Review Weighs Trastuzumab's Benefits and Risks in Breast Cancer

By Fran Lowry
Medscape Medical News

April 17, 2012 — Trastuzumab significantly improves overall and disease-free survival in HER2-positive women with early and locally advanced breast cancer, according to a systematic review published online today in Cochrane Database of Systematic Reviews. However, it also significantly increases their risk for heart problems.

For this reason, doctors need to discuss the cardiovascular risk with each of their patients and weigh the drug's potential benefits, lead author Lorenzo Moja, MD, from the University of Milan in Italy, told Medscape Medical News.

"It's all about balance. The most important thing is for doctors to determine whether the patient has a high risk for developing cardiotoxicity with trastuzumab. Hypertension, a family or personal history of heart failure, and myocardial infarctions are all warning signs. For these patients, trastuzumab may not be indicated as much as it would be for other patients with no risk," Dr. Moja said.

It has already been established that trastuzumab is of benefit for early and locally advanced HER2-positive breast cancer, but its net benefit and associated cardiotoxicity has not been fully addressed, Dr. Moja said.

Accordingly, he and his group set out to assess the evidence supporting the efficacy and safety of trastuzumab to help clinicians and their patients more intelligently weigh its risks and benefits.

The researchers searched the Cochrane Breast Cancer Group Specialised Trials Register and identified 8 randomized controlled trials involving 11,991 women with HER2-positive operable breast cancer, including women with locally advanced breast cancer.

The randomized controlled trials examined the efficacy and safety of trastuzumab alone, trastuzumab in combination with chemotherapy, no treatment, and standard chemotherapy alone. The women were followed for an average of 3 years.

The review found that overall, breast cancer mortality was reduced by one third in the women treated with trastuzumab (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.57 to 0.77; P < .00001).

Disease-free survival was also significantly reduced with trastuzumab (HR, 0.60; 95% CI, 0.50 to 0.71; P < .00001).

However, the risk for congestive heart failure rose 5-fold in women receiving trastuzumab, compared with those receiving standard therapy alone. The relative risk for congestive heart failure with trastuzumab was 5.11 (90% CI, 3.00 to 8.72; P < .00001). The relative risk for left ventricular ejection fraction decline was 1.83 (90% CI, 1.36 to 2.47; P = .0008).

"If 1000 women were given standard therapy with no trastuzumab, 900 would survive and 5 would have experienced heart toxicities after 3 years. If 1000 women were treated with standard chemotherapy and trastuzumab for a year, about 933 would survive, so for every 1000 women treated with trastuzumab, 33 more will have their lives prolonged," Dr. Moja said.

However, "for every 1000 women treated with trastuzumab, 26 would have serious heart toxicity, 21 more than the chemotherapy-alone group. The risk for cardiotoxicity increases as the woman's baseline risk increases, so the balance between risk and benefit must be discussed with the patient," he explained.

Trastuzumab Remains an Important Treatment

This meta-analysis adds to the data showing that trastuzumab provides a benefit for both overall and disease-free survival in patients with HER2-positive breast cancer, particularly those with high-risk disease, Alissa Huston, MD, from the James P. Wilmot Cancer Center in Rochester, New York, told Medscape Medical News.

"The cardiac toxicity that has been observed, and which is highlighted in the analysis, underscores the importance of always weighing the risks and benefits of any treatment, particularly in patients who have underlying cardiac risk factors and who may be more susceptible," Dr. Huston said.

"Trastuzumab remains an important and extremely effective treatment for patients with HER2-positive breast cancer," she added.

This study was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco). Dr. Moja and Dr. Huston have disclosed no relevant financial relationships.

Cochrane Database Syst Rev.2012;4:CD006243.