Breast Cancer Treatments' Links to Heart Disease Calculated

HOUSTON, Aug. 15 -- The cardiotoxicity levels of two effective approaches to breast cancer, Herceptin (trastuzumab) for HER2-positive disease and radiation to the left breast, have been newly quantified.

As many as one in four breast cancer patients treated with Herceptin (trastuzumab) will develop cardiotoxicity, while women who undergo adjuvant radiation therapy to the left breast have a significant increase in risk of heart attacks, according to studies published today in the Journal of Clinical Oncology.

The link between Herceptin and congestive heart failure has been reported before-most recently last December at the San Antonio Breast Cancer Symposium when researchers reported that Herceptin in combination with anthracyclines interact to cause cardiotoxicity.

Likewise, a number of studies have reported an increased risk of heart disease among patients who undergo radiation treatment.

In the current study, 28% of 173 women with metastatic breast cancer who were treated with Herceptin-based therapy for at least a year had some cardiotoxicity, although the heart damage was usually reversible, wrote Valentina Guarneri, M.D., of the University of Texas M.D. Anderson Cancer Center here, and colleagues.

Data from 961 consecutive patients treated from 1977 through 1994 found no significant increase in cardiac deaths, but women who had left-sided radiation had higher rates of angina, coronary artery disease and myocardial infarction (P ? 0.002), wrote Eleanor E. R. Harris, M.D., and colleagues of the University of Pennsylvania.

Taken together, the studies present a cautionary tale about the potential downside of two effective treatments, but in both cases the authors suggested that the benefits-increased breast cancer survival-outweighed the risks of increased cardiac morbidity.

Dr. Guarneri and colleagues reported that 49 women had a cardiac event, but only 15 of these women were symptomatic. Two asymptomatic women were diagnosed with congestive heart failure, although both had normal left ventricular ejection fractions. One of these two women died of congestive heart failure.

Fourteen of the 15 symptomatic women stopped Herceptin treatment and 11 recovered after treatment with beta blockers or ACE inhibitor treatment, or both.

One woman recovered so quickly on cardiac specific therapy that Herceptin was not discontinued. Three women did not recover full cardiac function.

Herceptin was discontinued in 17 of the 34 asymptomatic women and 15 of these women recovered when Herceptin was stopped with or without cardiac drugs. Herceptin was not stopped in the other 17 asymptomatic women and 13 of them recovered heart function completely without either beta blockers or ACE inhibitors.

Herceptin was reinitiated in 26 women who recovered heart function, and 16 of these women had no additional cardiac events. Cardiac toxicity recurred in `10 women, of whom five recovered completely when Herceptin was again stopped. Five continued on Herceptin but had slightly diminished ventricular function.

At baseline the median age of the women was 50 and the median cumulative time of Herceptin treatment was 21.3 months. The median time from their last anthracycline treatment was 14.5 months with a range of 0 to 181.9 months. Sixty-three percent of the women had concomitant Navelbine (vinorelbine) and 84% received concomitant taxanes.

In the second study, Dr. Harris and colleagues reported a non-significant difference in the cardiac death rate between women who had right-sided radiation (2%) versus left-side-radiation (3.5%). But 20 years after treatment the rate of cardiac deaths was higher among women who received radiation to the left breast so that the cumulative risk was 6.4% (95 CI 3.5% to 11.5) versus 3.6% (95% CI 1.8% to 7.2%).

Women who underwent left-sided radiation were more likely to develop symptomatic heart disease, which was especially true for women who had a history of hypertension. "Among patients with hypertension, the risk ratio for development of coronary artery disease is 1.59 for left- versus right-sided patients," they wrote.

Based on these observations, the authors advised that women who have radiation to the left breast should be monitored long term for hypertension and other cardiac risk factors.

In an editorial in the JCO, Daniel F. Hayes, M.D., of the University of Michigan Comprehensive Cancer Center in Ann Arbor, and Michael H. Picard, M.D., of Harvard Medical School, said, "It is essential that we continue to deliver the 'astonishing' beneficial effects of [Herceptin] therapy to those who will benefit, while avoiding major short- and long-term toxicities." However, they did indicate two situations where the use or Herceptin should be avoided.

"Given that all of the clinical trials of trastuzumab have excluded women with obvious pre-existing heart failure, we cannot determine if this condition should preclude a patient's receiving it;" they wrote. "However, until data to the contrary are reported, we believe it should."

They added, "for now, the presence of left ventricular dysfunction or heart failure symptoms should exclude the addition of trastuzumab."

In a second editorial, Abram Recht, M.D., of Harvard wrote that radiation therapy for left-sided breast cancers is a delicate calculation.

"For now, I use 1.8-Gy daily fractions for all patients with left-sided cancers, hoping (without proof) that smaller fraction size will reduce the risks of cardiac disease, and alternative radiotherapy positioning and newer treatment techniques in selected patients," he wrote.

"I strongly encourage patients to vigorously treat their hypertension and hyperlipidemia-and, for God's safe, stop smoking," Dr. Recht concluded.