One Year of Trastuzumab Remains the Standard of Care

Caroline Helwick

March 2013, Highlights - Breast Cancer


For patients with HER2-positive early breast cancer, 1 year of treatment with trastuzumab (Herceptin) remains the standard of care, according to the HERA trial and a subanalysis of the PHARE study.

The optimal duration of anti-HER2 adjuvant therapy has never been clearly established, and the issue continues to be studied in current trials, but for now, 1 year is the recommended treatment.

HERA: Trastuzumab Shows Robust Effect at 8 Years


The 8-year update of the HERA trial showed a sustained benefit for trastuzumab 8 years after patients were randomized, and it determined that 2 years of treatment were not better than 1 year.

The study was presented by Martine Piccart-Gebhart, MD, PhD, Associate Professor of Oncology at the Université Libre de Bruxelles and Head of the Department of Medicine at the Jules Bordet Institute in Brussels, Belgium.

Between 2001 and 2005, HERA randomized 5102 patients to 1 year of trastuzumab, 2 years of trastuzumab, or observation. The striking finding of a 50% reduction in recurrence risk with adjuvant trastuzumab led to the drug’s approval.

In the current landmark analysis with 8 years of median follow-up, there was no evidence of long-term benefit with the longer duration of treatment when trastuzumab was administered as sequential treatment after chemotherapy, Dr Piccart-Gebhart reported.

“One year of trastuzumab remains the standard of care as part of adjuvant therapy for patients with HER2-positive early breast cancer,” she noted. Disease-free survival (DFS) at 8 years was 75.8% with 2 years of trastuzumab and 76.0% with 1 year (hazard ratio [HR], 0.99; P = .86). Overall survival (OS) rates were 86.4% and 87.6%, respectively (P = .63). The same pattern held true for both hormone receptor–positive and hormone receptor–negative subgroups, although there was a hint of greater benefit after 2 years of treatment with trastuzumab in the hormone receptor–negative cohort—raising a hypothesis that will be further explored, Dr Piccart-Gebhart explained.

HERA also determined the overall benefit of trastuzumab versus observation at 8 years, showing that a robust treatment effect could still be observed despite 52% of the observation arm crossing over to receive trastuzumab, she added.

The HR favoring trastuzumab was 0.76 for both DFS (P <.001) and OS (P = .005). Rather than attenuating because of crossover, the OS benefit has actually increased since the previous analysis 4 years ago.

It is likely that the true effect of 1 year of trastuzumab is even greater because of the contamination of the crossover, the investigators suggested.

Six Months Probably Not Sufficient

Whether 6 months of trastuzumab is as effective as 1 year of therapy was not answered by the HERA trial. This was the question evaluated in the PHARE trial, which randomized 3480 patients to 6 or 12 months of maintenance trastuzumab. The study was designed to test noninferiority of the shorter regimen.

PHARE failed to show noninferiority for 6 months of trastuzumab versus 1 year, also validating 1 year as the proper duration of this treatment, reported Xavier Pivot, MD, PhD, of the University Hospital of Besançon, France.

After 42.5 months of median follow-up, disease-related events occurred in 10.4% of the patients treated for 1 year and 13.0% of those treated for 6 months, yielding a 28% increased risk with the shorter treatment.

The DFS rate was significantly better with 1 year of the drug at all time points; at the end of the study, 4-year DFS was 87.8% with 1 year of treatment versus 84.9% with 6 months of treatment.

“The results were inconclusive for the noninferiority analysis, and there was a trend favoring the standard 12 months of treatment,” Dr Pivot said.

Subgroup analyses suggested that the overall results were driven by worse outcomes in patients with estrogen receptor–negative tumors who received sequential systemic therapy and who had a 57% increased risk for an event with 6 months of trastuzumab. Breast cancer experts said that the results establish 1 year of trastuzumab as the standard of care, but findings from ongoing and future studies are still awaited.

The relative benefit of 6 months versus 1 year of trastuzumab will be evaluated by the PERSEPHONE trial (which is also evaluating sequential and concurrent trastuzumab) and the HELLENIC trial (concurrent therapy). The SHORT-HER and SOLD trials are evaluating 9 weeks versus 12 months of trastuzumab given in conjunction with a taxane, similar to the FinHER trial, which found a benefit for 9 weeks of treatment.

Dr Piccart-Gebhart noted, “PHARE doesn’t really tell us that giving 12 months [of trastuzumab] is superior to 6 months. There is still a gray zone, and efforts to determine the optimal duration should continue.”