Trastuzumab-Tied Cardiotoxicity Same at 5 Years


CHICAGO – No increase was seen in the cumulative incidence of cardiac dysfunction associated with trastuzumab for HER2-positive, node-positive breast cancer after 5 years of follow-up, said Dr. Priya Rastogi, who reported on behalf of the National Surgical Adjuvant Breast and Bowel Project B-31 trial.

Updated results of the NSABP B-31 trial, which compared treatment regimens with and without trastuzumab (Herceptin), showed that the incidence of cardiac events in patients taking trastuzumab remained essentially unchanged from its value 2 years before, at 3.8%, Dr. Rastogi said at the annual meeting of the American Society of Clinical Oncology.

Trastuzumab, a monoclonal antibody that blocks human epidermal growth factor receptor 2 (HER2) from instigating the growth of breast cancer cells, has been a major advance in the treatment of both early- and late-stage breast cancer, but at the price of increased cardiotoxicity.

In the original NSABP B-31 trial (N. Engl. J. Med. 2005;353:1673-84), the addition of trastuzumab significantly improved 3-year disease-free survival and overall survival when combined with anthracycline-based chemotherapy plus paclitaxel.

However, the incidence of cardiotoxicity, specifically congestive heart failure, among the 850 patients randomized to the regimen with trastuzumab, was 4.1%, compared with 0.8% among the 814 patients who did not get trastuzumab (J. Clin. Oncol. 2005;23:7811-9).

With an additional 2 years of follow-up, the cumulative incidence of cardiac events in the patients who received chemotherapy plus trastuzumab was 3.8%, compared with 0.9% in those who received chemotherapy alone.

Importantly, the majority of patients who had a decline in cardiac function experienced a recovery in ejection fraction within 18 months of taking trastuzumab.

“We were very heartened by this result,” Dr. Rastogi, also of the University of Pittsburgh Medical Center, said at a press briefing.

The update also allowed the NSABP investigators to create a model to predict which women would be most likely to develop cardiotoxicity from trastuzumab. (See box.) Age, use of antihypertensive medications, and poor heart function as measured by a low ejection fraction at baseline were the most important predictors of risk.

“Incorporating these factors into the model allows us to calculate a cardiac risk score, which gives a percentage of risk of a cardiac event within 3 years. This is important because it now lets us choose trastuzumab-containing regimens based on an individual patient's risk and benefit profile,” Dr. Rastogi said in an interview.

She added that the next step is to validate the model in a similar group of patients. “But we do have the model now, and it can be used. So you can tell the patient who is sitting face to face with you that, based on these risk factors of age, hypertensive medication, and baseline cardiac function, this is her risk for developing a cardiac event.”

Dr. Julie Gralow, moderator of the press briefing, told reporters that such a model represented a very important development for women with HER2-positive breast cancer, who account for roughly 25% of breast cancer patients. “I am thrilled to have a new risk model to help me discuss with my patients the risks and benefits from adding trastuzumab,” said Dr. Gralow of the University of Washington, Seattle.

Dr. Gralow also reminded reporters that trastuzumab cut the incidence of recurrences by almost 50% and deaths by approximately one-third in such patients, and that it was very reassuring to see no increase in cardiotoxicity in the B-31 update.

In the discussion that followed Dr. Rastogi's formal presentation, Dr. Sharon Hunt, professor of medicine at Stanford (Calif.) University, cautioned that 5 years of follow-up is not long enough to assuage concerns about the cardiotoxic effects of trastuzumab.

The cardiotoxicity that is being noted with these 3- and 5-year follow-ups is “probably the tip of a very big iceberg. Left ventricular dysfunction, which you are rather simply measuring as ejection fraction, is a lifelong problem in many patients, and even though the numbers may improve, the structural damage done to the heart persists for the life of the patient,” Dr. Hunt said.

Decrying the lack of information in the B-31 study about whether any therapy for heart failure had been given to patients, Dr. Hunt called for greater collaboration between oncologists and cardiologists.

“We need to know the time course of this cardiotoxicity. Is the optimistic view that it is reversible and not a cause for concern valid? Will preemptive therapy with well-proven heart failure prevention medications such as ACE inhibitors and β-blockers abrogate any of this cardiotoxicity?”

Finding the balance between improved survival from breast cancer and the down side of cardiotoxicity “is one of the most important things we need to do in the field,” she said.

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