Biomarker Predicts Development of Lung Cancer

WASHINGTON--One key element to increasing survivorship among lung cancer patients lies in finding ways to detect the disease early, and recent results in the quest for a preclinical biomarker for the malignancy offer great promise, a National Cancer Institute scientist told a Capital Hill briefing.

"When we find early cancers of other sorts, we do well--skin cancer, cervical cancer. We cure them 90% of the time when they are limited," said James L. Mulshine, head of the Intervention Section of the NCI’s Medicine Branch. He spoke at a session sponsored by the National Coalition for Cancer Research.

Although the prevalence of cigarette smoking in the United States has declined 25% since 1993, the nation’s 46 million current smokers are at high risk and the 46 million former smokers are at increased risk of lung cancer. The number of new cases likely will remain high for at least the next 20 to 30 years in spite of prevention efforts--thus the interest in research to detect preclinical lung cancers and find better ways to treat them.

In his talk, Dr. Mulshine cited a paper he co-authored with Melvyn S. Tockman, MD, PhD, of the H. Lee Moffitt Cancer Center, Tampa, and investigators from 11 collaborating institutions comprising the Lung Cancer Early Detection Working Group. The studies, done in collaboration with Chiron Inc., were published in Clinical Cancer Research (Dec. 1997).

The article reported early results from two prospective studies of the feasibility of using the heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 as a bio-marker for preclinical lung cancer.

One study involves 638 patients in the United States and Canada with resected stage I non-small-cell lung cancer, all clinically disease free at the time of screening but at high risk of developing a second primary lung tumor.

The second study consists of 6,285 current and former Chinese tin miners with no prior malignancy whose exposure to tobacco smoke, radon, and arsenic gives them an average annual incidence of 1% for primary lung cancer.

All participants had their sputum cells screened for an overproduction of hnRNP A2/B1. The new report covers results 1 year after screening, in which the researchers compared the predictive powers of hnRNP A2/B1 with those of routine cytology.

Overexpression of the ribonucleoprotein in the US-Canadian study accurately predicted the outcome of 32 of 40 participants, whereas cell changes suggestive of lung cancer were found in only one patient. Among the Chinese miners, the biomarker accurately predicted the outcome in 69 of 94 with elevated hnRNP A2/B1; cytology indicated lung cancer in only 10.

"Up-regulation of hnRNP A2/B1 indicated at least a 67% probability of a person’s developing lung cancer within 1 year," the team reported. "In the future, additional markers may further improve the accuracy of sputum-based early lung cancer detection."

Dr. Mulshine said that a group of intramural scientists at the NCI is working with Battelle (a company based in Columbus, Ohio) to develop a means of more effectively treating early lung cancers via aerosol drug delivery.

Research shows that certain vitamin A derivatives appear to control the development of early disease, he said. However, when given to people for long periods, they cause side effects.

"We are proposing to move the delivery of the drug from the mouth and the GI tract to direct aerosolization, the same way as the nicotine gets to the smoker," he said. This approach mimics the technique used successfully to deliver antibiotics to the lungs of patients with cystic fibrosis.

"A comprehensive solution to reducing lung cancer mortality will involve a lot of things," Dr. Mulshine said. "But a piece of it will be the interaction between the new molecular diagnostics with biochemical and molecular interventions that are woven together in a way that we can create prevention tools that can be cost-effective, safe, and effective."