Three studies presented at the Era of Hope Department of
Defense Breast Cancer Research Program meeting described ways in
which the bodys own genes and immune system are being used to
guide and develop promising new therapeutic approaches.
Overexpressed HER2/neuNot Always Problematic
According to findings from one recent study, overexpression of HER2/neuwhich
has been tied to poor prognosisis not necessarily a problem.
New data suggest that the protein has to be switched on, or
activated, to exert a harmful effect, and in many women
whose tumors overexpress the substance, researchers found that it is dormant.
If this work holds up after larger follow-up studies, it may
help guide treatment choices for women with breast cancer, said
Michael P. DiGiovanna, MD, PhD, assistant professor of medicine and
pharmacology at Yale University School of Medicine. For
example, it may help determine which women need adjuvant therapy and
the aggressiveness of that treatment.
Normal cells have two copies of the HER2/neu gene and a low
amount of cell-surface HER2/neu protein. In an estimated 30%
of women with breast cancer, the tumor has extra copies of the HER2/neu
gene and produces excess cell-surface HER2/neu protein.
Investigators examined breast cancer specimens for evidence of
phosphorylated HER2/neu (PNeu), the proteins activated
form. They detected PNeu in 12% of breast cancers that overexpressed HER2/neu.
Women with overexpressed but inactive HER2/neu had clinical
profiles similar to those of women with normal levels of the protein,
indicating less aggressive tumors. However, women with detectable
PNeu tended to have clinical features that are strongly linked to
poor prognosis, including more cancer-involved lymph nodes,
estrogen-receptornegative tumors, and abnormal p53.
When normal p53 senses cell damage, it orders imperfect cells
to die. By failing to trigger this suicide pathway,
abnormal p53 may allow cancer cells damaged by chemotherapy to
survive and replicate. The women with detectable PNeu also had an
increased rate of relapse and a decreased survival.
On the basis of this study, the Yale team expanded its related
research to refine the use of HER2/neu status in treatment
decisions. Three new breast cancer trials will investigate whether
women with overexpressed and activated HER2/neu have (1) a
worse response to tamoxifen, (2) a better response to trastuzumab
(Herceptin), and (3) an altered response to CAF (cyclophosphamide
[Cytoxan, Neosar], doxorubicin [Adriamycin], fluorouracil).
Intratumoral Delivery of IL-12 Prolongs Survival, Decreases Toxicity
A single injection of a gene encoding a protein produced by the
immune system caused shrinkage of breast cancer metastases in the
livers of mice and significantly extended the animals survival,
reported investigators of another study.
What distinguishes this approach, called immunomodulatory gene
therapy, from other types of gene therapy is that the gene is
injected directly into the tumor, where it triggers the production of
disease-fighting substances and kills the tumors, allowing the
animals to live longer, said Savio L. C. Woo, PhD, professor
and director, Institute of Gene Therapy, Mount Sinai School of Medicine.
Among mice receiving the gene injection, 20% to 40% survived for more
than 160 days, whereas all control mice died within 75 days. The gene
is packaged inside a common cold virus that has been
genetically altered so that it cannot reproduce but can stimulate
production of interleukin-12 (IL-12). The process creates a tiny
biological factory that makes a constant supply of IL-12
right inside the tumor, which in turn continually stimulates the
recruitment of natural killer cells.
According to Dr. Woo, another advantage of intratumoral delivery of
the IL-12 gene is reduced toxicity compared with intravenous delivery
of the IL-12 protein. IL-12 quickly becomes toxic when injected into
the blood, but with intratumoral delivery of the gene, the
concentration of IL-12 is very high within the tumor and very low in
Antiangiogenesis Therapy and Immunotherapy Better When Combined
Investigators from the University of Pittsburgh reported that a new
approach involving the combination of two experimental cancer
treatmentsantiangiogenesis compounds and immunotherapyhas
demonstrated a more potent antitumor effect than either modality used
Though this is very early research, it is the first time that
immune therapy and antiangiogenic agents have been used together, and
the first time these antiangiogenic compounds have been studied in
breast cancer, said lead investigator Elieser Gorelik, MD, PhD,
professor of pathology.
We decided to investigate whether we could improve results by
double-teaming the tumorsfirst by cutting off new blood
supplies with endostatin or angiostatin, then by prompting the
bodys immune system to launch an attack on the remaining tumor
cells, said Dr. Gorelik.
After testing several experimental cancer lines, Dr. Gorelik and
colleagues concluded that the angiogenesis inhibitors had a stronger
impact against immunogenic tumors than against nonimmunogenic tumors.
This effect was influenced strongly by the immune status of the
animals. In mice bred to have deficient immune systems, angiostatin
and endostatin had a significantly lower therapeutic effect than in
normal mice. Researchers also found that when they stimulated the
immune system by antitumor vaccination or with IL-12, the antitumor
effects of the angiogenesis inhibitors increased.
Immunostimulation and endostatin treatment achieved a complete
regression of established tumors in approximately 50% of
immunocompetent mice, compared with no regression in mice treated
with either endostatin or immunotherapy alone. In this study,
immunotherapy was given shortly before antiangiogenesis treatment
stopped and again several days later.
Since the researchers found that endostatin showed a stronger
anticancer effect than angiostatin, it was the only angiogenesis
inhibitor used in this breast cancer study and will remain the focus
of future research by this group. The researchers acknowledge the
small scale of the study but are optimistic about the potential
benefit of stimulating the immune system to complement angiogenesis
inhibition and destroy residual cancer cells.