Do anthracyclines still have a role as adjuvant treatment of breast cancer?

BALTIMORE—Anthracyclines have been a cornerstone in the adjuvant treatment of breast cancer for more than 25 years and have well-established risks and benefits. But new molecular assays may make it possible to predict which women will benefit from this therapy, and new agents may offer better alternatives.

Given the changing landscape, experts in the field convened at the Era of Hope 2008 meeting to debate whether anthracyclines still have a role in this setting. Aman U. Buzdar, MD, of M.D. Anderson, argued in favor of a continued role for anthracyclines, while Dennis J. Slamon, MD, PhD, of UCLA, took the view that the age of adjuvant anthracycline chemotherapy in breast cancer is over.

‘They keep more patients alive’

“We are able to keep more patients alive free of disease today and keep more patients alive period because of utilization of anthracyclines,” said Dr. Buzdar, deputy chairman of the Department of Breast Medical Oncology, M.D. Anderson Cancer Center.

As established by the 2005 Oxford Overview of breast cancer therapies in thousands of women, receipt of only a few cycles of adjuvant anthracycline-based chemotherapy reduces both recurrences and deaths (Lancet 365:1687-1717, 2005). The magnitude of benefit, shown by data from the MA-5, NEAT, and SCTBG BR9601 trials, amounts to a 25% to 30% decreased risk of recurrence and a 25% to 35% decreased risk of death relative to CMF, Dr. Buzdar said.

Anthracyclines are well known to adversely affect cardiac function, but in the contemporary era, only about 1% of patients develop clinical cardiotoxicity, according to Dr. Buzdar.

“The risk of cardiac dysfunction I think is smaller, and it is being blown way out of proportion,” he asserted. “We may be doing more harm to the patients by scaring them about effective therapy.”

He observed that the risk appears to be mainly confined to middle-aged patients, and that the cardiotoxicity risk is far outweighed by the breast cancer benefit.

No validated predictors

Validated and standardized predictors of response to anthracyclines—which would allow some patients to skip these agents—are lacking, Dr. Buzdar said.

A large meta-analysis suggested that HER2 overexpression is a predictor (Gennari A et al: J Natl Cancer Inst 100:14-20, 2008), and subsequent studies have suggested that topoisomerase IIa (Topo II), typically coamplified with HER2, is the actual target; however, all of these studies have been retrospective, and Topo II status has been assessed in many differing ways, he emphasized.

“We don’t have a single prospectively validated study, so if any one of us has that delusion, I think they are totally wrong because there are no data,” he said. “I do not think that we are ready to give up effective therapies in any subset of patients without having prospective data.”

In addition, Topo II amplification may occur in the absence of HER2 amplification, suggesting that the latter cannot be used to guide decisions about anthracyclines, Dr. Buzdar cautioned.

For example, roughly 1% to 10% of HER2-negative patients may still have amplification of Topo II (Knoop AS et al: J Clin Oncol 23:7483-7490, 2005) and may therefore benefit from these agents.

He further noted that at least one study has found that anthracyclines, used in high doses, are superior to other chemotherapy, regardless of Topo II amplification status, with HEC (full-dose epirubicin(Drug information on epirubicin) plus cyclophosphamide(Drug information on cyclophosphamide)) yielding better event-free survival than CMF in a HER2-positive population (Di Leo A et al: Clin Cancer Res 8:1107-1116, 2002).