One year of adjuvant trastuzumab following standard chemotherapy is associated with significantly improved long-term, disease-free survival in women with early-stage HER2-positive breast cancer, according to updated findings from the ongoing international, randomized phase III Herceptin Adjuvant trial.
Disease-free survival at a median follow-up of 48.4 months was 78.6% in 1,703 women who were initially randomized to receive 1 year of treatment with trastuzumab (Herceptin) following chemotherapy, compared with 72.2% in 1,698 women randomized to observation following chemotherapy (hazard ratio, 0.76), Dr. Luca Gianni of the Istituto Nazioniale dei Tumori in Milan and colleagues from the HERA Trial Study Team reported online in the Feb. 25 issue of the Lancet Oncology.
Overall survival did not differ significantly between the treatment and observation groups (89.3% and 87.7%, respectively), but the investigators attributed this to the substantial crossover from the observation group to the treatment group after 1-year follow-up results from this study, which were published in 2005.
"This effect was not recorded at 2-year median follow-up, probably because of the short duration of follow-up after crossover at that time" (median, 2.6 moths vs. 29.1 months in this analysis)," they explained.
More than half (52%) of the observation group patients crossed over to receive trastuzumab after the 1-year analysis, beginning treatment at a median of 22.8 months after randomization. Those patients were found in the current study to have fewer disease-free survival events than did those who did not cross over (adjusted hazard ratio, 0.68), the investigators said (Lancet Oncol. 2011 Feb. 25 [doi:10.1016/S1470-2045(11)70033-x]).
Women in the HERA trial had early-stage HER-2-positive breast cancer, an aggressive form of breast cancer that represents about 15%-25% of breast cancers and confers an increased risk of recurrence and mortality. They were enrolled between December 2001 and June 2005, and were randomized to an observation group, a 1-year treatment group, or a 2-year treatment group. Treatment group patients received trastuzumab, a humanized monoclonal antibody that targets the extracellular domain of the HER2 receptor. Treatment was given as an intravenous infusion over 90 minutes every 3 weeks at an initial loading dose of 8 mg/kg and at a dose of 6 mg/kg thereafter.
Trastuzumab was generally well tolerated, although higher incidence of grades 3/4 and fatal adverse events occurred in the 1-year treatment group than in the observation group, they noted, adding that the most common of these – cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhea – each occurred in fewer than 1% of patients.
The interim analysis at 1 year showed that 12 months of treatment with trastuzumab was associated with a 46% reduction in disease recurrence. The 2-year follow-up data that were published in 2007 confirmed the disease-free survival benefit (HR, 0.64) and also demonstrated an overall survival benefit (HR, 0.66), the investigators noted.
"The HERA trial results confirm that treatment with adjuvant trastuzumab for 1 year is associated with persisting benefit in women with HER2-positive early breast cancer," the investigators said, concluding that trastuzumab given sequentially to chemotherapy "remains an appropriate treatment modality" in these patients.
They also noted that the possibility that women might derive further benefits from treatment for longer than 1 year is currently being explored in a comparison of the outcomes in the 1-year and 2-year treatment groups of the HERA trial.
F. Hoffmann-La Roche and the Michelangelo Foundation funded the study, which was conducted by the Breast International Group (BIG). Several authors, including Dr. Gianni, reported receiving funding from Roche, such as for advisory board membership, research support, speakers honoraria, consultancy, and travel. One author, Susanne Muehlbauer, is an employee of Roche and has stock options in the company.