Is Lung Cancer in the Nonsmoker a Different Disease?

Abstract

Cigarette smoking is without any doubt the leading cause of preventable death in the United States. The health-related economic loss associated with cigarette smoking is approximately $157 billion, and 440,000 premature deaths occur annually only in this country.1Annual smoking-attributable mortality, years of potential life lost, and economic cost United States, 1995–1999.MMWR Morb Mortal Wkly Rep. 2002; 251: 300-303Google Scholar Worldwide, 10 million people will die annually from tobacco-attributable diseases by 2030.2Schroeder SA Tobacco control in the wake of the 1998 master settlement agreement.N Engl J Med. 2004; 350: 293-301Crossref PubMed Scopus (132) Google Scholar Eighty percent of the particle products of Nicotiana tabacum liberated through a lit cigarette deposit in the tracheobronchial tree. At least 55 of the > 2,000 chemical compounds identified in the tobacco leaf are proven carcinogens.3Kuper H Boffetta P Adami HO Tobacco use and cancer causation: association by tumour type.J Intern Med. 2002; 252: 206-224Crossref PubMed Scopus (220) Google Scholar The epidemiologic evidence accumulated over almost 6 decades since the reports of Doll and Hill4Doll R Hill AB Smoking and carcinoma of the lung: preliminary report.BMJ. 1950; 2: 739-748Crossref PubMed Scopus (1282) Google Scholar5Doll R Hill AB The mortality of doctors in relation to their smoking habits: a preliminary report.BMJ. 1952; 1: 1451-1455Crossref Scopus (509) Google Scholar prove an association between smoking and lung cancer. Tobacco smoke has a causal role as well in the tragic worldwide epidemic of lung cancer. Tobacco products not only cause harm to the users, but nonusers are affected as well (environmental tobacco exposure). Tobacco smoking exposure is associated with all of the histologic subtypes of lung cancer.6Yang P Cerhan JR Vierkant RA et al.Adenocarcinoma of the lung is strongly associated with cigarette smoking: further evidence from a prospective study of women.Am J Epidemiol. 2002; 156: 1114-1122Crossref PubMed Scopus (45) Google Scholar Patients who acquire adenocarcinoma, the most common subtype of lung cancer,7Fry WA Phillips JL Menck HR Ten-year survey of lung cancer treatment and survival in hospitals in the United States: a national cancer data base report.Cancer. 1999; 86: 1867-1876Crossref PubMed Scopus (235) Google Scholar are at least as susceptible to the different carcinogens present in the tobacco smoke. Furthermore, patients with adenocarcinoma had less smoking exposure (fewer pack-years) and a prolonged excess risk after smoking was stopped (longer time since quitting smoking).6Yang P Cerhan JR Vierkant RA et al.Adenocarcinoma of the lung is strongly associated with cigarette smoking: further evidence from a prospective study of women.Am J Epidemiol. 2002; 156: 1114-1122Crossref PubMed Scopus (45) Google Scholar Although TNM classification and morphologic status may be indicative of prognosis, it is difficult to predict which surgically managed patient is at risk for early relapse, or which rare patient with advanced stage disease may experience prolonged survival. Furthermore it is not possible, at this time, to predict likelihood of response to a particular treatment based on any morphologic or molecular variables. A systematic review8Brundage MD Davies D Mackillop WJ Prognostic factors in non-small cell lung cancer: a decade of progress.Chest. 2002; 122: 1037-1057Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar investigating patients and tumor factors predictive of survival in non-small cell lung cancer identified 887 articles published between January 1990 and July 2001, examining 169 different prognostic factors. This highlights not only the importance, but also the complexity of reaching a uniformly applicable, clinically useful prognostic model for non-small cell lung cancer. With the evolution of targeted therapies for cancer, a better understanding of tumorigenesis and genetic changes leading to the cancer phenotype is essential. There is also a clear need for a clinically available prognostic model for survival and response, by which patients can be stratified into different categories when enrolled into clinical trials. In this context, the study by Nordquist et al published in this issue of CHEST (see page 347) is important. The authors attempted to compare patient characteristics and survival between current smokers and never-smokers with adenocarcinoma of the lung. They postulated that differences found in the natural history of adenocarcinoma of the lung would serve as further evidence that the tumor biology is different in these groups. Their study showed that never-smokers with adenocarcinoma of the lung are older, more often female, have a higher proportion of bronchoalveolar cell histology, and have better overall and cancer-specific survival when compared to current smokers. Smoking was an independent negative prognostic factor. This study was a well-performed evaluation of a pertinent question. However, interpretation of these results first requires the reader to determine the validity of the reported differences in the characteristics and natural history of the groups studied, and we must evaluate whether the differences are suggestive enough to be used as a surrogate marker of differences in tumor biology. When assessing the validity of the reported differences, a few things should be considered. Patient characteristics—age, sex—were clearly different between the groups studied. Internally, the self-reported nature of smoking status could affect validity. Externally, the population studied appears different than commonly encountered in practice, with more women than men reported in the current smoking group as well as the never smoking group. All factors that could influence the natural history were not considered, the most important of these being performance status and treatments received. It is well established that these factors are important determinants of survival.9Buccheri G Ferrigno D Prognostic factors in lung cancer: tables and comments.Eur Respir J. 1994; 7: 1350-1364Crossref PubMed Scopus (116) Google Scholar10Sorensen JB Badsberg JH Olsen J Prognostic factors in inoperable adenocarcinoma of the lung: a multivariate regression analysis of 259 patients.Cancer Res. 1989; 49: 5748-5754PubMed Google Scholar It is also reasonable to postulate that they may differ between active smokers and never-smokers. Other prognostic factors, including small differences in stage distribution as well as differences in the proportion of bronchoalveolar cell histology,11Grover FL Piantadosi S Recurrence and survival following resection of bronchioloalveolar carcinoma of the lung: the Lung Cancer Study Group experience.Ann Surg. 1989; 209: 779-790Crossref PubMed Scopus (80) Google Scholar and sex, were well described in the study and controlled for in multivariate analyses. Including former smokers, although adding complexity, may have influenced the conclusions drawn about the meaning of apparent differences in natural history. Thus, this study is unable to stand alone to establish differences in tumor biology, but must be evaluated in the context of other work in this area. Assuming the above points do not influence the results, it is not unreasonable to suspect that differences in natural history are related to differences in tumor biology; in this regard, the current study is in keeping with others who have evaluated similar epidemiologic questions.12Tammemagi CM Neslund-Dudas C Simoff M et al.Smoking and lung cancer survival: the role of comorbidity and treatment.Chest. 2004; 125: 27-37Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar There is also a growing body of literature on differences in tumor biology between smokers and never-smokers. Identifying smoking history as an independent prognostic factor in patients with adenocarcinoma of the lung could point out the difference in tumors arising in smokers compared to those in nonsmokers. A high susceptibility to smoking-related lung cancer has been associated with CYP1A-1 polymerism status. This gene is responsible for the metabolic activation of benzopyrene found in cigarette smoke. In addition, the susceptible genotype is associated with higher recurrence rates and lower survival rates.13Goto I Yoneda S Yamamoto M et al.Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer.Cancer Res. 1996; 56: 3725-3730PubMed Google Scholar It is possible that lung carcinomas in smokers and never-smokers may arise via distinct pathogenetic mechanisms. Genetic analyses have revealed that widespread chromosomal abnormalities are frequent in lung adenocarcinoma in smokers but are infrequent in never-smokers.14Sanchez-Cespedes M Ahrendt SA Piantadosi S et al.Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers.Cancer Res. 2001; 61: 1309-1313PubMed Google Scholar15Wong MP Fung LF Wang E et al.Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers.Cancer. 2003; 97: 1263-1270Crossref PubMed Scopus (91) Google Scholar16Wistuba II Lam S Behrens C et al.Molecular damage in the bronchial epithelium of current and former smokers.J Natl Cancer Inst. 1997; 89: 1366-1373Crossref PubMed Scopus (420) Google Scholar The differences in smokers are most likely due to direct repeated exposure to tobacco-related carcinogens such as benzopyrene and N-nitrosamines, which are known to induce widespread genetic damage. Such a genetic environment would lead to alteration of important oncogenes and tumor suppressor genes, thus allowing tumor progression and possibly leading to tumor resistance. In nonsmokers, the frequency of chromosomal instability per tumor is significantly lower compared with tobacco-related tumors.14Sanchez-Cespedes M Ahrendt SA Piantadosi S et al.Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers.Cancer Res. 2001; 61: 1309-1313PubMed Google Scholar Loss of heterozygosity on chromosomes 9p and 17p, likely targeting the p16 and p53 genes respectively, are observed far more frequently in tobacco-induced tumors. Also, a high frequency of alteration on chromosome 19 was observed in smokers, pointing to the existence of an important tumor suppressor gene on that chromosome.14Sanchez-Cespedes M Ahrendt SA Piantadosi S et al.Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers.Cancer Res. 2001; 61: 1309-1313PubMed Google Scholar17Virmani AK Fong KM Kodagoda D et al.Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types.Genes Chromosomes Cancer. 1998; 21: 308-319Crossref PubMed Scopus (178) Google Scholar Loss of heterozygosity at chromosome 3p21.3 is one of the most common and one of the earliest events that occur in the pathogenesis of lung cancer.18Kok K Osinga J Carritt B et al.Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancer.Nature. 1987; 330: 578-581Crossref PubMed Scopus (383) Google Scholar19Wistuba II Behrens C Virmani AK et al.High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints.Cancer Res. 2000; 60: 1949-1960PubMed Google Scholar20Naylor SL Johnson BE Minna JD et al.Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer.Nature. 1987; 329: 451-454Crossref PubMed Scopus (433) Google Scholar RASSF1A (Ras association domain family 1A) gene is a candidate tumor suppressor gene at 3p21.3. Kim et al21Kim DH Kim JS Ji YI et al.Hypermethylation of RASSF1A promoter is associated with the age at starting smoking and a poor prognosis in primary non-small cell lung cancer.Cancer Res. 2003; 63: 3743-3746PubMed Google Scholar found that early age smoking is associated with hypermethylation of the RASSF1A promoter, and is an independent poor prognostic factor in non-small cell lung cancer. Studies22Hashimoto T Tokuchi Y Hayashi M et al.Different subtypes of human lung adenocarcinoma caused by different etiological factors: evidence from p53 mutational spectra.Am J Pathol. 2000; 157: 2133-2141Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar23Hainaut P Pfeifer GP Patterns of p53 G–>T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke.Carcinogenesis. 2001; 22: 367-374Crossref PubMed Google Scholar of candidate genes, eg, p53 and K-ras, in malignant lung tumors from smokers and nonsmokers have identified significant differences in their mutational spectra, suggesting that different molecular carcinogenic pathways are involved in their development. One of the most well-characterized cigarette oncogenes is K-ras, a downstream component of the epidermal growth factor receptor cascade.24Arteaga CL The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia.J Clin Oncol. 2001; 19: 32S-40SPubMed Google Scholar However, activating K-ras mutations are found very rarely in never-smokers with primary adenocarcinomas.25Ahrendt SA Decker PA Alawi EA et al.Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.Cancer. 2001; 92: 1525-1530Crossref PubMed Scopus (391) Google Scholar In a study of patients with bronchoalveolar cell cancer (the least of lung cancer tumor types to be linked to smoking), only 2 of 20 tumors were found to have K-ras mutation; both tumors were derived from patients with significant smoking histories.26Rusch VW Reuter VE Kris MG et al.Ras oncogene point mutation: an infrequent event in bronchioloalveolar cancer.J Thorac Cardiovasc Surg. 1992; 104: 1465-1469PubMed Google Scholar Thus, adenocarcinoma in smokers and nonsmokers represent a heterogenous group of genetically different entities. This difference could result in the observed difference in survival observed by Nordquist et al. More complicated, however, is the interaction of a specific treatment effect with a potential prognostic indicator. Do smokers and never-smokers respond to treatment differently? Clearly, that may be the case. For instance, amplification of PI3-Kα, an antiapoptotic protein occurs in association with smoking in squamous cell carcinoma of the head and neck, is associated with resistance to the chemotherapeutic agent, cisplatin.27Singh B Reddy PG Goberdhan A et al.p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas.Genes Dev. 2002; 16: 984-993Crossref PubMed Scopus (178) Google Scholar Miller et al28Miller VA Kris MG Shah N et al.Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer.J Clin Oncol. 2004; 22: 1103-1109Crossref PubMed Scopus (723) Google Scholar recently reported a response rate of 38% to the epidermal growth factor receptor inhibitor gefitinib, among lung cancer patients who never smoked, compared to 8% among smokers (p < 0.001). Because tumors in never-smokers seem to be less genetically complex than their counterparts in smokers, they may be more dependent on signaling through one or a few critical signaling pathways for tumor maintenance and survival. Given the lack of a ready approach to identify a molecular fingerprint associated with prognosis and response to various therapies, a clinical profile or characteristic that could predict response to a specific treatment is very useful. The report by Nordquist et al further highlights the importance of stratification of patients for smoking history in future clinical trials. Applying a validated instrument to record smoking history in patients participating in clinical trials of lung cancer is essential.