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The National Cancer Institute (NCI) is capitalizing on other technologies besides imaging to look for ways to screen people who are at high risk for developing lung cancer.

The estimated 90 million current and former smokers in this country make up the biggest population at risk for lung cancer. But even if all smokers quit today, there would still be lung cancer cases for 50 years due to the damage already caused. Currently, less than 30 percent of lung cancers are diagnosed at an early stage, when conventional wisdom suggests they ought to be more curable. Because spiral computerized tomography (CT) detects smaller lesions than X-rays, some scientists believe it will catch tumors before they spread outside the lung. But small is not always early when it comes to lung cancer, says Denise Aberle, M.D., University of California Los Angeles, co-director of the NCI-funded National Lung Screening Trial launched in September 2002. Some tumors have already metastasized by the time they can be found on spiral CT scans. NLST will help determine if spiral CT is better than X-rays in reducing deaths due to lung cancer by detecting tumors early.

Both spiral CT and X-rays will detect small lesions. The challenge will be how to tell the difference between a deadly tumor and a scar or other noncancerous abnormality.

Answers may come from an array of new biological tools. Vanguard technologies to detect changes in genes, such as polymerase chain reaction (PCR) assays and microarrays, are being employed to find lung cancer markers. In addition, proteomics-markers defined by protein expression patterns-which holds promise for early detection of ovarian and prostate cancers, may also prove useful for lung and other cancers. Gene or protein marker detection may then be used in tandem with imaging studies to help clinicians determine if someone has lung cancer.

A New Look at Sputum

The new tools are allowing scientists to re-examine the usefulness of clinical samples, such as sputum. Twenty years ago, researchers conducted large lung screening trials that involved the collection of sputum to see if it contained cells that would lead to the detection of cancer. The conclusion of these trials was that sputum wasn't a useful screening tool. But sputum examination in those days relied on skilled people looking at cells in the samples through a microscope-a subjective technique that could leave experts disagreeing about whether cellular features indicated that cancer was present in the patient.

Today, tools that detect changes at the molecular level take the observer out of the picture, providing a much clearer answer about whether cancer gene markers or proteins produced by cancer genes are present. Research has shown that some molecular markers are present in sputum three or more years prior to diagnosis of lung cancer. Scientists are also probing for molecular changes in the blood.

So far, though, none of the markers in sputum, blood, or other samples such as bronchial lavage-a "wash" obtained by delivering a solution into the lungs via a fiberoptic bronchoscope and sucking it out again-is sensitive and specific enough to be useful for mass screening. But changes in the field of markers may bring them closer to being used for routine screening.

As in other cancers, scientists studying lung cancer are shifting their focus to develop a panel of markers, rather than rely on just one. "There's a big graveyard of markers that haven't panned out," says William Bigbee, Ph.D., who is part of the NCI-funded Early Detection Research Network and the NCI-supported Lung Cancer Specialized Program of Research Excellence (SPORE) at the University of Pittsburgh Cancer Institute.

Beyond the Marker Graveyard

Constructing a screening tool that employs many markers may be the ticket to making screening of sputum, blood, or other samples commonplace. With current advances in technology, it may soon be possible to probe for many common cancer-causing genetic changes in biological specimens of asymptomatic individuals. Possible candidate genes to comprise such a panel include: p16, MGMT (06-methylguanine-DNA methyltransferase), hnRNP A2/B1 (heterogeneous nuclear ribonucleoprotein A2/B1), K-ras, and p53. Genes located on chromosomes 3p and 9p are also known to be involved in lung cancer. The first two genes, p16 and MGMT, contain many extra methyl groups and other hypermethylated genes are also being examined for a link to lung cancer.

Lung Cancer SPORE researchers-Steven Belinsky, Ph.D., Lovelace Respiratory Research Institute in Albuquerque, NM, and James Herman, M.D., and Stephen Baylin, M.D., at The Johns Hopkins Oncology Center in Baltimore, MD, and colleagues from University of Colorado Cancer Center in Denver, CO-are conducting a study examining a particular set of hypermethylated genes in the sputum of 3,000 smokers. The participants, who enter the trial without lung cancer, are being followed over time to see if they develop cancer. So far, the markers, which are detected using a methylation-specific PCR assay, have proved predictive in about 100 people who have already developed lung cancer. "The results are very promising," says Dr. Baylin.

Although no markers are ready yet to be taken to the level of testing that spiral CT is undergoing in NLST, the new molecular tools, especially proteomics, have the potential to be scaled up to handle the demand for lung screening tests and could be economical, as well.

Proteomics is particularly promising because protein markers can be detected from the amount of blood serum obtained with a finger prick, and some NCI-supported scientists, including Dr. Bigbee, are investigating this approach for early detection of lung cancer. But, some scientists say serum markers may appear too late in the development of lung cancer-by the time a tumor has developed blood vessels into which to shed tumor cells, it is already big enough to metastasize. Lung tumors develop blood vessels when they grow to approximately 3 millimeters, about the minimum size that can be detected on spiral CT.

Other researchers say cancer-associated proteins found in the blood may not come directly from the tumor. The body has a complex response to tumors, and the immune system gears up to fight cancer before a tumor metastasizes, says Dr. Bigbee. So what may be reflected in serum are proteins from an immune response to the cancer rather than proteins from the tumor itself.

Scale Up

Scaling up the new molecular tools to handle millions of screening tests per year will not be easy, says Jim Mulshine, M.D., of NCI's Center for Cancer Research. But even if the markers don't work for early detection, they may be useful for identifying individuals at the highest risk for developing lung cancer. In addition, markers may help in monitoring the effects of new and experimental treatments or for monitoring for recurrence of the tumor.

Markers may also support individualized treatment in the future, says Dr. Mulshine. Recently published microarray studies reveal that lung cancer is actually several different diseases at the molecular level. The ability to characterize the diseases with molecular markers may eventually make it easier to give a patient the most effective treatment for his or her tumor.

Additional Reading:

Hirsch, FR, Franklin, WA, Gazdar, AF, Bunn, PA, Jr. Early Detection of Lung Cancer: Clinical Perspectives of Recent Advances in Biology and Radiology. Clin Can Res 2001;7:5-22.

Mulshine, JL, Cuttitta, F, Tockman, MS, De Luca, LM. Lung Cancer Evolution to Preinvasive Management. Clin Chest Med 2002;23(1):37-48.

Palmisano, WA, Divine, KK, Saccomanno, G., et al. Predicting Lung Cancer by Detecting Aberrant Promoter Methylation in Sputum. Cancer Res 2000;60:5954-5958.

Petricoin, III EF, Ardekani, AM, Hitt, BA, Levine, PJ, Fusaro, VA, Steinberg, SM, Mills, GB, Simone, C, Fishman, DA, Kohn, EC, Liotta, LA. Use of Proteomic Patterns in Serum to Identify Ovarian cancer. Lancet 2002;359:572-577.

Other Information:

NCI Lung Cancer Specialized Programs of Research Excellence (SPORE): http://spores.nci.nih.gov/current/lung/lung.html

NCI Early Detection Research Network (EDRN): http://www3.cancer.gov/prevention/cbrg/edrn/

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