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.