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(Chest. 2004;126:347-351.)
© 2004 American College of Chest Physicians

Improved Survival in Never-Smokers vs Current Smokers With Primary Adenocarcinoma of the Lung*

Luke T. Nordquist, MD; George R. Simon, MD, FCCP; Alan Cantor, PhD; W. Michael Alberts, MD, FCCP and Gerold Bepler, MD, PhD

* From the H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Correspondence to: George R. Simon, MD, FCCP. H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Suite 3170, Tampa, FL 33612; e-mail: simongr{at}moffitt.usf.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Study objectives: Adenocarcinoma of the lung is now the most common histologic subtype of lung cancer in the United States. To determine if there are survival differences in never-smokers and current smokers with adenocarcinoma, we conducted an analysis of lung adenocarcinomas seen at the H. Lee Moffitt Cancer Center, and looked for demographic and survival differences in the two groups.

Design: Data were gathered through the tumor registry at the H. Lee Moffitt Cancer Center and confirmed by chart review. A total of 132 documented never-smokers and 522 current smokers with lung adenocarcinoma were included. Detailed demographic survival information were gathered and tabulated. Former smokers were not included in the study. Multivariate analyses were performed using the Cox regression method to identify variables with independent prognostic significance. Life table actuarial analyses were performed to determine survival. Differences between survival curves were estimated using the log-rank test.

Results: The mean age at diagnosis for never-smokers was higher as compared to current smokers: 63.5 years vs 59.4 years (p = 0.0005). In addition, there was an increased percentage of female subjects in the never-smoker category: 78% vs 54% (p < 0.0001). There was a statistically significant difference in survival between current smokers and never-smokers (p = 0.004). The Kaplan-Meier estimates at 5 years were 16% for current smokers and 23% for never-smokers. On multivariate analyses, smoking was identified as an independent negative prognostic factor.

Conclusion: Our data show that never-smokers with adenocarcinoma are predominantly female, present at a higher mean age, and have improved survival when compared to current smokers. By multivariate analyses, the never-smoking status was found to be an independent predictor of improved survival. The survival difference may be partly influenced by less comorbidity among never-smokers. Nevertheless, owing to differences in the mechanism of carcinogenesis (in smokers vs nonsmokers), demographic factors, tumor behavior and survival, adenocarcinomas occurring in never-smokers may display a distinct natural history and may warrant further investigation as a separate entity with epidemiologic studies and clinical trials designed specifically for this category of non-small cell lung cancer.

Key Words: adenocarcinoma • bronchioloalveolar carcinoma • current smokers • never-smokers • non-small cell lung cancer


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
The incidence of lung cancer has steadily declined in men (2.4%/yr) and has reached a plateau in women. Despite this apparent improvement, it is estimated that 171,900 individuals received a diagnosis of lung cancer, resulting in 157,200 deaths in the United States in 2003.1 The vast majority of lung cancer cases are attributed to smoking.2 Historically, adenocarcinoma is the most common type of lung cancer occurring in nonsmokers. However, in the United States, adenocarcinoma has become the most common histology occurring in smokers as well. The adenocarcinoma subtype has increased in incidence over the past 20 years from 20% of lung cancer cases to nearly 40%.345 The reason for the increase is not clear. Possible factors include changes in smoking habits or tobacco products, such as switching to low tar and/or the use of filtered cigarettes.6 Additionally, changes in environmental factors such as asbestos, air pollution, radiation exposure, and radon may partially contribute.7

The management of all non-small cell lung cancer (NSCLC) subtypes is identical, regardless of histology, gender, or risk factors such as smoking, and is primarily determined by stage. Since adenocarcinomas in never-smokers arose without the growth promoting effects of the carcinogens present in cigarette smoke, one could postulate that the mechanism of carcinogenesis of adenocarcinomas arising in smokers and never-smokers are distinct. Distinct tumorigenic mechanisms would imply differences in tumor biology, demographic characteristics, and survival. We therefore evaluated the patient characteristics and survival in adenocarcinomas occurring in current smokers vs never-smokers. Since histology by itself can have prognostic implications and adenocarcinoma is the most common histologic subtype of NSCLC occurring in nonsmoking patients, we decided to evaluate the demographic characteristics and survival in adenocarcinomas occurring in never-smokers vs current smokers. Differences in patient characteristics and survival would suggest that the genesis, natural history, and tumor biology in adenocarcinomas occurring in never-smokers and current smokers would be different. An understanding of these differences could then be utilized for better prognostication and therapeutic benefit.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Patients with lung cancer seeking treatment at the H. Lee Moffitt Cancer Center between 1985 and 2000 filled out a questionnaire developed by the thoracic oncology program, in which detailed smoking information was collected. Hence, demographic data including a detailed smoking history were prospectively collected. All patients who were histopathologically confirmed to have adenocarcinoma (or bronchioloalveolar carcinoma [BAC]) of pulmonary origin were included in this analysis. Survival data from never-smoking and current-smoking patients with lung adenocarcinoma were collected from the tumor registry of the H. Lee Moffitt Cancer Center and confirmed by chart review. Prospectively collected demographic variables examined included age at diagnosis, stage at presentation, gender, tumor histology and smoking status, and number of metastatic sites. Data regarding performance status and secondhand smoke were not consistently prospectively collected or consistently available in the primary source documentation, and hence could not be reliably assessed. Former smokers (abstinence > 1 year at the time of diagnosis) were not included in the study. For the analyses of overall survival, each patient’s time began on the date of diagnosis and ended on the date of death or on the date last seen alive. Cancer-specific mortality was also evaluated. To calculate cancer-specific mortality, deaths clearly documented to be resulting from noncancer causes (example myocardial infarction, ischemic stroke, motor vehicle accident, etc.) were treated as withdrawals in the cancer-specific survival analyses.

Statistical Considerations
Overall survival and cancer-specific survival probability estimates are based on the Kaplan-Meier method.8 Differences between survival curves were estimated using the log-rank test. Multivariate analysis was performed using the Cox regression method to identify variables with independent prognostic significance. The {chi}2 test was used to detect statistically significant differences between nonparametric data. A two-sided p value ≤ 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
A total of 141 documented never-smokers with primary adenocarcinoma of the lung were registered between 1985 and 2000. Seven of the 141 patients were excluded from the study due to ambiguity of stage assigned at presentation, and 2 patients were excluded after chart review revealed a smoking history. There were 542 current smokers identified. Twenty of the 542 patients were excluded from the study secondary to ambiguity in staging assigned.

The demographic characteristics of both the cohorts are shown in Table 1 . There were a statistically significant higher percentage of women in the never-smoker category: 78% vs 54% (p < 0.0001). The mean age at diagnosis for never-smokers was higher as compared to current smokers (63.5 years vs 59.4 years), and this difference was statistically significant (p = 0.0005). There were no statistically significant differences in the stage of presentation between both cohorts. There was a statistically significantly higher number of BAC cases in the never-smoker category: 24% vs 10% (p = 0.0009).


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  		Table 1.. Characteristics of the Study Population*

 
There was a statistically significant difference in the 5-year survival between current smokers and never-smokers: 16% vs 23% (p = 0.004) [Fig 1 ]. The cancer-specific 5-year survival was 28%, vs 22% for never-smokers vs current smokers (p = 0.018) [Fig 2 ]. Smoking was identified as an independent and negative prognosticator by multivariate analysis. Hence, despite the higher presence of good prognostic variables, ie, female gender and BAC histology in the never-smoking category, the never-smoking status is a statistically significant independent predictor of survival on multivariate analyses. Additionally, male gender and higher stage were also significant independent negative predictive factors of survival. The results of the multivariate analysis are shown in Table 2 .



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  		Figure 1.. Overall survival of never-smokers (nonsmokers) vs current smokers (smokers) [p = 0.004]. Mon = months.

 


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  		Figure 2.. Cancer-specific survival of never-smokers (nonsmokers) vs current smokers (smokers) [p = 0.018]. See Figure 1 legend for expansion of abbreviation.

 

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  		Table 2.. Multivariate Analyses of Factors Related to Overall Survival

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
Multiple chemicals in cigarette smoke are presumed to induce carcinogenesis in smokers. However, no such insult exists in never-smokers, suggesting an alternate mechanism of carcinogenesis and therefore a distinct natural history and tumor biology. We performed this analysis to determine whether demographic characteristics and survival would be disparate in the never-smokers vs current smokers with lung adenocarcinoma.

Our studies indicate that never-smoking patients with lung adenocarcinoma tend to be older, and predominantly women, and more likely of BAC subtype. Cancer-specific and overall survivals were significantly better in favor of the never-smoker category. The never-smoking cohort had statistically significant preponderance of women and BAC histology, both of which are favorable prognostic variables; therefore, one would have predicted better survival in the never-smoker category secondary to these factors alone. However, on multivariate analysis, we identified smoking status as a statistically significant independent predictor of improved survival. One of the caveats of our study was that data regarding performance status were not consistently available from the source documents, and therefore the smoking cohort of patients could be presumed to have increased incidence of comorbidities and therefore poorer prognosis and survival. To offset the influence of comorbidities on survival, we looked at cancer-specific survival and found it to be significantly in favor of never-smokers.

Multiple studies reported in the literature suggest significant behavioral and survival differences in never-smokers vs smokers with lung cancer. Capewell et al9 reported a study of lung cancer in never-smokers; of the 3,070 lung cancer patients reviewed, only 74 patients (2%) were classified as never-smokers. Similar to our results, 77% of never-smokers were women compared to 26% of smokers, and the mean age at presentation was higher for never-smokers (75.4 years vs 68 years). In addition, more never-smokers had adenocarcinoma than smokers (42% vs 13%). In another study, de Perrot et al10 found that women were more likely to be never-smokers compared to men (27% vs 2%, p < 0.001), and have adenocarcinoma as the predominant NSCLC subtype (54%). Furthermore, women had a superior survival (hazard ratio, 0.72; p = 0.009) independent of age, presence of symptoms, smoking habits, histology, or stage of disease.

A genetic predisposition may augment lung cancer susceptibility in smokers and may be pivotal in never-smokers. When the incidence of lung cancer among relatives of current smokers with lung cancer and that of relatives of currently smoking control subjects were evaluated, a 40 to 87% increased risk of familial aggregation was noted.11 A major gene for lung cancer susceptibility has not been identified. However, polymorphisms in carcinogen detoxifying enzymes have been associated with small increases in disease-specific risk. Glutathione S-transferases (GSTs) are a family of enzymes that detoxify hydrophobic electrophiles, including polycyclic aromatic hydrocarbons that have been implicated in the pathogenesis of lung cancer. For instance, individuals with the GST M1-null genotype are deficient in the GST M1 and GST M3 isoenzymes. Additionally, a recent investigation12 has shown that the GST M1-null genotype combined with CYP1A1, NAT2, or GST P1 polymorphisms confers a greater risk of lung cancer than the GST M1-null genotype alone.

Using gene expression arrays, multiple studies13141516 have compared the genetic profiles of smokers and never-smokers, and have arrived at the conclusion that lung cancers in never-smokers have genetic changes distinct from those found in adenocarcinomas of smokers. Powell et al13 compared expression profiles from normal and malignant lung tissue in six never-smokers and six smokers with adenocarcinoma. Though limited by the small numbers, their results demonstrated many differences. Sanchesz-Cespedes et al14 compared adenocarcinomas from 18 never-smokers with those from 27 smokers. They found that chromosomal abnormalities were infrequent in adenocarcinomas occurring in never-smokers.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
Our data show that never-smokers with adenocarcinoma are predominantly women, present at a higher age, and have improved survival when compared to current smokers. The survival difference may be partly influenced by less comorbidity among never-smokers. We conclude that owing to differences in mechanism of carcinogenesis, demographic factors, tumor behavior, and survival, adenocarcinomas occurring in never-smokers may warrant further investigation as a separate entity. A better understanding of lung cancers occurring in never-smokers could lead to development of cohort-specific treatment strategies.


   Acknowledgements
 
The authors thank Mr. K. G. Rajan for editorial assistance.


   Footnotes
 
Abbreviations: BAC = bronchioloalveolar carcinoma; GST = glutathione S-transferase; NSCLC = non-small cell lung cancer

Received for publication October 22, 2003. Accepted for publication March 4, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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  3. Franceschi, S, Bidoli, E The epidemiology of lung cancer. Ann Oncol 1999;10,S3-S6
  4. Brownson, RC, Loy, TS, Ingram, E, et al Lung cancer in nonsmoking women: histology and survival patterns. Cancer 1995;75,29-33[CrossRef][ISI][Medline]
  5. Osann, KE, Anton-Culver, H, Kurosaki, T, et al Sex differences in lung-cancer risk associated with cigarette smoking. Int J Cancer 1993;54,44-48[ISI][Medline]
  6. Levi, F, Franceschi, S, La Vecchia, C, et al Lung carcinoma trends by histologic type in Vaud and Neuchatel, Switzerland. Cancer 1997;79,906-914[CrossRef][ISI][Medline]
  7. Kabat, GC Aspects of the epidemiology of lung cancer in smokers and nonsmokers in the United States. Lung Cancer 1996;15,1-20[CrossRef][ISI][Medline]
  8. Kaplan, EL, Meier, PL Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53,457-481[CrossRef][ISI]
  9. Capewell, S, Sankaran, R, Lamb, D, et al Lung cancer in lifelong non-smokers. Thorax 1991;46,565-568[Abstract]
  10. de Perrot, M, Licker, M, Bouchardy, C, et al Sex differences in presentation, management and prognosis of patients with non-small cell lung carcinoma. J Thorac Cardiovasc Surg 2000;119,21-26[Abstract/Free Full Text]
  11. Ooi, WL, Elston, RC, Chen, VW, et al Increased familial risk of lung cancer. J Natl Cancer Inst 1986;76,217-222[ISI][Medline]
  12. Mohr, LC, Rodgers, JK, Silvestri, GA Glutathione S-transferase M1 polymorphism and the risk of lung cancer. Anticancer Res 2003;23,2111-2124[ISI][Medline]
  13. Powell, C, Spira, A, Derti, A, et al Gene expression in lung adenocarcinomas of smokers and non-smokers. Am J Respir Cell Mol Biol 2003;29,157-162[Abstract/Free Full Text]
  14. Sanchesz-Cespedes, M, Ahrendt, SA, Piantadosi, S Chromosomal alteration in lung adenocarcinoma from smokers and nonsmokers. Cancer Res 2001;61,1309-1313[Abstract/Free Full Text]
  15. Wong, MP, Fung, LF, Wang, E Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers. Cancer 2003;97,1263-1270[CrossRef][ISI][Medline]
  16. Wong, MP, Wang, E, Lam, WK Primary adenocarcinomas of the lung in nonsmokers show a distinct pattern of allelic imbalance. Cancer Res 2002;62,4464-4468[Abstract/Free Full Text]



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