Biologic Markers May Help Predict Recurrence of NSCLC

CHICAGO--Molecular biologic markers may be able to identify patients with early-stage non-small-cell lung cancer (NSCLC) who are at the highest risk for metastasis and therefore may benefit from aggressive therapy.

Preliminary data indicate that four biologic markers in particular--angiogen-esis, the p53 tumor suppressor gene, the nuclear protein K1-67, and the growth factor receptor erbB-2 (also known as HER-2/neu)--appear to be good predictors of survival, David Harpole, MD,associate professor of surgery, Duke University, said at the International Conference of the American Thoracic Society and the American Lung Association.

Because the vast majority of patients with early-stage NSCLC eventually die of distant metastases, scientists are seeking ways of determining which subsets of patients may be candidates for repeat resection, novel treatments such as gene therapy, or more active chemotherapy.

Although there are a number of factors that suggest poor prognosis (eg, the presence of symptoms; tumor greater than 3 cm in diameter; high mitotic index; visceral, pleural, or pulmonary vascular invasion), these are indirect measures of tumor activity. The goal for investigators is to find molecular biologic tools that can more directly and accurately predict survival based on the biology of lung cancer, Dr. Harpole said.

Among these tools are proto-onco-genes and apoptotic growth regulators, such as the tumor suppressor gene p53, which operate at the time when metaplastic or dysplastic cells change to carcinoma in situ. The K-ras proto-oncogene, which is a large signal transduction protein receptor on the outside of the cell, has been most commonly linked with adenocarcinoma, and codon 12 mutations appear to be important diagnostic predictors for all stages of lung cancer.

However, Duke University researchers have shown that the growth factor receptor erbB-2 is an especially sensitive predictor of survival. Among 275 patients with stage I NSCLC, there was a 12% decrease in survival for those whose tumors expressed erbB-2.

Markers of cell cycle mechanics may be used to find tumors that require aggressive cytotoxic agents because their cells are more active. Tumors with higher indices of the non-histone neural protein K1-67 tend to be more active, and highly active tumors have been associated with decreased survival.

Angiogenesis Important Predictor

In order for carcinoma in situ to progress to invasive carcinoma, tumor cells must have a source of nutrition. That is why angiogenesis is a potentially powerful prognostic indicator.

Angiogenesis, in fact, was the most important independent predictor of survival in a multivariate analysis of molecular biologic factors conducted by Duke University scientists. Angiogenesis had a risk ratio of 1.60. For p53, the risk ratio was 1.51; for erbB-2, it was 1.52; and for K1-67, it was 1.39.

Of 275 patients with stage I NSCLC, those who expressed none of the four markers were almost twice as likely to survive 5 years as those with one or more markers. Patients with no markers had a 5-year survival rate of 81%. Survival dropped significantly, however, when patients had two of the four factors (54%) or as many as three or four factors (49%).

"These are early data, but this is a very nice testament that if you have zero or one of these factors present, you actually do reasonably well, with a better than 70% survival. If you have more than two, your survival is worse than 50%. So this may suggest that the subset of patients with three or four of these biologic markers should be treated more aggressively," Dr. Harpole said.