Two new approaches to help diagnose lung cancer could enable doctors to determine which patients need surgery, which is often highly invasive and potentially dangerous. Researchers at Vanderbilt University have identified a set of molecular biomarkers, some found in blood and some in biopsied tissue, that improved the accuracy of lung-cancer diagnosis in tissue and blood samples from patients whose diagnosis had already been confirmed with surgery. Larger clinical trials of the biomarkers are now needed to determine the power of the tests to diagnose patients whose lung-cancer status is not yet known.

Lung cancer presents a serious challenge to oncologists. While it is responsible for the greatest number of cancer-related deaths in the United States–there are approximately 215,020 new cases per year and 161,840 deaths–“there is no screening and no early-detection tools validated to reduce mortality,” says David Carbone, an oncologist at the Vanderbilt-Ingram Cancer Center, in Nashville, TN. By the time symptoms appear, the cancer is usually at an advanced stage and very difficult to treat. “If we could change those ratios slightly, we’re talking about saving 10,000, 20,000, maybe 50,000 lives,” says Carbone.

To diagnose lung cancer, patients typically undergo x-ray or CT scans to detect abnormal growths on the lungs. However, highly sensitive CT scans can detect small nodules that may or may not be cancerous. Physicians must then decide whether to send the patient for surgery, which often involves cutting open the chest, or take a more conservative approach and recommend another scan in six months. A recent study found that as many as one in five people diagnosed with lung cancer did not in fact have it and underwent surgery unnecessarily.

This issue may soon become an even bigger problem. In an attempt to diagnose lung cancer earlier, a large nationwide study is under way to determine if screening heavy smokers with CT scans can reduce death rates. “If studies show that early CT scanning can help find cancers earlier, then more and more patients will come into doctor’s offices with difficult to interpret scans,” says Pierre Massion, a pulmonary physician at Vanderbilt. “CT scans can give lots of false positives, so we need a companion test that is highly specific.”

Tumors shed cells into the blood or sputum, signs of which could theoretically be picked up in noninvasive tests. But finding biomarkers that can aid in diagnosis of lung cancer has been challenging. “In the past, we have tried to look in the blood for differences between healthy people and cancer patients,” says Carbone. “We’ve had some success, but it’s not as specific as we would like.” So researchers are now looking for markers specific to tumor cells, and then determining whether those markers are detectable in blood.

Using mass spectrometry to identify tumor-derived proteins, scientists have so far identified a promising set of candidate biomarkers. In a study of tissue samples from about 100 patients, researchers found that adding the blood test to standard imaging tests could more accurately diagnose lung cancer. In a second study, researchers used a genetic analysis technique called array CGH, which detects small structural variations, such as extra copies of a piece of the genome, to identify a number of variations found specifically in the very early stages of lung cancer.

The researchers then designed a diagnostic test to detect four of the cancer-specific structural variations. In a similar retrospective study of tissue samples, researchers found that the new test improved the odds of correctly diagnosing the disease. The downside to this approach, however, is that it requires a biopsy to get tumor-cell samples, which is more invasive than a simple blood test.

Massion and his collaborators are now studying the genes affected by these variations for clues to their role in lung cancer. They would also like to identify biomarkers that can distinguish dangerous cancers from potentially less troublesome ones. Several studies show that early screening can detect small cancers, which scientists had assumed were precursors to the larger cancers seen in patients in later stages of the disease. However, the results of these studies suggest that “the cancers detected very early on seem to be biologically distinct from those detected later,” says Massion. If that is the case, a wait-and-see approach may be more suitable for these smaller cancers than invasive surgery.