Interstitial lung disease represents a heterogeneous designation of pathologic states diffusely affecting the lung parenchyma. Of the interstitial lung diseases of known etiology, pulmonary asbestosis conveys the
highest lung cancer risk, with a more than sevenfold increased incidence in nonsmokers and an even greater synergistically increased risk in smokers.19-21 Similarly, some connective tissue disease-associated interstitial lung diseases are also associated with an increased incidence of lung cancer.22-24 In a large retrospective observational study of US veterans, the adjusted OR for lung cancer in patients with rheumatoid arthritis was 1.43 (95% CI, 1.23-1.65).24 Likewise, a Danish population-based study of scleroderma reported a standardized lung cancer incidence ratio of 1.6 (95% CI, 1.2-2.0).23 Of the interstitial lung diseases of unknown origin, idiopathic pulmonary fibrosis is the most strongly associated with lung cancer,3-5,25-27 with adjusted lung cancer IRRs ranging from 4.96 (95% CI, 3.0-8.18) to 8.25 (95% CI, 4.70-11.48).4,5 This literature shows evidence of the relation between more severe parenchymal abnormalities and carcinogenesis. The current study assessed whether asymptomatic interstitial abnormalities, incidentally detected on screening LDCT imaging, are an independent risk factor for subsequent lung cancer. A secondary analysis of the Danish Lung Cancer Screening Trial found an association of ILA with lung cancer incidence (OR, 5.4; P < .01) that varied according to ILA subtype: centrilobular nodules (OR, 2.5; P < .01), ground-glass opacities (OR, 5.4; P < .01), reticulation (OR, 4.3; P < .01), and honeycombing (OR, 14; P < .01).28 However, these analyses were unadjusted and did not account for smoking exposure, concomitant presence of COPD, or radiographic emphysema, all major confounders of the association of ILA with lung cancer risk.9,29-34 Nishino et al35 assessed the relationship between ILA and lung cancer mortality in a cohort of 120 patients with treatment-naive, advanced lung cancer and showed that ILA was associated with worse survival (HR, 2.09; P ¼ .03) after adjusting for age, smoking
496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536
482
537
483
538
484
TABLE 3
] Unadjusted Lung Cancer Incidence and Mortality in Participants With and Without ILAs on Baseline
486
541 P Value
Lung Cancer Incident Cases per 100,000 Person-Years (95% CI)
ILA
121 (2.4)
< .01
398 (333-476)
1.61 (1.30-1.99)
543
No ILA
304 (1.5)
248 (221-227)
Reference
544
Variable
488 489 490
Lung Cancer Deaths, No. (%)
491 493
ILA
494
No ILA
495
540
Lung Cancer Cases, No. (%)
487
492
539
Screening, Low-Dose CT Scan
485
68 (1.3) 151 (0.8)
Unadjusted IRR (95% CI)
542
545 546
P Value
Lung Cancer Deaths per 100,000 Person-Years (95% CI)
< .01
217 (171-275))
1.82 (1.37-2.42)
548
120 (103-141
Reference
549
Unadjusted HR (95% CI)
550
HR ¼ hazard ratio; IRR ¼ incidence rate ratio. See Table 1 legend for expansion of other abbreviation.
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551 552 553 554
TABLE 4
] Lung Cancer Characteristics According to Presence of ILAs on Baseline Screening, Low-Dose CT Scan
Characteristic
No Baseline ILA (n ¼ 300)
Baseline ILA (n ¼ 120)
606 607
P Value
608
Stage, No. (%)
609
555
I
122 (42)
39 (33)
556
II
24 (8)
16 (14)
611
557
III
59 (20)
20 (17)
612
558
IV
89 (31)
43 (36)
559 560 561
Upper lobe
158 (55) 24 (8)
563
Lower lobe
79 (28)
Other
25 (9)
566
Small cell carcinoma
616
3 (3)
617
40 (36)
618
8 (7)
52 (17)
Squamous cell carcinoma Adenocarcinoma
571
615
.11
619 620
568 570
61 (55)
Histology, No. (%)
567 569
613
Location, No. (%)
Middle lobe
565
610
614
562 564
.14
Other
28 (23)
85 (28)
37 (31)
108 (36)
37 (31)
55 (18)
15 (15)
621
.55
622 623 624 625 626
See Table 1 legend for expansion of other abbreviation.
572
627
573
628
574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596
exposure, and type of first-line systemic therapy. Hoyer et al11 determined that ILA was associated with lung cancer mortality in the Danish screening population (HR, 3.2; 95% CI, 1.7-6.2) after adjusting for age, sex, BMI, smoking exposure, and FEV1. However, FEV1 alone does not adequately capture cases of COPD or radiographic emphysema, and thus residual confounding by COPD/emphysema may explain why their reported estimate was higher than reported in our study. In the current study, we found that asymptomatic ILA was independently associated with lung cancer incidence and mortality even following careful adjustment for confounders, suggesting that ILAs are an independent risk factor for lung cancer. There are several potential explanations for the relationship between ILAs and lung cancer. First, some individuals with ILA develop clinically significant pulmonary fibrosis, an established risk factor for lung cancer.6 However, the small percentage of those with ILA who are expected to develop clinically significant interstitial lung disease within the follow-up period
597 598
TABLE 5
suggests that the severity and progression of ILA alone are unlikely to explain our findings. Second, some histopathologic features associated with ILAs may play a role in lung cancer risk. Miller et al36 reported increased odds of atypical adenomatous hyperplasia, fibroblast foci, and subpleural fibrosis in biopsy specimens of subjects with preclinical ILA. Atypical adenomatous hyperplasia is recognized as a preinvasive adenocarcinoma, potentially explaining our findings.37 In addition, fibroblast foci, a pathologic hallmark of pulmonary fibrosis that arises in the setting of myofibroblast activation, may be important for supporting tumorigenesis.38 Third, ILAs are associated with genetic changes that may predispose to lung cancer development. MUC5B is a glycoprotein required for optimal mucociliary clearance; a promoter variant (rs35705950) is associated with MUC5B overexpression, ILAs, and pulmonary fibrosis.39-42 Although no studies have reported a direct relationship with lung cancer incidence, MUC5B expression in lung tumors has been associated with worse prognosis,43-45 suggesting a
633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653
Dose CT Scan
600 601
Study Arm
602
ILA vs no ILA
654 Model 1 Adjusted IRR (95% CI)
Model 2 Adjusted IRR (95% CI)
Model 3 Adjusted HR (95% CI)
Model 4 Adjusted HR (95% CI)
1.33 (1.07-1.65)
1.39 (1.11-1.74)
1.51 (1.13-2.03)
1.58 (1.17-2.15)
655 656 657
603 605
631 632
] Adjusted Lung Cancer Incidence and Mortality based on Presence of ILAs on Baseline Screening, Low-
599
604
629 630
Models 1 and 3 were adjusted for the presence of radiographic emphysema and the Bach index. Models 2 and 4 were adjusted for age, race, sex, marital status, socioeconomic status, BMI, lung cancer family history, smoking history, COPD, presence of radiographic emphysema, asbestos exposure, and other occupational exposures. See Table 1 and 3 legends for expansion of other abbreviations.
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658 659 660
661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698
potential role in cancer biology. Similarly, galectin-3, a lecithin involved in tumor angiogenesis and metastases,46-51 has also been implicated in the development of ILA.52 However, the detailed pathways underlying the relationship between ILA and lung cancer remain unclear. Further research in this area may unveil unknown mechanisms, potentially offering new therapeutic targets for these conditions. There are strengths and limitations of our study that should be noted. We analyzed data from a large, wellcharacterized multisite study with uniform and comprehensive ascertainment of lung cancer incidence and long-term follow-up of study participants. In addition, there was standardization in the collection and reporting of radiographic findings and detailed information regarding confounding risk factors that allowed for careful adjustment in our models. Our results should be generalizable to most screening populations. However, our data cannot be extrapolated to nonsmokers with ILAs who did not meet selection criteria for the NLST trial. Although the NLST provided a detailed description of lung nodules, a relatively heterogeneous group of interstitial radiologic findings was reported as a single ILA category. Thus, we were unable to determine if certain ILA subtypes or whether the extent of abnormalities have a differential effect on lung cancer risk. Our reported prevalence of ILA in the LDCT arm was 20% compared with a prevalence of 5% to 10% for definitive ILA and 20% to 36% for indeterminate ILA reported in the literature.6,9,10,53-55 However, if a proportion of NLST participants with equivocal changes were classified as having ILAs, our results would be biased toward the null. Regarding ILA subtypes, Hoyer
et al11 reported that all subtypes (honeycombing, ground-glass opacities, nodular, and reticular changes) were associated with lung cancer risk, with the highest risk conveyed by honeycomb changes. We were unable to test these relationships due to the heterogeneous designation used by radiologists. In addition, although the study radiologists used standardized forms, there was no standardized process in defining an ILA. A larger problem is that there is currently no standardized definition of ILA in the literature. Therefore, further study into lung cancer risk in ILA subtypes ascertained by validated quantitative and qualitative methods, accounting for radiographic emphysema, should be conducted. Only a subset of participants in the NLST trial underwent spirometry; thus, we were unable to fully assess whether spirometric data acted as a mediator between the relationship between ILA and lung cancer. Because our study used data from a screening trial, some of the lung cancers may be overdiagnosed cases. However, ILA was also associated with increased lung cancer mortality, suggesting that differences in the incidence of lung cancer could not be explained by a higher prevalence of nonaggressive cancers among participants with ILAs.
716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743
Conclusions
744
The current study found that ILA is an independent risk factor for lung cancer in smokers. These results suggest the need for additional research to unveil the mechanisms linking pulmonary fibrosis and lung carcinogenesis. In addition, the presence of ILA could be used to further stratify lung cancer risk following baseline screening LDCT to select the best subsequent screening regimen.
699
745 746 747 748 749 750 751 752 753 754
700
755
701
756
702
757
703
758
704
759
705
760
706
761
707
762
708
763
709
764
710
765
711
766
712
767
713
768
714
769
715
770
7
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Acknowledgments
772 773 774 775 776 Q9 777
Q10
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. P. has served as a consultant to Boehringer Ingelheim. She has also served as faculty presenter on lectures supported by Genentech and the France Foundation; and has been an investigator on several multisite clinical trials on idiopathic pulmonary fibrosis sponsored by various pharmaceutical companies. M. S. has been a speaker for Genentech, Boehringer Ingelheim, and Eastern Pulmonary Conference; and a consultant for Genentech and Boehringer Ingelheim. C. H. is a named inventor on a number of patents and patent applications relating to the evaluation of pulmonary nodules on CT scans of the chest which are owned by Cornell Research Foundation. Since 2009, she does not accept any financial benefit from these patents, including royalties and any other proceeds related to the patents or patent applications owned by Cornell Research Foundation. She is President and serves on the board of the Early Diagnosis and Treatment Research Foundation and receives no compensation from the Foundation. The Foundation is established to provide grants for projects, conferences, and public databases for research on early diagnosis and treatment of diseases. Recipients include the International Early Lung Cancer Action Program, among others. The funding comes from a variety of sources, including philanthropic donations, grants and contracts with agencies (federal and nonfederal), imaging, and pharmaceutical companies relating to image processing assessments. The various sources of funding exclude any funding from tobacco companies or tobacco-related sources. D. Y. is an equity owner in Accumetra, a privately held technology company committed to improving the science and practice of imagebased decision-making. He also serves on the advisory board of GRAIL. In addition, he is a named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest, including measurement of nodules. Some of these, which are owned by Cornell Research Foundation, are nonexclusively licensed to General Electric. As an inventor of these patents, he is entitled to a share of any compensation that Cornell Research Foundation may receive from its commercialization of these patents. J. W. has received consulting honorarium from Sanofi and Banook and research grants from Sanofi and Quorum. None declared (S.-A. W. B., G. M., C. P., K. S., J. P. d.-T.).
Q11
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
778 779 780
Q18
781 782 783 784
Q12
785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825
Author contributions: All authors contributed to conception and design; manuscript writing; and collection, assembly, analysis, and interpretation of data. All authors gave final approval of the manuscript as submitted.
8 Original Research
Other contributions: The authors are grateful to the National Cancer Institute for providing access to data from the NLST. The analysis and manuscript are solely the responsibility of the authors. Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.
References 1. Lee T, Park JY, Lee HY, et al. Lung cancer in patients with idiopathic pulmonary fibrosis: clinical characteristics and impact on survival. Respir Med. 2014;108(10): 1549-1555. 2. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J. 2015;46(4):11131130. 3. Tomassetti S, Gurioli C, Ryu JH, et al. The impact of lung cancer on survival of idiopathic pulmonary fibrosis. Chest. 2015;147(1):157-164. 4. Le Jeune I, Gribbin J, West J, Smith C, Cullinan P, Hubbard R. The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med. 2007;101(12):2534-2540. 5. Hubbard R, Venn A, Lewis S, Britton J. Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med. 2000;161(1):5-8. 6. Jin GY, Lynch D, Chawla A, et al. Interstitial lung abnormalities in a CT lung cancer screening population: prevalence and progression rate. Radiology. 2013;268(2):563-571. 7. Washko GR, Lynch DA, Matsuoka S, et al. Identification of early interstitial lung disease in smokers from the COPDGene Study. Acad Radiol. 2010;17(1):48-53. 8. Doyle TJ, Washko GR, Fernandez IE, et al. Interstitial lung abnormalities and reduced exercise capacity. Am J Respir Crit Care Med. 2012;185(7):756-762. 9. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med. 2011;364(10):897-906. 10. Putman RK, Hatabu H, Araki T, et al. Association between interstitial lung abnormalities and all-cause mortality. JAMA. 2016;315(7):672-681. 11. Hoyer N, Wille MMW, Thomsen LH, et al. Interstitial lung abnormalities are associated with increased mortality in smokers. Respir Med. 2018;136:77-82. 12. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with lowdose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.
combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):11501155. 15. Li K, Husing A, Sookthai D, et al. Selecting high-risk individuals for lung cancer screening: a prospective evaluation of existing risk models and eligibility criteria in the German EPIC cohort. Cancer Prev Res (Phila). 2015;8(9):777-785.
826 827 828 829 830 831 832 833
16. Ten Haaf K, Jeon J, Tammemagi MC, et al. Risk prediction models for selection of lung cancer screening candidates: a retrospective validation study. PLoS Med. 2017;14(4):e1002277.
834
17. Edge SBBD, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. 2010. New York, NY.
838
18. Fritz AG. International Classification of Diseases for Oncology: ICD-O. 3rd ed. Geneva, Switzerland: World Health Organization; 2000.
840
843 844 845 846 847 848 849
21. Erren TC, Jacobsen M, Piekarski C. Synergy between asbestos and smoking on lung cancer risks. Epidemiology. 1999;10(4):405-411. 22. Enomoto Y, Inui N, Yoshimura K, et al. Lung cancer development in patients with connective tissue disease-related interstitial lung disease: a retrospective observational study. Medicine (Baltimore). 2016;95(50):e5716. 23. Olesen AB, Svaerke C, Farkas DK, Sorensen HT. Systemic sclerosis and the risk of cancer: a nationwide populationbased cohort study. Br J Dermatol. 2010;163(4):800-806. 24. Khurana R, Wolf R, Berney S, Caldito G, Hayat S, Berney SM. Risk of development of lung cancer is increased in patients with rheumatoid arthritis: a large case control study in US veterans. J Rheumatol. 2008;35(9):1704-1708. 25. Ozawa Y, Suda T, Naito T, et al. Cumulative incidence of and predictive factors for lung cancer in IPF. Respirology. 2009;14(5):723-728. 26. Harris JM, Johnston ID, Rudd R, Taylor AJ, Cullinan P. Cryptogenic fibrosing alveolitis and lung cancer: the BTS study. Thorax. 2010;65(1):70-76.
850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872
27. Park J, Kim DS, Shim TS, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2001;17(6):1216-1219.
873 874
13. Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst. 2003;95(6): 470-478.
28. Wille MM, Thomsen LH, Petersen J, et al. Visual assessment of early emphysema and interstitial abnormalities on CT is useful in lung cancer risk analysis. Eur Radiol. 2016;26(2):487-494.
14. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a
29. Lederer DJ, Enright PL, Kawut SM, et al. Cigarette smoking is associated with
FLA 5.6.0 DTD CHEST2471_proof 4 September 2019 9:11 pm EO: CHEST-19-0114
839 841
20. Weiss W. Asbestosis: a marker for the increased risk of lung cancer among workers exposed to asbestos. Chest. 1999;115(2):536-549.
-#- CHEST - 2019
837
842
19. Markowitz SB, Levin SM, Miller A, Morabia A. Asbestos, asbestosis, smoking, and lung cancer. New findings from the North American insulator cohort. Am J Respir Crit Care Med. 2013;188(1):90-96.
[
835 836
]
875 876 877 878 879 880
881
subclinical parenchymal lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA)-lung study. Am J Respir Crit Care Med. 2009;180(5):407-414.
882 883 884
30. Araki T, Nishino M, Zazueta OE, et al. Paraseptal emphysema: prevalence and distribution on CT and association with interstitial lung abnormalities. Eur J Radiol. 2015;84(7):1413-1418.
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31. Denholm R, Schuz J, Straif K, et al. Is previous respiratory disease a risk factor for lung cancer? Am J Respir Crit Care Med. 2014;190(5):549-559.
889 890 891
32. Henschke CI, Yip R, Boffetta P, et al. CT screening for lung cancer: importance of emphysema for never smokers and smokers. Lung Cancer. 2015;88(1):42-47.
892 893 894
33. de Torres JP, Bastarrika G, Wisnivesky JP, et al. Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest. 2007;132(6):1932-1938.
895 896 897 898
34. Smith BM, Pinto L, Ezer N, Sverzellati N, Muro S, Schwartzman K. Emphysema detected on computed tomography and risk of lung cancer: a systematic review and meta-analysis. Lung Cancer. 2012;77(1):58-63.
899 900 901 902
35. Nishino M, Cardarella S, Dahlberg SE, et al. Interstitial lung abnormalities in treatment-naive advanced non-small-cell lung cancer patients are associated with shorter survival. Eur J Radiol. 2015;84(5): 998-1004.
903 904 905 906 907
Q13
36. Miller ER, Putman RK, Vivero M, et al. Histopathology of interstitial lung abnormalities in the context of lung nodule resections. Am J Respir Crit Care Med. 2018;197(7):955-958.
Q14
37. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Fourth edition. IARC; 2015.
908 909 910 911 912 913 914
38. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582-598. 39. Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503-1512. 40. Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med. 2011;364(16):1576-1577. 41. Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med. 2013;368(23):2192-2200. 42. Putman RK, Gudmundsson G, Araki T, et al. The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes. Eur Respir J. 2017;50(3). 43. Kim YK, Shin DH, Kim KB, et al. MUC5AC and MUC5B enhance the characterization of mucinous adenocarcinomas of the lung and predict poor prognosis. Histopathology. 2015;67(4):520-528. 44. Yu CJ, Yang PC, Shun CT, Lee YC, Kuo SH, Luh KT. Overexpression of MUC5 genes is associated with early postoperative metastasis in non-small-cell lung cancer. Int J Cancer. 1996;69(6):457465. 45. Nagashio R, Ueda J, Ryuge S, et al. Diagnostic and prognostic significances of MUC5B and TTF-1 expressions in resected non-small cell lung cancer. Sci Rep. 2015;5:8649. 46. Chung LY, Tang SJ, Wu YC, Sun GH, Liu HY, Sun KH. Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with beta-catenin. Oncotarget. 2015;6(7):4936-4952.
47. Kosacka M, Piesiak P, Kowal A, Golecki M, Jankowska R. Galectin-3 and cyclin D1 expression in non-small cell lung cancer. J Exp Clin Cancer Res. 2011;30:101.
936 937 938 939
48. Szoke T, Kayser K, Baumhakel JD, et al. Prognostic significance of endogenous adhesion/growth-regulatory lectins in lung cancer. Oncology. 2005;69(2):167174.
940
49. Nangia-Makker P, Balan V, Raz A. Galectin-3 binding and metastasis. Methods Mol Biol. 2012;878:251-266.
944
941 942 943 945
50. Nishi Y, Sano H, Kawashima T, et al. Role of galectin-3 in human pulmonary fibrosis. Allergol Int. 2007;56(1):57-65. 51. Mackinnon AC, Gibbons MA, Farnworth SL, et al. Regulation of transforming growth factor-beta1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012;185(5):537-546. 52. Ho JE, Gao W, Levy D, et al. Galectin-3 is associated with restrictive lung disease and interstitial lung abnormalities. Am J Respir Crit Care Med. 2016;194(1):77-83.
946 947 948 949 950 951 952 953 954 955 956
53. Araki T, Putman RK, Hatabu H, et al. Development and progression of interstitial lung abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med. 2016;194(12):1514-1522.
957 958 959
54. Shah RD, Hutchison PJ, Nicholson TT. Risk factors for development of acute lung injury, physicians’ decision-making roles in critical illness, and prevalence of interstitial lung abnormalities in lung cancer screening populations. Am J Respir Crit Care Med. 2014;189(10):12731274.
960
55. Salvatore M, Henschke CI, Yip R, et al. JOURNAL CLUB: evidence of interstitial lung disease on low-dose chest CT images: prevalence, patterns, and progression. AJR Am J Roentgenol. 2016;206(3):487-494.
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