Anthracyclines May Not Be Necessary for HER2+ Breast Cancer

Debate continues as to whether all patients with early human epidermal growth factor receptor type 2 (HER2)-positive breast cancer need an anthracycline with trastuzumab. Updated data from the Breast Cancer International Research Group (BCIRG)-006 trial suggest that eliminating the anthracycline will have comparable efficacy and be less toxic.

Dennis Slamon, MD, PhD, of the University of California, Los Angeles, announced that a nonanthracyclinebased regimen with trastuzumab was not associated with significantly more breast cancer recurrences or deaths at 5.5 years, and no subgroup demonstrated special benefit from the anthracycline- based regimen. Further more, by eliminating the anthracycline, risk of heart failure and leukemia was significantly reduced, he said.

"We should no longer think that the high-risk patient needs anthracyclinebased chemotherapy," Slamon commented at a press briefing. "The data do not support that."

The trial included 3222 HER2-positive patients who were randomized to one of three arms: standard anthracycline- based therapy with doxorubicin, cyclophosphamide, and docetaxel (AC-T), the same regimen plus trastuzumab (AC-TH) or the nonanthracycline regimen of docetaxel and carboplatin plus trastuzumab (TCH).

Findings from the third planned analysis, based on 65-month follow-up, led to the following main conclusions:

• Trastuzumab provides a similar and significant advantage for both disease- free survival (DFS) and overall survival (OS) when used with either anthracycline-based chemo therapy (AC-TH) or a nonanthracycline regimen (TCH), in both low-risk and high-risk patients.
• The acute and chronic toxicity profiles of TCH are better than those seen with the AC-TH regimen in almost all parameters measured.
• There is no statistical advantage of AC-TH over TCH, but there is a 29-event numerical advantage in DFS events with AC-TH.
• This numerical advantage comes at a cost: increases in congestive heart failure and leukemias, all in patients receiving AC as part of the treatment.

DFS at 65 months was 84% with AC-TH compared with 81% for TCH and 75% for AC-T. With the AC-T regimen as the reference (control), AC-TH reduced risk by 36%, whereas TCH reduced risk by 25%. These differences were less robust at this time point than at the first analysis, when risk was reduced by 51% and 49%, respectively.

OS was 92% with AC-TH, 91% with TCH, and 87% with TCH, with risk reduced by 37% and 23%, respectively, he reported.

Anthracycline-based therapy was expected to benefit the high-risk patients the most, Slamon added; however, even in patients with four or more positive lymph nodes, the two trastuzumab regimens resulted in identical DFS outcomes.

BCIRG-006 also demonstrated that incremental benefit conferred by AC in HER2-positive patients is restricted to the 35% of patients whose tumors coamplify the topoisomerase II alpha (TOP2A) gene, a close genetic neighbor of HER2. Slamon advocated the nonanthracycline regimen for patients regardless of TOP2A status, to "avoid the long-term and lifealtering toxicities seen with anthracycline- based regimens."

He emphasized the toxicity of the AC-TH regimen, which led to 21 cases of congestive heart failure, compared with four cases in the TCH arm. Additionally, 194 patients had sustained reductions in left ventricular ejection fraction, compared with 97 with TCH, and eight versus zero developed leukemia.

"The acute and chronic toxicity profiles of TCH are better than those seen with the AC-TH regimen in almost all parameters measured," he told the press.

"At this point, when we see an HER2-positive patient, we have elected to treat those patients with a nonanthracycline-containing regimen to get close to equivalent efficacy but considerably better safety, in particular, not for the acute toxicity but more important for the life-changing toxicities," he said.

Questions remain
Eric Winer, MD, of Dana-Farber Cancer Center, Boston, however, is not convinced that anthracyclines can be safely eliminated. He told The Oncology Nurse, "Ultimately, the most important thing is survival. The differences shown between the arms in the trial are not statistically significant [versus each other], and the two arms were, in fact, never intended to be compared with each other, and the study is therefore not powered to show equivalence between anthracyclineand nonanthracycline-based regimens," he said.

"I don't have a problem with using TCH to avoid cardiac problems. It is an acceptable regimen, but I am not of the view that it should be a preferred regimen," he said. "There are some patients for whom TCH might be appropriate, based on the need to avoid the side effects. But in someone at low risk for developing cardiac problems, I think one has to think long and hard before opting for a regimen that might be slightly less effective. And I think we must be very cautious before adopting new standards."