More evidence on older women, newer cancer drugs

The risk of developing cardiac complications was higher in older women who received trastuzumab as adjuvant treatment for early stage breast cancer than was shown in clinical trials, and use of this therapy in older women is growing, according to a recent study. The results underline the importance of studying the cardiotoxic side effects of biological therapies as more agents enter clinical practice, the lead author told Cardiovascular Business.

“Cancer is all about anti-angiogenic effects, that is, reducing blood supply to cancer cells to kill the cancer,” said Jersey Chen, MD, MPH, of the Yale University School of Medicine in New Haven, Conn. “In cardiology, what we care about are pro-angiogenic effects; we want to increase blood supply to the heart. There will always be, for those medications, a natural tension between killing cancer cells and causing cardiovascular problems.”

Anthracycline, a chemotherapy drug, is known to increase the risk of heart failure (HF) or cardiomyopathy (CM) in women being treated for breast cancer. Trastuzumab (Herceptin, Genentech), a monoclonal antibody agent, also has been associated with an increase in the incidence of HF and cardiac abnormalities. Clinical trials for these drugs typically enrolled younger and healthier patients, with results showing anthracycline was associated with a 2 percent increase in HF or CM and anthracycline plus trastuzumab (A+T) was associated with a 4 percent increase.

Single center studies in real world populations suggest the risk is substantially higher for older women, and a recent retrospective cohort study that enrolled 12,500 women found a fourfold increase in the risk of HF and CM in trastuzumab recipients and a sevenfold increase in the risk in women who received A+T.

Chen and colleagues’ study, which was published Nov. 14 in the Journal of the American College of Cardiology, focused exclusively on women who were at least 67 years old with early stage breast cancer. They noted that 40.8 percent of women in the U.S. diagnosed with breast cancer are 65 years or older, and that increasing age is a risk factor for cardiovascular events. That makes for a logical partnership to prevent and manage potential cardiac complications.  

“As these new technologies and drugs emerge, there will be an increasing need for cardiologists and oncologists to put their heads together and figure who should be best served by these newer therapies,” Chen said.

The researchers selected 45,537 patients between 2000 and 2007 who were identified through the Surveillance, Epidemiology, and End Results-Medicare linked database. They calculated three-year incidence rates for HF and CM, with patients broken into treatment groups: trastuzumab with or without nonanthracycline chemotherapy (1 percent of the patients); A+T (0.9 percent); anthracycline without trastuzumab and with or without nonanthracycline chemotherapy (11.5 percent); other nonanthracycline chemotherapy (5.9 percent); and no adjuvant chemotherapy or trastuzumab therapy (80.6 percent). They included a cancer-free control group as well.

The mean age of patients was 76.2 years. Women who received trastuzumab, A+T or anthracycline were on average younger and had fewer cardiovascular conditions compared with women who received no adjuvant therapy.

The adjusted three-year HF and CM incidence rate was significantly higher in the trastuzumab and A+T groups compared with the no adjuvant therapy group, at 32.1 per 100 patients and 41.9 per 100 patients vs. 18.1 per 100 patients. The researchers found that trastuzumab on top of anthracycline therapy added 12.1, 17.9 and 21.7 HF or CM events per 100 patients over one, two and three years of follow-up, respectively.

“Although these three-year HF or CM incidence rates seem high, they must be considered in the context of the baseline HF or CM rates in the female cancer-free Medicare cohort (observed three-year HF or CM incidence of 18.7 per 100 patients),” Chen and colleagues wrote. “However, comparisons of HF or CM rates from clinical trials remain challenging because the definition of cardiotoxicity events vary considerably, and it is likely that the sensitivity and specificity of HF or CM events between clinically based and claims-based assessments also differ.”

The researchers wrote that the proportion of patients who received any adjuvant chemotherapy, trastuzumab or both stayed nearly constant between 2000 and 2007. But of those who received any form of adjuvant therapy, the proportion to receive trastuzumab or A+T jumped from 2.6 percent to 22.6 percent.

“There is not that much information about trends in older patients,” Chen noted. “Once trastuzumab was introduced, it took off very quickly among oncologists to treat HER-2 positive breast cancers.”

The findings will help inform physicians and breast cancer patients about potential cardiac-related risks, Chen said, but he emphasized the benefit of trastuzumab, which has has been shown to improve survival in HER-2 positive patients. “In the future, perhaps with personalized medicine or having initial information about cardiac risk factors, we can more accurately say who will be at high or low risk (of developing cardiovascular complications) and tailor the therapy better,” Chen said. “But right now this research is at the beginning stages.”