LOS ANGELES--A monoclonal antibody directed at the HER2 receptor
greatly enhances the effect of chemotherapy for women whose breast
cancer overexpresses the HER2 gene. This encouraging finding comes as
experts are beginning to suspect that increasing dose intensity of
conventional chemotherapy may have "gone about as far as it can
go," said Dennis Slamon, MD, PhD, chief, Division of
Hematology-Oncology, UCLA School of Medicine.
At an ASCO symposium on HER2 research, Dr. Slamon reported that
combining conventional chemotherapy with the anti-HER2 antibody
trastuzumab (Herceptin) improved response rates by 50%, response
duration by 57%, and time to progression by 67% in women with
metastatic breast cancers that overexpressed HER2.
Based on these results, trastuzumab has been "fast-tracked"
by the FDA. Dr. Slamon predicted that the drug, developed by
Genentech, Inc, will be approved before the end of 1998.
The Slamon study was a randomized, double-blind, multicenter trial in
469 women with metastatic breast cancers overexpressing HER2 (also
referred to as HER2/neu)."We dont think this antibody is
going to be effective for non-overexpressing tumors," Dr. Slamon said.
HER2 overexpression is a non-inherited alteration found in 25% to 30%
of breast cancers. It is associated with swifter disease progression
and poorer response to chemotherapy. "Patients who have HER2
overexpressing tumors really do have a different type of breast
cancer and should be considered accordingly," Dr. Slamon said.
The results of his study also suggest that all breast cancer patients
should be routinely examined for HER2 overexpression, a test that is
widely available but not routinely done. "Overexpression"
was defined in this study as more than 15% to 20% of cells positive
for HER2 using immunostaining (see Figure).
None of the women in Dr. Slamons study had been treated with
cytotoxic chemotherapy for metastatic disease, although many had
received either paclitaxel (Taxol) or anthracycline-based
chemotherapy for their primary disease.
Patients who had received previous doxorubicin were assigned to
treatment with paclitaxel, with or without trastuzumab. Those with no
previous exposure to doxorubicin received either doxorubicin
(Adriamycin)/cyclophosphamide (AC), epirubicin/cyclophosphamide, or
paclitaxel. Half the patients in each group were then randomized to
also receive the anti-HER2 antibody.
Median time to progression was 7.6 months for chemotherapy with
antibody vs 4.6 months for chemotherapy alone (P = .0001). For
patients who received AC, median time to progression was 8.1 months
with antibody vs 6.1 months without. For those on paclitaxel, median
time to progression was 6.9 months with antibody vs 3.0 months
without (P = .0001).
One-year survival was 78% for chemotherapy plus antibody vs 67%
without antibody. (However, these figures are complicated by the fact
that patients on chemotherapy alone whose disease progressed were
crossed over to chemotherapy plus antibody.)
The overall response rate was 32% for chemotherapy alone vs 49% for
chemotherapy plus antibody. Among the patients who received AC, the
overall response rate was 52% with antibody vs 43% without. These
improvements were achieved without an increase in adverse events.
Dr. Slamon reported that a syndrome of myocardial dysfunction similar
to that observed with anthracyclines was reported more commonly with
AC plus antibody than with AC alone, paclitaxel plus antibody, or
In an interview, Dr. Slamon said that most patients with this
cardiomyopathy were treated successfully with ACE inhibitors,
diuretics, or digoxin, and were able to continue the antibody. He
advised clinicians treating patients with trastuzumab to monitor
cardiac function with echocardiography every 12 weeks.
From Discovery to Phase III
Dr. Slamon, who is perhaps more closely associated with HER2 than any
other researcher, began searching for a way to use HER2 to fight
breast and other cancers more than a decade ago when he first
discovered that the gene is overproduced in many breast cancers and
that these cancers are more aggressive. Women whose cancer
overexpress HER2 have a median survival of 3 years vs 6 to 7 years
for women without HER2 overexpression.
Funding From Revlon Accelerated HER2 Research
Revlon Inc. has provided more than $13 million to the Revlon/UCLA
Dr. Slamon explored this finding in the laboratory by transferring
additional HER2 genes into cultured breast cancer cells that did not
overexpress the gene, to see if this would change these tumor cells
into the more virulent variety. He found that increasing HER2
expression increased DNA synthesis, cell growth, tumorigenicity,
metastatic potential, and growth in soft agar.
"Our goal was to discover what is involved in converting a
normal cell into a malignant cell," Dr. Slamon said. If we could
find something that was broken and might be potentially targeted, we
might be able to develop therapeutics around that." HER2
overexpression clearly fit that role and in addition is easily
detected using immunostaining.
Trastuzumab inhibits HER2 overexpressing breast cancer cells in vitro
but apparently does not affect normal cells or breast cancer cells
that lack HER2 overexpression. Once it was shown that the antibody
alone has efficacy, Dr. Slamon moved forward with this phase III trial.
"Throwing bigger and better bombs at the disease isnt
necessarily going to get us a lot further," Dr. Slamon said.
"Our data prove the paradigm for development of targeted therapy
with less toxicity in breast cancer." He also suggested that the
most logical place to use trastuzumab is likely to be "earlier
and up front."