NEW ORLEANSA study of biologic markers in non-small-cell lung
cancer (NSCLC) has identified several that appear to predict disease
recurrence. They also offer some insight into the mechanisms by which
NSCLC tumors spread.
The study, from Leicester Royal Infirmary, Leicester, UK, aimed to
identify predictive markers, to construct a molecular staging model,
and to suggest novel therapeutic targets through better understanding
of the molecular biology of the tumors. Currently, the best
prognostic index for operable NSCLC remains the TNM staging system.
Lead investigator Giles Cox, MD, reported the results at the 36th
Annual Meeting of the American Society of Clinical Oncology (ASCO).
Dr. Cox and his colleagues studied surgically removed tumors from 168
patients with stage I to IIIa NSCLC. Paraffin-embedded tissue from
these patients tumors was stained for substances that have been
implicated in the pathogenesis of NSCLC:
Matrix metalloproteinases (MMP) 2 and 9, which are
endopeptidases capable of digesting the extracellular matrix and
allowing migration of tumor and endothelial cells.
The levels of two epidermal growth factors (EGFR and HER2/neu,
also known as c-erB-2) on the tumor surface, which may be involved in
the upreg-ulation of MMP-9.
The microvessel marker CD34, to evaluate for angiogenesis.
The DAKO HercepTest evaluated for HER2/neu overexpression. All
immunohistochemical evaluations were conducted by two independent
observers blinded to outcomes. Clinical characteristics such as
disease stage, nodal status, and tumor grade were also considered in
The analysis showed that the presence of MMP-9 in tumor cells
predicted a poor outcome, but the prognosis was even worse when both
EGFR and MMP-9 were found in the same tumor. If all three markers
were presentEGFR, MMP-9, and angiogenesis5-year
cancer-related mortality was as high as 84%, Dr. Cox reported.
On multivariate analysis, the following factors were independent
predictors of poor prognosis: high microvessel counts (P =
.002), tumor cell MMP-9 (P = .009), nodal status (P =
.01), and tumor grade (P = .05).
EGFR expression itself was not associated with outcome, but was
inversely correlated with angiogenesis (P = .04) and
positively correlated with tumor cell MMP-9 expression (P <
.001). Patients with microvessel counts over the median number and
expressing both EGFR and MMP-9 had a particularly poor outcome (P
< .0001), he said.
Membranous HER2 expression was positive in only 3 of 168 cases. MMP-2
was not associated with outcome.
In the subgroup of 25 patients who expressed EGFR, MMP-9, and
high microvessel count, 21 patients have died from a recurrence of
cancer, giving a cancer-specific mortality of 84% in this group,
Dr. Cox said. There was one long-term survivor in this group,
but he has just been admitted to the hospital for a mediastinal recurrence.
He concluded that angiogenesis and tumor cell MMP-9 both confer
poor prognosis in NSCLC, and EGFR is associated with MMP-9 in vivo.
We can induce MMP-9 mRNA by stimulating epidermal growth factor in
vitro. This suggests there is a signaling pathway between EGFR and
The investigators developed a staging model using the three major
immunohistochemical markers, with which to predict patients at high
risk for recurrence after surgery. These high-risk patients would be
potential targets for adjuvant treatment, at this time with
conventional chemotherapy but, in the future, using therapy targeting
the pathway that is activated in the particular tumor. Such therapy
might include tyrosine kinase inhibitors, MMP inhibitors, or
antiangiogenesis agents, which have fewer side effects than
conventional agents, he said.