In Brief

From OncoLog, November 2006, Vol. 51, No. 11

In Brief

Herceptin’s Cardiac Toxicity Reversible

The first study to look at the longterm use of trastuzumab (Herceptin) in metastatic breast cancer patients outside a clinical trial found a higher incidence of cardiac toxicity than clinical trials of the drug have reported to date, but it also concluded that for most patients, the damage could be reversed with treatment.

The study, published in the September 1 issue of the Journal of Clinical Oncology, weighs the drug’s risks and benefits and concludes that use of Herceptin in patients with metastatic breast cancer “is an acceptable risk,” said the study’s lead author, Francisco J. Esteva, M.D., Ph.D., an associate professor in the Department of Breast Medical Oncology at M. D. Anderson Cancer Center.

In clinical trials testing Herceptin in combination with chemotherapy, 10% to 26% of patients experienced cardiac toxicity, depending on the treatment protocol. That led to a Food and Drug Administration warning in 2003 that Herceptin use can result in congestive heart failure or ventricular dysfunction.

According to Dr. Esteva, before this study, no one had looked at what happened to patients treated in a clinic, outside of an organized trial, after they used Herceptin for a year or longer. “We often give it for several years if patients are responding to the treatment, so we set out to quantify the risks,” he said.

“We found that the drug substantially prolongs survival, and while we also found substantial cardiac toxicity, we also discovered that this side effect can be successfully treated, which was not clearly known before this study,” said Dr. Esteva. “If the cardiac side effects of Herceptin treatment can be managed, the drug is safe to use.”

In most patients who developed cardiac toxicity on this study, the effects were reversed by discontinuing Herceptin and administering beta blockers and ACE inhibitors. After the damage was repaired, patients could resume Herceptin treatment. Dr. Esteva pointed out that these results do not apply to use of the drug in patients with early-stage disease, for whom the risks of cardiac toxicity may outweigh the benefits of Herceptin.

Dr. Esteva stressed that patients with advanced breast cancer should receive a baseline cardiac assessment before the drug is used and then follow-up care by a cardiologist. “This is an accurate representation of clinical practice in that patients often have important comorbidities that place them at increased risk for cardiotoxicity,” Dr. Esteva said. “It illustrates the need for good cardiac care for advanced breast cancer patients.”

Nanoparticles Target Ovarian Tumors

A molecular “off” switch packaged in a liposome penetrates deeply into ovarian tumors, stifling a troublesome protein and drastically reducing the size of tumors, researchers at M. D. Anderson Cancer Center report in the August 15 edition of Clinical Cancer Research.

The experiment in mice demonstrates a potent delivery system for short interfering RNA (siRNA) to attack cancer, said senior authors Anil Sood, M.D., a professor in the Departments of Gynecologic Oncology and Cancer Biology, and Gabriel Lopez-Berestein, M.D., a professor in the Department of Experimental Therapeutics at M. D. Anderson. “Short interfering RNA is a great technology we can use to silence genes; it shuts down production of proteins that promote survival of ovarian cancer cells,” Dr. Sood said. “It works well in the lab, but the question has been how to get it into tumors.”

Short pieces of RNA don’t make it inside a tumor without being injected directly, and injection methods used in the lab are not practical for clinical use. To address that problem, the research team took siRNA and packaged it into neutral liposomes, nanoparticles that can penetrate deeply into tumors.

Getting the siRNA inside tumor cells is important, Dr. Sood said, because the targeted protein, focal adhesion kinase (FAK), is inside the cell rather than on the cell surface where most proteins targeted by cancer drugs are found. “Intracellular targets like FAK, which are difficult to reach with a drug, can be attacked with this therapeutic liposomal approach,” Dr. Sood said.

Mean tumor weight in mice receiving the FAK-silencing liposome dropped 44% to 72% compared with mice in the control groups. When researchers combined the FAK-silencing liposome with the drug docetaxel, tumor weight reduction was boosted to the 94% to 98% range.

These results also held up in experiments with ovarian cancer cell lines resistant to docetaxel and cisplatin. The treatment may also show promise for other cancers in which FAK is overexpressed.

These findings suggest that the therapeutic liposomal FAK siRNA in combination with docetaxel or cisplatin may have promising clinical applications, even for patients with chemotherapy-resistant tumors.

Multi-Drug Approach Required for Acute Myelogenous Leukemia

The road to better treatment for the most common form of adult leukemia will require blocking multiple molecular pathways that fuel the disease, researchers at M. D. Anderson Cancer Center report in the October 1 edition of the journal Blood.

The research team examined blood and bone marrow samples from 188 adults with acute myelogenous leukemia (AML) and then followed the patients’ progress to gauge the cumulative impact of a trio of cell-signaling chain reactions on the disease.

The research team looked at activation of three components, one from each pathway, in the leukemic blasts found in newly diagnosed patients. Activation of each component—PKCa, pERK2, and pAKT—had an adverse effect on the patient’s prognosis that was independent of other traditional prognostic factors. Their cumulative impact was greater than simply adding their individual effects would suggest, the research team found.

“We found that the more of these pathways that are active in a patient, the worse their prognosis,” said first author Steven Kornblau, M.D., associate professor in the Department of Stem Cell Transplantation.

Patients who had none of the three molecular cascades active had a median survival time of 78.6 weeks. For those with one highly active pathway, median survival was 57.9 weeks. With two, it was 42.3 weeks. Patients with high activation of all three pathways had a median survival time of just 23.4 weeks.

“Targeting just one of these pathways won’t be effective because we also found that they cross-activate each other; they essentially cover for each other,” Dr. Kornblau said. “New therapies will have to target multiple pathways to be effective.”

This presents several challenges to discovering a successful treatment for AML, the research team noted. New drugs are typically evaluated individually during development, so a medication that blocks one of these pathways is likely to fail to treat AML by itself. It would probably be discarded as a single therapy when it could become part of a multiple-drug attack on the disease.

Race Influences Survival in Breast Cancer

African-American women with breast cancer are more likely to have larger, later-stage tumors that are more difficult to treat than Hispanic and Caucasian women who receive the same treatment, according to two independent series of clinical trials examined by researchers from M. D. Anderson Cancer Center.

The analysis, published online October 23 by Cancer, indicates that race is associated with unfavorable tumor biology, which, along with other factors, likely contributes to the lower rate of breast cancer survival among African-Americans. This group was more likely to have estrogen-receptor negative tumors, which are considered more difficult to treat.

“These findings should prompt additional research on how we can improve outcomes for African-American patients by understanding and addressing tumor biology,” said first author Wendy Woodward, M.D., Ph.D., assistant professor of radiation oncology at M. D. Anderson. “Not all African-American women will have worse survival prospects, but there are probably subsets of patients for whom we could be doing something better.”

African-American women are less likely than Caucasian women to have breast cancer but are more likely to die from it. Many factors have been implicated in this disparity, the researchers note, including access to health care and screening, differing treatments, socioeconomic status, and racial bias. However, they doubt socioeconomic factors could fully explain differences in survival rates because Hispanic and African-American women have similar socioeconomic status in M. D. Anderson’s patient referral area.

The study looked at 2,140 breast cancer patients who were treated in two prospective series of clinical trials at M. D. Anderson involving use of doxorubicin before and after a radical or modified radical mastectomy.

A multivariable analysis that took into account age, estrogen-receptor-negative status, primary tumor size, and whether the disease had spread to the lymph nodes showed that African-American race is an independent factor in a lower overall survival rate. “We interpret these data as suggesting that intrinsic biological differences in the disease and response to treatment among racial groups contributed to the poorer overall survival rates seen in the African-American cohorts,” the researchers concluded.

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