Heart Problems From Trastuzumab (Herceptin®) Do Not Increase in the Short Term
It’s known that women with HER2-positive breast cancer who take the drug trastuzumab (Herceptin®) in addition to chemotherapy are at greater risk of heart problems during treatment. Now a study has shown that the incidence of such problems does not increase in the short term and that many women regain heart health after an initial decline. However, the long-term effects of trastuzumab on the heart remain to be determined.
American Society of Clinical Oncology (ASCO) annual meeting, Chicago, June 4, 2007 (see the meeting abstract). See also results published online June 7, 2010, in the Journal of Clinical Oncology (see the journal abstract).
About 20 percent of breast cancers make too much of (overexpress) a protein called HER2. Such tumors tend to grow faster and are more likely to come back (recur) than tumors that don’t overproduce the protein.
The targeted drug trastuzumab kills cells that overexpress HER2. In 2005, results from several randomized clinical trials showed that taking trastuzumab in addition to chemotherapy reduces the risk of breast cancer recurrence by about half for women whose tumors overexpress HER2 (called HER2-positive breast cancer).
However, these trials also found that women who took trastuzumab had an increase in congestive heart failure (where the heart has trouble beating normally because of damage to the heart muscle) or other heart problems. In the study described below, investigators examined the data from five years of follow up from a randomized clinical trial of trastuzumab to see if this risk of heart damage changes over time.
The investigators looked at data from five years of follow up from the National Surgical Adjuvant Breast and Bowel Project trial NSABP-B-31. This trial randomly assigned women with HER2-positive breast cancer that had spread to nearby lymph nodes to receive chemotherapy with the drugs doxorubicin (Doxil®) and cyclophosphamide, followed either by the drug paclitaxel (Taxol®) and 52 weeks of trastuzumab (experimental group) or paclitaxel alone (control group).
In order to be eligible to take trastuzumab, participating women had to have normal heart function and no past or current heart disease. All women had scans of the heart before the start of treatment, and at 3, 6, 9, and 18 months after the start of treatment. The investigators compared the difference in number of cardiac events—defined as either congestive heart failure or death due to heart problems—between women taking trastuzumab and women in the control group for up to five years after the start of treatment.
The trial was organized by the National Surgical Adjuvant Breast and Bowel Project (NSABP). The author of the five-year follow-up study is Priya Rastogi, M.D., from the NSABP.
At five years after the start of treatment, 3.8 percent of women in the trastuzumab group had experienced a cardiac event, compared to 0.9 percent of women in the control group. These numbers remained essentially unchanged from those seen at three years of follow up (4.1 percent in the trastuzumab group and 0.8 percent in the control group), showing that the cumulative incidence of cardiac events did not increase.
In addition, substantial recovery in heart function was seen in approximately two-thirds of women who experienced an initial decline in function.
The investigators identified three risk factors for congestive heart failure in women taking trastuzumab: age (women over the age of 50 have higher risk), the use of hypertensive medications (medications taken to lower high blood pressure), and low normal heart function.
Importantly, explained Sharon Hunt, M.D., professor of cardiovascular medicine at Stanford University, who presented a discussion of these results at the ASCO meeting, doctors still do not know what the long-term effects of trastuzumab on the heart will be.
“I don’t think that a three-year follow up or a five-year follow up are adequate to tell us the real natural history of any chemotherapy-related cardiotoxicity,” she stated. “We don’t know…the predicted 10-year cumulative toxicity of the chemotherapy. I think this is incredibly important data to obtain…so that when we face a patient with the option of having trastuzumab…we can be able to share with them the absolute risk/benefit ratios.”
The long-term risk data will be particularly important, she explained, because even the women who recovered heart function did not recover to the levels they had before treatment. These patients may be especially vulnerable to additional damage to the heart, from conditions such as high blood pressure or viral infection.
Even though questions about the long-term effects of trastuzumab on the heart remain to be answered, “it’s amazing to me how incredibly effective trastuzumab is. It has obviously been a major addition to the chemotherapy of…metastatic breast cancer, as well as [in] the adjuvant setting,” said Hunt. “It is in this context of the remarkable efficacy of this drug that we need to discuss its downside.”
“Trastuzumab is a very active treatment, and it’s something we’re all excited about in terms of treating breast cancer, so in the short term these results are reassuring,” agreed Jennifer Eng-Wong, M.D., a breast cancer specialist from the National Cancer Institute’s Center for Cancer Research.