Seminars in Oncology
Volume 32, Issue 3 , Pages 259-268, June 2005

Novel Strategies for the Early Detection and Prevention of Lung Cancer

  • Noel R. Wardwell Jr
    • ,
  • Pierre P. Massion

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Pierre P. Massion, MD, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN 37232-6838

Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt Ingram Comprehensive Cancer Center, Vanderbilt University Medical Center, Nashville, TN, and Veterans Affairs Medical Center, Nashville, TN

Article Outline

Lung cancer is the leading cause of cancer death in the United States. Despite evidence of molecular abnormalities in biological specimens, progress in this disease is hampered by the lack of diagnostic markers useful for clinical practice. The majority of patients with lung cancer are still diagnosed at an advanced stage, when prognosis is poor. This article reviews new strategies being studied for the early detection of lung cancer. These strategies involve new methods of imaging (including low-dose computed tomography [CT] scanning), DNA analysis, and proteomic-based techniques. These strategies have not only improved our understanding of lung cancer but show promise in offering better survival to patients with this deadly disease. Of paramount importance in the search for methods of early detection is the need for the identification of the ideal population to screen, a multidisciplinary approach, and validation of promising techniques.

 

Lung cancer remains the leading cause of cancer death in the United States with more than 163,000 deaths expected in this year alone.1 Despite efforts to improve early detection and prevention of lung cancer, the incidence continues to rise among women and has only slightly declined in men in recent years.2 Current estimates based on population growth predict a doubling of overall cancer rates in the United States by 2050, leading to a huge financial burden to society.3 More than 85% of all lung cancers are directly attributable to smoking, but national smoking rates have declined only slightly over recent years despite programs aimed at prevention.2 These data give little reason to expect a significant change in lung cancer incidence based on smoking cessation efforts alone.

Compounding the problem is the fact that the majority of lung cancers are diagnosed at an advanced stage with a dismal prognosis. Survival rates in lung cancer vary significantly by stage; overall, less than 15% of newly diagnosed patients will survive for 5 years. If patients are diagnosed at the earliest stage (IA), survival rates approach 70%.4 When patients are diagnosed at stage IIA and IIIA, survival rates fall dramatically to 34% and 13%, respectively.4 These differences underscore the need for early detection in lung cancer. Currently, only 16% of patients are diagnosed at stage I; if this percentage can be significantly increased, there is hope that survival rates for lung cancer will also improve.5 Screening tests for the early detection of cervical, colon, and breast cancers have been proven to reduce cancer related mortality; however, efforts to develop a screening test for lung cancer have not been successful to date and there are currently no data to support screening for lung cancer with any method.6

Lung cancer screening has major obstacles to overcome. Ideally, a screening test will be very sensitive, so that disease will not be missed. It must be specific enough, however, to avoid a large population of false positive cases, in which case patients would undergo a needless, potentially harmful, and expensive work-up. The lung is a challenging organ to screen due to its large surface area, which makes accessing biological material that may represent the state of health of all airways (central and peripheral) difficult. Further, current limitations of resolution limit the utility of lung imaging. High-resolution computed tomography (CT) can identify lung nodules less than a centimeter in size, but it is not sensitive enough to detect the vast majority of bronchogenic invasive lesions. Bronchoscopic techniques of detection are limited to direct visualization of only a small portion of the bronchial tree and have limited sensitivity. The lung is also highly prone to develop small, benign granulomas and other findings, which can mimic early and preinvasive disease, so the potential for false positive findings is significant.

Recent technological advances have led to new methods of investigating lung cancer. New lung imaging modalities and a better understanding of the genetic and proteomic changes that occur in neoplastic cells have renewed our efforts in the search for methods of early detection and treatment. This article will review these methods with a particular emphasis on the use of new imaging techniques and the discovery of biomarkers of disease and of disease progression.

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The Case for Early Detection 

The central hypothesis behind early detection is that by detecting and treating lung cancer at an early stage, its natural history can be altered and patient mortality can be improved. We know that patients who undergo surgical resection for stages I-IIIA tumors have improved survival over those who are unresected, suggesting that we can alter the natural history of the disease. A successful screening strategy should diagnose more patients at an earlier stage of disease and improve overall survival rates from lung cancer.

There are many obstacles to be overcome before reaching this goal, including the possibility of overdiagnosis. This bias occurs with a disease that does not become clinically relevant before the patient dies from other causes. Screening may not lead to a reduction in lung cancer-related mortality because of a biased selection for less aggressive disease or because cancer patients die of other comorbidities. There appear to be significant differences in the aggressiveness of lung cancers. Yet, whether smaller lesions are less aggressive in nature remains the subject of controversy. Unresected stage I lung cancer is almost invariably fatal,7 implying that overdiagnosis is rare. Contrary to this argument are the following facts: first, up to one in six lung cancers found at autopsy is not clinically recognized nor related to the patient’s cause of death8; second, the percentage of adenocarcinomas and bronchoalveolar cell carcinomas (BAC) detected in patients undergoing CT screening is out of proportion to what has traditionally been found in clinical practice; and third, a recent study of mass CT screening in Japan demonstrated a lung cancer rate of 0.46% in nonsmokers compared with 0.52% in smokers.9 This small difference highlights the possibility that mass CT scanning is detecting lung cancers that are destined to have an insignificant medical course. To cure these cancers, new methods of early detection must be developed, and screening techniques should not focus on less aggressive diseases. Table 1 outlines the potential of some currently available strategies. Randomized, controlled trials will be very important in understanding the prevalence of overdiagnosis and are necessary to validate some of the biomarkers proposed. The National Lung Screening Trial will be the first randomly controlled trial with a goal of recruiting 50,000 high-risk patients to be randomized to either a CT-based screening protocol or to a chest radiograph.10

Table 1. Strategies of Early Detection for Targeted Lesions
CXRCTPETFluorescence BronchoscopySputum CytologySputum BiomarkersEBCBALFNASerum
Endobronchial tumors+/−++++***−*
Peripheral tumors+/−++−+*****
GGO−+−−−*****
Preinvasive lesions (not GGO)−−*+−+****

Abbreviations: +, Able to be detected with reasonable sensitivity; −, unable to be detected; *potential for detection, but as yet nunproven; GGO, ground glass opacities; CXR, chest x-ray; CT, computed tomography of the chest; PET, positron emission tomography; EBC, exhaled breath condensate; BAL, bronchioalveolar lavage; FNA, transthoracic fine-needle aspirate.

High rates of second primary tumors further complicate the search for methods to improve long-term survival in patients with lung cancer. The rate of second primary tumors has been estimated to be between 1% and 4% per patient per year.11, 12, 13, 14 Patients who smoke expose their entire lungs to carcinogens. Therefore, it is not surprising that a large percentage of patients will develop second primary tumors. This illustrates the concept of field carcinogenesis. Even in this high-risk group, there remains no method of early detection capable of altering mortality. Chemopreventive agents capable of altering the risk of developing lung cancer are being tested in high-risk groups in an effort to improve long-term survival for patients with lung cancer.

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The High-Risk Population: A Susceptible Subgroup 

A critical approach to early detection of lung cancer is to select the high-risk population. The cumulative risk of dying from lung cancer for a lifelong smoker is estimated to be 16% in men and 10% in women.15 Therefore, identifying patients who carry the greatest predisposition to develop lung cancer is a critical goal of this research. Selecting patients based on their smoking history, their professional exposure to asbestos, the presence of airflow obstruction, and their family history of lung cancer is logical as these are risk factors known to be associated with lung cancer.

Cytologic atypia in a sputum sample reflects the abnormalities developed in the bronchial epithelium and has been shown to predict lung cancer risk.16 The presence of moderate dysplasia or worse was recently shown to be associated with an increased risk of developing lung cancer (adjusted hazards ratio of 2.8) in a cohort of heavy smokers with airflow obstruction.17 This translates into a cumulative lung cancer incidence of 10% at 3 years and 20% at 6 years. Given the limitations of cytologic evaluation of sputum samples, the study of molecular abnormalities in the sputum (eg, methylation patterns of specific genes involved in lung cancer progression) will strengthen the assessment of risk for lung cancer in this population.

Molecular epidemiology has advanced the field by identifying genes, single-nucleotide polymorphisms (SNPs), and other genetic traits associated with increased susceptibility for lung cancer.18 While autosomal dominant genes (such as Rb1) have not been found in association with lung cancer, there is epidemiologic evidence demonstrating a 2.5 times increased risk in patients with a family history of lung cancer after controlling for smoking.19 At the level of risk assessment, looking at SNPs in low-penetrance genes may explain a large proportion of lung cancers. While many genotypes show increased risk (relatively low odds ratios) with lung cancer (eg, CYP2A6, thymidylate synthase, GSTM1, and XPA, a DNA-repair gene), their large number and low penetrance make targeted intervention quite challenging. Further complicating the picture is the role of the environment in modifying these specific genes and the interaction between genes. There is also evidence to support a genetic predisposition to smoking addiction. A study of smoking patterns in twins showed significantly greater concordance of habits between monozygotic twins compared to dizygotic pairs.20 A more recent study has suggested that genes involving dopamine receptors and transporters, among others, may play a role in susceptibility to nicotine addiction.21 Assessing genetic susceptibility for lung cancer may allow the identification of susceptible subgroups most likely to represent ideal candidates for early detection. If markers of these genetic predispositions can be firmly established, intensive intervention to alter risk factors in these selected populations may change their clinical outcome. The recently described susceptibility locus on chromosome 6q23–25 in familial lung cancer shows such promise.21a

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Imaging Approach 

Early trials centered on regular monitoring of chest radiographs with or without analysis of sputum cytology and none of these trials were able to show a cancer-related survival advantage.6, 22, 23, 24, 25, 26 The last decade has seen a dramatic improvement in technology allowing for faster, higher resolution imaging of the chest. The CT scanner first became available in the 1970s but was impractical for screening due to its slow speed and radiation exposure. In the mid 1990s low-dose spiral (or helical) scanners capable of imaging the chest in less than 15 seconds using radiation doses equivalent to 10 radiographs became available, opening the door to their potential use for screening.27 New bronchoscopic methods have shown promise for the detection of preinvasive lesions. Other imaging modalities such as positron emission tomography (PET) scans are able to provide metabolic information on lesions and can be combined with CT scanning to give detailed resolution.

Low-Dose Spiral CT Scan 

All data on screening for lung cancer with low-dose spiral CT scanning are based on observational studies, as no randomized, controlled trials have been published. These studies have been reviewed in detail elsewhere28, 29 and show lung cancer prevalence rates between 0.4% and 2.7%, depending on the population screened. In general, these rates are significantly higher than historic prevalence rates. Incidence rates based on detection of new malignancies at annual repeat screening are typically 0.2% to 1.1% based on the studies listed in Table 2, Table 3. These studies have also shown an increase in tumors found at a resectable stage.28, 30 In the Early Lung Cancer Action Program (ELCAP) study, 30 (2.5%) of 1,184 CT scans repeated 1 year after a normal scan showed a new nodule. Seven (0.59%) of these nodules were shown to be malignant, although two patients did not complete their work-up. Six of these seven were non-small cell carcinomas (NSCLCs), and five were stage IA.31 The data on CT screening trials are encouraging; however, long-term survival data are still lacking. Extended follow-up of these patients will be very important to exclude lead-time bias (simply diagnosing the cancer earlier, but not altering its outcome) as a confounder for an improved survival and a reduced disease-related mortality.

Table 2. Selected CT Screening Trials: Results of Initial Screening
Study (first author)DatePatients ScreenedNo. of Abnormal ResultsMalignancies DetectedDetected at Stage I (%)
Henschke122199910002332781
Swensen36200215207822259
Sobue37200216111861477
Sone382001548367622100
Pastorino43200310351991155
Table 3. Selected CT Screening Trials: Results of Repeat Screening
Study (first author)DatePatients ScreenedNo. of Abnormal ResultsMalignancies DetectedDetected at Stage I (%)
Henschke312001118463785
Swensen362002146419130
Sobue37200278917212282
Sone382001830351834100
Pastorino4320039969911100

CT scanning has also shown promise in the detection of some preinvasive lesions. High-resolution CT has proven to be sensitive enough to detect ground glass opacities, some of which may represent inflammatory lesions, BAC, adenocarcinomas, or alveolar atypical hyperplasia (AAH). AAH is a presumed precursor lesion to adenocarcinoma.32, 33, 34, 35 Since adenocarcinoma is now the most common histologic type of lung cancer in the United States, there is some hope that CT may be able to improve survival for these patients by detecting a precursor lesion before its transformation to invasive carcinoma. While the potential to detect lung cancers at a curable stage is encouraging, there is still concern over the possibility of overdiagnosis as discussed above.

Another significant problem encountered during CT screening trials is the high false positive rate. On initial screening of at-risk populations false positive rates as high as 50% have been reported, although most studies report rates between 10% and 20%. Positive predictive values range from 2.8% to 11.6%.31, 36, 37, 38 Table 3 summarizes data from four large screening trials. False positives can have a substantial impact on patients through the expense and risk of unneeded further evaluation and emotional stress. False positive rates and positive predictive values are somewhat improved in annual follow-up CT scans, but there is still significant room for improvement.

In the context of a screening effort for populations at high risk for lung cancer, we are now finding a large number of small pulmonary nodules. While nodules less than 0.5 mm in diameter are unlikely to be cancerous, those 5 to 10 mm in diameter (25%–40% of noncalcified nodules detected) are of uncertain significance. The management of these patients usually consists of repetitive CT scans over time to see if the nodules grow, attempted fine-needle aspirates, or surgical resection. PET has limited usefulness in detection of lesions less than 1 cm and has shown to be of limited value in adenocarcinoma, particularly of the bronchoalveolar subtype.39 Each of these tests is costly, and some have significant morbidity. The impact of waiting to assess nodule growth on patient outcome is also not clear, but can only decrease curability. Even for patients with disease that is highly suspicious for lung cancer on clinical grounds, there is a 10% to 20% incidence of “futile thoracotomies,” where the suspicious lesion is found to be benign, and thus the patient unnecessarily incurred the morbidity and potential mortality of a thoracotomy.40, 41 Eliminating unnecessary surgeries should be one of our priorities, although this may not be feasible without the development of other strategies of early detection.

PET Scan 

Many CT screening protocols now employ PET scanning as a method of reducing this high false positive rate. PET scanning attempts to identify malignancy based on glucose metabolism by measuring the uptake of fluorodeoxyglucose F18 (18F-FDG). Lung cancers will preferentially take up 18F-FDG and appear as a “hot spot.” To date, PET mostly has been used for staging and detection of metastases in lung cancer. In combination with another imaging modality, PET may provide information about the metabolic state of lung nodules. Combined PET-CT scanning has been shown to improve the accuracy of staging in lung cancer compared to visual correlation of PET and CT or either study alone.42 The added information gained from PET or combined PET-CT may help reduce the high false positive rates seen in trials using CT only.

A recently published trial of low-dose CT, used in combination with PET scanning of 1,035 patients, resulted in only six false positives, defined as a surgical biopsy of a benign nodule, out of 27 surgical biopsies of suspicious nodules.43 However, there are important limitations to this study. First, lung nodules ≤5 mm in size were followed, with repeat CT in 1 year, and no other intervention. Second, PET scanning was only performed on larger nodules (≥7 mm). Typically, PET scan has not performed well in the identification of small nodules, so its usefulness in lesions less than 7 mm remains in question. There is still no evidence of a survival benefit using PET scan a part of a screening protocol.

Fluorescence Bronchoscopy 

Fluorescence endoscopy was introduced in the 1990s as a method of detecting preinvasive lesions in the epithelium of major bronchi.10 This technique uses differences in the autofluorescence characteristics of normal and neoplastic epithelium to localize lesions. It is performed using a standard bronchoscope fitted with a blue light source from a helium-cadmium laser and a fluorescence camera.44 Fluorescence bronchoscopy has been shown to be more sensitive than white light bronchoscopy in the detection of pre-neoplastic lesions in many studies, including a randomized trial.44, 45, 46, 47 A randomized trial demonstrated that use of the fluorescence endoscopy procedure resulted in a 46.9% absolute increase in the sensitivity of detecting moderate dysplasia or worse in high-risk patients when compared with white light bronchoscopy, although specificity was worse.45 The procedure is time-consuming, however, and it is not widely available. Further, it is only able to examine as far as the fourth generation bronchus (out of 20), so only a very small portion of the bronchial tree is directly surveyed.

Fluorescence bronchoscopy has not been proven as a validated method of early detection of lung cancer, but it is a very important research tool. In particular, it is powerful at providing biopsy specimens of preinvasive lesions, especially mild and moderate dysplasia, as these lesions are notoriously difficult to identify by traditional white light bronchoscopy. In addition, this method allows the study of the biology controlling this human model of tumor development.

Other Imaging Techniques 

New imaging techniques are currently being developed not only to improve resolution but also to image lesions based on biologic activity. Radiography using a monochromatic source of x-rays has the potential to improve imaging by filtering x-rays at the source. This results in the removal of both very high-energy beams and low-energy beams, which contribute to excess radiation and background noise in images. This may eventually allow improved resolution with lower radiation doses and faster imaging times than even the low-dose CTs available today.48

Molecular imaging techniques similar to the PET scan are being developed to help detect lesions based on their metabolic activity. Both magnetic resonance and gamma camera techniques are being tested.49, 50, 51 As understanding of the molecular determinants of lung cancer development improves, new markers of preinvasive lesions may be developed, which could be used as a marker for these types of imaging.49, 50, 51

Near-infrared Raman spectroscopy uses differences in the frequency of photons emitted from tissue that has been struck with a laser to distinguish normal tissue from malignant. A recent study of tissue obtained by autofluorescence bronchoscopy showed that there were distinguishable differences between normal tissue, adenocarcinoma, and squamous cell carcinoma.52 If this technique can be used in vivo, it has the potential to improve the detection of early, preinvasive lesions.

There are also new imaging techniques capable of working at the cellular level in vivo. Optical coherent tomography uses the constructive interference of light traveling over a known distance and over the target tissue to create an image with resolution at the micrometer scale.53 This modality is currently being investigated in the diagnosis of dermatologic, ophthalmologic, and gastrointestinal disease.53, 54, 55 Confocal microscopy uses optical differences within tissue to allow imaging of individual cell nuclei. This technology is being adapted for use during endoscopic examinations and may be able to provide real-time histologic evaluation of bronchial mucosa. The ability of these techniques to detect invasive and preinvasive lesions has not been studied to this point, but examination of the nuclear structures of cells during bronchoscopy would be of great interest in assessing extent of disease, margins, and response to local therapy or chemoprevention.

Imaging techniques available to date are limited in two significant ways. First, they are unable to image the entire lung at a resolution high enough to detect preinvasive lesions (with the exception of AAH), and second, they are unable to provide complete functional information about the lesions they uncover. Limits in imaging techniques have inspired efforts to understand the development of lung cancer at a molecular level.

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Genetic Approach 

Because cancer is a genetic disease, the focus has traditionally been to understand the genetic alterations that transform the normal epithelium into a malignant phenotype. More recently, proteomic based approaches have led to the detection of proteins that are preferentially expressed in lung cancers.56 If biomarkers can be identified in nonsurgical specimens such as blood, sputum, or exhaled breath condensate, the potential application of this information is enormous. The discovery of proteins or DNA changes that correlate with invasiveness, metastatic potential, or outright metastasis, can have a large impact on patient care. If biomarkers can more accurately stage nodal status and metastasis, patients can be treated more appropriately and needless surgeries avoided. The potential to unlock a more complete picture of tumors with nonsurgical specimens has made this an area of active research. The study of genetic alterations in precursor lesions, the analysis of genomic instability, molecular profiling, and epigenetic alterations of tumors are areas of active research for the discovery of new methods of early detection.

Genetic Alterations in Precursor Lesions 

The natural history of lung cancer remains poorly understood. Squamous cell carcinoma is presumed to progress from normal epithelium to metaplasia, dysplasia, in situ carcinoma, and finally invasive carcinoma.57, 58 Not all cancers progress linearly though these stages. Biopsy specimens have been shown to proceed and regress along this path and even revert to normal epithelium.59 Adenocarcinoma may progress from AAH as previously mentioned. To date, both large cell and small cell carcinoma have no clear precursor lesions.

Obtaining preinvasive specimens has been a particular challenge for this area of research. Preinvasive lesions (particularly low-grade) are rarely identifiable by white light bronchoscopy. Early studies relied on complete dissection of autopsy specimens for material.60 Lesions of varying preinvasive grades routinely coexist in patients with lung cancer. This observation, together with the multifocal nature of tumors of the aerodigestive tract, led to the concept of field carcinogenesis, suggesting that smoking exposes the entire bronchial epithelium to carcinogens that cause diffuse alterations at different rates of acquisition. Fluorescence bronchoscopy has been of considerable value for obtaining these rare lesions. The identification of the determinants of tumor progression using the human model of tumorigenesis is an intense area of investigation. Laser microdissection has provided a means for obtaining material from these small lesions for genetic and proteomic analysis.61 This technique allows for the extraction of very small amounts of preinvasive material from a heterogeneous sample. In this way, preinvasive material, uncontaminated by invasive tumor or normal epithelium, can be obtained for further testing.

Transformation of normal bronchial epithelium to invasive carcinoma is accompanied by changes in the genetic make-up of cells. Genetic lesions precede the occurrence of morphologic changes occurring in preinvasive bronchial dysplasia or AAH. There has been considerable research effort in identifying the genes affected and understanding their function. Genes and molecular pathways identified to this point have been summarized in detail elsewhere.62 Recent studies have demonstrated that there is a multistep accumulation of genetic changes, which occur in pre-neoplastic cells, ultimately leading to invasive phenotype.63, 64, 65, 66, 67, 68 In squamous cell carcinoma, the earliest changes appear as gene copy number loss on chromosome 3p. Changes at 5q are followed by 9p and eventually k-Ras mutations.69, 70 Other changes involving p53 occur later in the process,71, 72, 73 along with acquisition of genomic amplification.74 Recent data from our laboratory suggest that acquisition of amplification of p63 or PIK3CA on chromosome 3q26–28 may be a predictive signature of progression to an invasive phenotype.68, 75 These genes are amplified and overexpressed at a critical step in the early development of NSCLC and therefore may prove to be good candidate biomarkers of squamous carcinoma progression.

Genomic Instabililty and Molecular Profiling 

The examination of lung cancers for genomic instability has shown promising results. Genomic instability is manifest as either microsatellite instability or loss of heterozygosity (LOH). Microsatellite instability refers to the insertion of repeating nucleotide units within the genome. These insertions result in frameshift mutations and aberrant protein expression. Examination of chromosomes for loss of heterozygosity has been used to identify the locations of tumor-suppressor genes (TSG) within chromosomes.

There is evidence that genomic instability can be identified in the bronchoalveolar lavage (BAL) of patients with lung cancer. One study showed a sensitivity of 73.9% and specificity of 76.5% for a panel of markers from BAL specimens.76 Other investigators have reported the presence of DNA markers in the serum of patients with lung cancer in the form of mutations, microsatellite alterations, or methylation of promoter regions of specific cancer related genes.77, 78, 79, 80 A small study found that seven of eight patients with small cell lung cancer and evidence of genetic instability in the tumor had similar findings in their serum.77 For patients with NSCLC, seven of 10 patients had serum evidence of genetic instability, which was also detected in the tumor. Recently, Sozzi et al reported an eightfold elevation of human telomerase reverse transcriptase (hTERT) by real-time polymerase chain reaction in the serum of patients with lung cancer.81 Further assessment of microsatellite instability in the blood of patients with lung cancer as compared to controls is warranted. The ability to identify these DNA changes in the serum holds great promise for the development of markers of early detection.

Gene expression profiling studies have been used to identify biomarkers specific to lung cancer.82 Beyond molecular classification of cancer, these studies also allow the identification of good and poor prognosis, stage I lung adenocarcinomas,83 or molecular pathways.84 However, very few studies used a blinded test cohort to confirm the predictive power of selected gene biomarkers. Using this methodologic approach, investigators have identified sets of genes that successfully discriminate tumor from normal tissue and lung primary cancer from metastasis, as well as different histologic subtypes and predictors of poor prognosis.85 This attempt to associate patterns of gene expression with tumor behavior will need to be validated in larger populations. Molecular markers could be used to identify patients with early-stage lung cancer. Expression profiling has the potential for the identification of biomarkers for early detection of lung cancer. Yet those biomarkers usually discovered in tissue samples will have to be detected by noninvasive approaches, such as measurement of DNA or proteins in the serum or in the sputum.

Epigenetic Alterations 

Epigenetic changes, particularly changes in the methylation pattern of DNA, also show promise in the early detection and therapy of lung cancer. Hypermethylation of CpG islands in the promoter regions of TSGs inhibit transcription and silence these genes. Changes in the methylation pattern of specific promoter regions have been shown to help discriminate histologic types of lung cancer.86 Another study demonstrated that in patients with tumors known to be hypermethylated at a specific location, 63% were detectible in the BAL fluid of those patients.87 Linking tumor biology with the vasculature, Usadel et al showed that 47% of patients with lung cancers demonstrating hypermethylation of the adenomatous polyposis coli gene promoter had these changes detectible in their serum.88 The presence of hypermethylation of lung cancer genes has also been show to correlate with worse prognosis.89 Therefore, the analysis of methylation changes in tumors and biological fluids is a promising method for early detection. While these techniques hold promise, there has been no proof yet of their utility as a screening tool.

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Proteomic Approach 

While examination of genetic alterations in preinvasive lesions has provided valuable information on the development of lung cancer, it has been difficult to apply to clinical screening. Detecting preinvasive changes would require recovery of tissue material and extraction of DNA for examination, which is not easily obtained noninvasively. Fragments of DNA may be recoverable from the serum, but so far, this small amount prohibits thorough evaluation in lung cancer detection. Proteins, however, are easily noninvasively obtained from a variety of sources, including blood, sputum, and exhaled breath condensate. While examining the changes in the DNA of tumors can provide clues to changes in transformed cell function, examination of the differential expression of proteins in malignant cells allows us to see exactly how these genetic changes are translated. In this way, a proteomic approach may not only allow us to diagnose lung cancers early, it may also give insight into the behavior and metastatic potential of these tumors.

Initial proteomic approaches relied on antibodies directed at known proteins thought to be important in lung cancer development. In 1988, Tockman et al first reported a monoclonal antibody directed at a protein that could be detected in the sputum of patients at high risk for developing lung cancer. This antibody, later determined to be HNRNP A2/B1, was 90% accurate in predicting patients who would develop lung cancer over the next few years.16 HNRNP A2/B1 has been detected in other biologic specimens, including BAL and blood, since that time.29, 90, 91 Many other proteins, including cyclo-oxygenase 2 (COX-2), farnesyl transferase, and epidermal growth factor receptor (EGFR), have also been found to be overexpressed in lung cancers.92, 93, 94, 95, 96 While these proteins are the targets of new therapies for lung cancer, they have not been useful as a method of early detection thus far.

The development of matrix-assisted laser desorption ionization-mass spectroscopy (MALDI-MS) has provided a new, powerful technique for the study of cancer proteomics.97 Traditional methods of identifying potential biomarkers are based on either the study of the products of genes found to be involved in lung cancer or time-consuming two-dimensional gel electrophoresis.98 MALDI-MS allows the generation of a protein “profile” based on the molecular weights and relative abundance of all proteins in a sample. Thus, instead of relying on the identification of a particular protein in a sample, this technique looks for changes in the expression of all proteins in lung tumors. The proteins that are differentially expressed can then be identified and tested as potential biomarkers. A recent study of resected tumors demonstrated that this technique was 100% accurate in identifying cancer from non-cancer and histologic type of cancer.56 This technique was also 75% accurate in predicting lymph node involvement when compared to light microscopic examination of resected nodes. The pattern of expression of just 15 proteins was able to separate patients with good and poor prognoses (median survival, 33 v 6 months).56 This study demonstrates the powerful potential of MALDI-MS profiling not only to diagnose lung cancer but also to provide important information on tumor behavior and prognosis. Additionally, it allows the identification of novel proteins involved in the disease for further study.

Recent studies have attempted to apply mass spectroscopy techniques to detect lung cancer in samples obtained from less invasive samples such as the serum. One study used a prediction model based on the analysis of serum from patients with head and neck cancer in the attempt to predict the presence of lung cancer in a separate patient group.99 This study demonstrated a sensitivity of 52% for adenocarcinoma, 34% for squamous cell carcinoma, and 40% for large cell carcinoma, with a false positive rate of 10%. Serum amyloid A has been proposed recently as a biomarker for lung cancer after screening the serum of 41 patients with lung cancer by MALDI-MS.100 Mass spectroscopy of serum also shows promise for the detection of serum biomarkers in prostate, ovarian, breast, head and neck, and pancreatic cancers. The examination of proteins expressed in sputum and exhaled breath is under investigation.

Validation of Biomarkers 

Rapid validation of relevant new biomarkers is quite challenging. The Early Detection Research Network (National Cancer Institute, Division of Cancer Prevention) has proposed a step-wise method for evaluating biomarkers, and for identifying people at risk (http://www.cancer.gov/edrn).101 The recent use of tissue microarrays has facilitated validation strategies.102 Selected immunohistochemical, molecular biologic, and cytogenetic techniques may allow evaluation of biomarkers on routinely processed paraffin-embedded material obtained from the pathology archives in a high-throughput manner.68 Assessment of accuracy, reproducibility, and intra- and intersample variability of any given assay will need to be carefully studied within and across laboratories. Validation in population studies with robust study design will then need to keep pace with rapid progress in assay development. Along with the validation of biomarkers, the understanding of their role in the biology of tumor development is essential.

Chemoprevention 

Even if these markers are found to be predictive of lung cancer risk, there is no method to alter this risk other than smoking cessation. Current curative techniques are primarily based on the resection of a lesion. Thus, even if a patient could be identified with a biomarker of lung cancer, the lesion must be localized in order to be resected. This is a very difficult task with current technologies. Also, as the concept of field carcinogenesis implies, removing one preinvasive or invasive lesion does not render the entire lung free of potential cancers. There is a need for systemic or regional therapy that could be applied to alter a patient’s risk of lung cancer. This is the potential benefit of chemoprevention.

Trials of chemoprevention for lung cancer have been ongoing for over 10 years. Retinoids were among the earliest agents to be tested. Retinoids act on a family of retinoic acid receptors to regulate cell proliferation and differentiation. Early small-scale studies demonstrated a decreased rate of second primary tumors in patients with resected lung and head and neck cancers.103, 104 Large randomized trials failed to demonstrate this protective effect, and actually found that beta-carotene increased the risk of developing lung cancer.105 Currently, compounds, that target specific receptors within the retinoic acid receptor family are being studied.

As the molecular pathways leading to oncogene regulation have become elucidated, specific blockers have been designed as potential chemotherapeutic agents. The overexpression of EGFR, COX-2, and farnesyl transferase in lung tumors has led to the development of specific molecules designed to block the function of these proteins.106, 107, 108, 109, 110, 111, 112, 113, 114, 115 Early trials of the EGFR blocker ZD1839 (Iressa, AstraZeneca, London, UK) have demonstrated the potential for efficacy and an acceptable side effect profile.116, 117 COX inhibition is also being studied, and two epidemiologic studies of nonsteroidal anti-inflammatory drugs have indicated potential protective effects on the development of lung cancer.108, 118

There are many other approaches currently being developed, such as attempts to reverse the accumulated genetic damage obtained in preinvasive lesions through gene transfer. Other drugs being studied include statins and prostaglandin I2 (PGI2). Statins have shown the potential to inhibit angiogenesis in high doses, and may inhibit tumor growth.119 Iloprost, a PGI2 analog, has been shown to inhibit tumor-induced platelet aggregation and to enhance the host immune response, which may inhibit metastatic spread of tumors.120 In addition, because increased pulmonary production of prostacyclin decreases lung tumor incidence and multiplicity in carcinogen-induced lung cancer models, prostacyclin analogs may be a useful chemotherapeutic strategy.121

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Conclusions 

The early detection and risk modification of lung cancer remain elusive problems. It is ironic that the most significant risk modifications (smoking cessation and prevention) while simple in concept, have proven to be very difficult to accomplish. There are many new techniques that attempt to overcome the obstacles to early detection. New sensitive imaging techniques hold the promise of diagnosing more patients at an earlier stage, while other imaging modalities such as PET scanning provide biochemical information about the lesions they image. New bronchoscopic techniques, such as fluorescence bronchoscopy, are changing our understanding of preinvasive lesions. Genetic and proteomic based searches for biomarkers of early invasive and preinvasive disease hold the potential for detecting patients at risk for or with lung cancer before it is radiographically evident. A combination of these techniques could be a powerful tool in the search of early detection methods (Fig 1). An especially powerful combination would be the identification of a biomarker in the serum to identify high-risk patients and sensitive imaging techniques to allow for localization and resection. The success of early detection strategies would lead to the identification of many patients at high risk for developing lung cancer. It would also provide those individuals with an opportunity to enter an intense screening protocol and to decide on participating in some chemopreventive strategy.

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 Supported by the Department of Veterans Affairs, the Flight Attendant Medical Research Institute, the Damon Runyon Cancer Research Foundation, and the SPORE in Lung Cancer 5P50 CA 90949-02.

PII: S0093-7754(05)00079-5

doi:10.1053/j.seminoncol.2005.02.009

Seminars in Oncology
Volume 32, Issue 3 , Pages 259-268, June 2005

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