New Model Calculates Trastuzumab-Induced Heart Failure Risk

Allison Gandey

June 08, 2007

June 8, 2007 (Chicago) — Experts have developed a new formula to help doctors determine the cardiovascular risk of trastuzumab (Herceptin, Genentech) and combination chemotherapy. Presenting here at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO), researchers unveiled the approach. "It makes sense clinically," press conference moderator Julie Gralow, MD, from the University of Washington, in Seattle, told reporters. During the question period following the presentation, attendees complimented the researchers on their "incredible contribution."

Trastuzumab has been shown to significantly improve the 3-year disease-free survival and overall survival in human epidermal growth factor receptor 2 (HER-2)–positive, node-positive breast cancer. But cardiac dysfunction has been associated with the addition of trastuzumab to anthracyclines.

Studying the 3-year cumulative incidence of cardiac events, researchers from the National Surgical Adjuvant Breast and Bowel Project reported a rate of 4.1%. Updating these numbers at ASCO, the group showed the risk for congestive heart failure did not increase over time. At 5 years, the rate remains virtually unchanged, at 3.8%.

"This is reassuring for women taking trastuzumab and chemotherapy," lead investigator Priya Rastogi, MD, from the University of Pittsburgh Cancer Institute, in Pennsylvania, told Medscape. "We're not seeing any late cardiotoxicity, and we've also observed that in patients who've experienced a decrease in cardiac function, the majority will recover."

Commenting on the work, Dr. Gralow agreed that these latest numbers should reassure women at low-risk for cardiac events. And for older women or those with hypertension or other risk factors, the new model should help physicians determine the benefits and risks of therapy.

During the discussion period following the presentation, cardiologist Sharon Hunt, MD, from Stanford University in Palo Alto, California, said there is no debate that trastuzumab has been a major addition to chemotherapy. "But of course, there's always a price to pay," she told attendees. "The main price with trastuzumab seems to be cardiotoxicity, and we're in the process of finding out how high that price will be. Is it a sleeping giant or a worthwhile trade-off?"

Vigilance Needed in Determining the Risks and Benefits of Trastuzumab and Anthracyclines

Dr. Hunt pointed out that while cancer can be a difficult way to die, heart failure can be a horrible way to go as well, and trading 1 fatal disease for another makes little sense. She said that while the new 5-year cumulative incidence of cardiac event numbers are encouraging, they are only mildly reassuring, and physicians should remain vigilant in determining the risks and benefits of trastuzumab and anthracyclines.

Of the roughly 2500 heart transplants performed a year in the United States, Dr. Hunt estimates that about 5%, or 125 transplants, are anthracycline-related. "Left ventricular dysfunction measured as ejection fraction in this study develops silently and often slowly. And it is very likely a vulnerability that affects the life of the patient," she said.

Dr. Hunt suggests that 3 to 5 years of follow-up are not adequate to determine long-term treatment-related cardiotoxicity, and she would like to see numbers that extend to 10 or more years of follow-up. "We may be seeing resolution of symptoms and major improvements in left ventricular ejection fraction, but the underlying vulnerability may never go away." She said that this is where oncologists and cardiologists will need to work more closely moving forward.

In the present analysis, researchers assessed cardiovascular side effects in 1850 women with HER-2 positive breast cancer. Study participants were initially randomized to receive 4 cycles of a standard combination chemotherapy regimen of doxorubicin and cyclophosphamide followed by paclitaxel or the same combination with trastuzumab added.

The research team compared the incidence of congestive heart failure between the 2 groups. They also identified possible risk factors for women who are more likely to develop heart failure with trastuzumab.

Prediction Model for Cumulative Incidence of Cardiac Events with Trastuzumab and Anthracyclines
Cardiac risk score =
[7.4 + (0.03 x age) – (0.1 x LVEF) + (0.68, if on blood pressure medication)] x 100
4.82

During the question period following the presentation, a delegate from the Dana-Farber Cancer Institute, in Boston, Massachusetts, applauded the group's efforts to quantify risk, but he questioned whether the formula will apply as well on an individual basis as it seems to on a population scale. Dr. Rastogi responded that the model would be validated in another data set with a regimen similar to that used in the present analysis.

During an interview with Medscape, Dr. Rastogi pointed to another limitation of the trial. She noted that the eligibility criteria required that patients had a normal left ventricular ejection fraction with no previous history of cardiac disease. Many patients requiring the addition of trastuzumab to their chemotherapy regimen may have more cardiovascular risk than the patients in the present analysis and may also be taking antihypertensive medications. Dr. Rastogi said that while higher-risk patients were not included in the study, the prediction model takes these factors into consideration. She said, "Clinicians can now make individualized assessments for risk vs benefit."

American Society of Clinical Oncology 43rd Annual Meeting: Late-Breaking Abstract 513. Presented June 4, 2007.

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