Using the Body’s Anticancer Defenses to Guide and Improve Breast Cancer Treatment

Three studies presented at the “Era of Hope” Department of Defense Breast Cancer Research Program meeting described ways in which the body’s own genes and immune system are being used to guide and develop promising new therapeutic approaches.

Overexpressed HER2/neu—Not Always Problematic

According to findings from one recent study, overexpression of HER2/neu—which has been tied to poor prognosis—is 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 protein’s 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-receptor–negative 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 the blood.

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 treatments—antiangiogenesis compounds and immunotherapy—has demonstrated a more potent antitumor effect than either modality used separately.

“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 tumors—first by cutting off new blood supplies with endostatin or angiostatin, then by prompting the body’s 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.