ATLANTAOverexpression of HER-2/neu may not be as critical to
breast cancer prognosis as its activation, according to research
reported by Michael P. DiGiovanna, MD, PhD, at the Era of Hope: U.S.
Department of Defense Breast Cancer Research Program Meeting. Dr.
DiGiovanna is assistant professor of medicine and pharmacology, Yale
University School of Medicine.
HER-2/neu, a growth factor receptor protein, is overexpressed in
about 30% of breast cancers, and its overexpression has been
considered a sign of poor prognosis. However, in Dr. DiGiovannas
review of 816 breast cancer cases, only those with the activated
protein had poorer outcomes (disease-free survival and
disease-specific overall survival).
We actually found activation in the minority of overexpressed
cases, Dr. DiGiovanna said in an interview with ONI.
The most important take-home message of my research is that
overex-pression itself may not be the important factor. The most
important factor may be the activation state.
The researchers also found a strong correlation between
phosphorylated HER-2/neu (PNeu), the proteins activated form,
and expression of epidermal growth factor (EGF) receptor.
We know the EGF receptor itself can activate HER-2/neu,
Dr. DiGiovanna said. Potentially, drugs that inhibit EGF
receptor might be a good regimen for breast cancer in clinical trials.
Dr. DiGiovanna used a database provided by Ann D. Thor, MD, a
pathologist at Evanston Northwestern Healthcare and Northwestern
University, Evanston, Illinois. The cases were diagnosed between 1976
and 1983 with a median follow-up of 16.3 years.
307 of the 816 cases (38%) showed overexpressed HER-2/neu, only 37
of these (12% or 5% of the total) had detectable PNeu. This group had
clinical features linked to poor prognosis (see Table), and follow-up
showed that these patients did, in fact, have a poorer outcome than
those without detectable PNeu.
PNeu was associated with a higher percentage of HER-2/neu-positive
cells in the tumor, higher number of involved lymph nodes,
estrogen-receptor (ER) negativity, and abnormal copies of the
tumor-suppressor gene p53.
In contrast, women with high levels of inactive HER-2/neu had
clinical profiles associated with less aggressive tumors, similar to
those of women with normal levels of HER-2/neu.
If this work holds up after larger follow-up studies, it may
help guide treatment choices for women with breast cancer, Dr.
DiGiovanna said. For example, it may help determine which women
need adjuvant therapy and the aggressiveness of that treatment.
Three New Studies
As a result of the study, three new breast cancer trials at Yale are
focusing on women with overexpressed and activated HER-2/neu. The
first asks whether these women have a worse response to tamoxifen
than do those without overexpressed and activated HER-2/neu.
The second explores whether they respond better to trastuzumab
(Herceptin), a monoclonal antibody that interferes with the
functioning of HER-2/neu. The third asks whether they respond
differently to CAF (cyclophosphamide, Adriamycin, 5-fluorouracil).
Tumors that overexpress HER-2/neu are better treated by CAF
than other therapies, Dr. DiGiovanna said. Again, we are
going to do a retrospective study to see whether the activated state
of HER-2/neu really makes a difference.
Among the overall questions still to be answered is why HER-2/neu
would be overexpressed but not activated in some breast cancers.
I suspect a continuum of activation, said Dr. DiGiovanna,
who created a monoclonal antibody that detects PNeu (PN2A) for use in
the study. Our test probably discriminated those with a low
level of activation from those with a high level of activation.
One possibility, he suggested, is that overexpression may be
important at the start of the cancer process. Weve known
for a time that overexpression is more common in ductal carcinoma in
situ [DCIS] than in invasive breast cancer. We dont understand
what that means; we only have theories, he said. Maybe it
means that HER-2 is very active in the genesis of a tumor.