Experts disagree on taxane use in HER2-/ ER+ breast ca

November 1, 2007

A widely publicized study shows that paclitaxel administered after adjuvant chemotherapy with doxorubicin plus cyclophosphamide (AC-T) provides no or only slight benefit to women with HER2-negative, ER-positive, node-positive breast cancer.

A widely publicized study shows that paclitaxel administered after adjuvant chemotherapy with doxorubicin plus cyclophosphamide (AC-T) provides no or only slight benefit to women with HER2-negative, ER-positive, node-positive breast cancer. This has raised the question of what, if any, immediate impact the findings will have on the practice of clinical oncology.

This subpopulation of node-positive patients represents a significant portion of women who currently receive AC-T, and the study authors noted the increased risk of adverse events associated with adding paclitaxel to AC chemotherapy. However, they cautioned that the results "require validation before adoption into clinical practice" (Hayes et al: N Engl J Med 357:1496-1506, 2007).

The advice seemed sound to Andrew D. Seidman, MD. "This is a retrospective, subset analysis," said Dr. Seidman, attending physician for breast cancer medicine at Memorial Sloan-Kettering Cancer Center and professor of medicine at the Weill Medical College of Cornell University. "I think these data simply state that there are subsets of patients who derive more or less benefit from the drug. For myself, I am not ready to abandon the use of taxanes because of these data."

'The ball is already rolling'

Franco M. Muggia, MD, professor of oncology and director of medical oncology at New York University Medical Center, envisions the paper as another step in identifying markers that will enable more tailored treatment.

"The ball is already rolling," he told ONI. "We are getting more and more molecular markers. In general, we are going to be much more selective in how we use chemotherapies in breast cancer."

Will this new study have an immediate impact on medical oncology? "Yes, I think it will," he said. "The paper comes from a very good source. It is just one of several papers that will undoubtedly change the current treatment."

Added Dr. Seidman: "These data allow us to apply some art to the science of medicine. For example, in a patient with a relatively small tumor whose lymph nodes are negative, where we know there is going to be a benefit of both chemotherapy and perhaps the use of an antiestrogen, these data suggest there would be little if any incremental advantage to adding paclitaxel."

Linda Bosserman, MD, who practices in California with the Wilshire Oncology Medical Group, said that "the article certainly should give pause to using AC-T in ER+ women." She also noted, however, that there are a lot of other treatment questions to sort out in this patient population, including whether to eliminate anthracyclines and which schedules are best. "Is TC 4 better than TC 6, and is either better than or equal to TAC 6?" she asked.

Retrospective analysis

In the new analysis, Daniel F. Hayes, MD, professor of internal medicine and clinical director of breast oncology at the University of Michigan Comprehensive Cancer Center, and his colleagues from the Cancer and Leukemia Group B reviewed data from the 3,121-patient CALGB 9344 trial, in which all participants were node positive.

The trial, begun in 1994, investigated the effects of increased doses of doxorubicin, above 60 mg/m2 in a four-cycle combination with cyclophosphamide at 600 mg/m2, followed by four subsequent cycles of paclitaxel. CALGB 9344 found no overall benefit from doses of doxorubicin above 60 mg/m2, but showed that adding paclitaxel improved disease-free and overall survival.

"This result changed clinical practice, and the use of adjuvant paclitaxel rose dramatically well before the publication of the results in 2003," noted Anne Moore, MD, professor of clinical medicine at Weill Cornell Medical College, in an accompanying editorial.

In the new study, the researchers examined whether a tumor's HER2 expression identified patients likely to benefit from doxorubicin doses above 60 mg/m2, the addition of paclitaxel after adjuvant treatment with doxorubicin plus cyclophosphamide, or both.

Dr. Hayes and his colleagues randomly selected 1,500 patients enrolled in CALGB 9344 who had received 60, 75, or 90 mg/m2 of doxorubicin. The 1,322 patients for whom they could obtain HER2 status were divided into four groups: HER2+/ER+, HER2+/ER-, HER2-/ER+, and HER2-/ER-.

They found no interaction between HER2 positivity and doxorubicin above 60 mg/m

2

, but positive status was associated with a significant benefit from paclitaxel (HR 0.59). HER2+ patients benefited from paclitaxel, regardless of ER status, but HER2-/ER+ women did not.

Other ways to include taxanes

Dr. Moore, in her editorial, argued the findings do not call for abandoning taxanes in these patients.

"The 3-week schedule with paclitaxel is not the only way to include taxanes in adjuvant therapy," Dr. Moore said. "In recent trials, dose-dense therapy using the same doses of doxorubicin plus cyclophosphamide and paclitaxel every 2 weeks has been shown to be more effective than the same regimen every 3 weeks."

She urged investigators in charge of these more recent trials to analyze their results retrospectively for HER2 and ER status.