A 9-week course of trastuzumab cannot be considered noninferior to a standard 1-year course of trastuzumab when considering the end point of disease-free survival (DFS) in women with hormone receptor (HR)-positive, early-stage breast cancer.1 Results from a randomized trial known as Short-HER demonstrated a significantly lower risk for cardiac toxicity with the shorter course, reported Pierfranco Conte, MD, Professor of Oncology, University of Padova, and Chief of Medical Oncology, the Veneto Cancer Institute, Padova, Italy, at the 2017 meeting of the American Society of Clinical Oncology.
“One year of trastuzumab is still standard,” said Dr Conte. “The Short-HER trial, however, reinforces the hypothesis that treatment de-escalation retains efficacy with less toxicity.” Shorter trastuzumab treatment may be an option for patients at low risk for relapse and/or high risk for cardiac toxicity, he added.
Numerous randomized trials have demonstrated the superiority of adding trastuzumab to adjuvant chemotherapy for 1 year for women with HR-positive, early-stage breast cancer. As a result, trastuzumab was granted accelerated approval as adjuvant therapy in this patient population, and the standard duration of therapy in this setting is 1 year.
“It was however clear that there was a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab administration. First of all, 1 year of administration was selected empirically,” Dr Conte said. In addition, the same magnitude of benefit was reported with 9 weeks of trastuzumab in a small trial.
Finally, in the real world, there are patients at lower risk for relapse, such as those with node-negative disease and smaller tumors, and others at higher risk for cardiotoxicity, such as older patients who are more likely to have comorbidities, he noted.
The hypothesis behind Short-HER was that a shorter duration of trastuzumab (9 weeks) administered concomitantly with chemotherapy may produce comparable efficacy with significantly lower toxicities and costs. In the study, patients with HER2-positive early breast cancer were randomized to 1 year of trastuzumab plus chemotherapy plus chemotherapy (“long” arm) or 9 weeks of trastuzumab plus chemotherapy (“short” arm).
For women with HR-positive tumors, hormonal therapy was started at the completion of chemotherapy.
Short-HER was a noninferiority trial with DFS as the primary end point. DFS included local, regional, and distant recurrence, contralateral breast cancer (excluding ductal carcinoma in situ), invasive nonbreast primary tumors, and death before recurrence. The noninferiority margin of the short arm was set as a hazard ratio of <1.29. Analysis of the primary end point was planned after 198 DFS events or at a median follow-up of 5 years.
From December 2007 to October 2013, 1253 patients were enrolled in the trial. At the time of the presentation, 189 DFS events had accrued at a median follow-up of 5.2 years.
The median age of patients was 55 years and 36.0% were aged ≥60 years, 53.5% were node-negative, 40.6% had stage I disease, 43.8% had stage II, and 15.2% had stage III. HR-positive tumors were detected in 68.2% of patients. Characteristics were balanced between the 2 arms of the trial.
In the long arm, 80 DFS events occurred, with a 5-year DFS of 87.5%. In the short arm, there were 100 DFS events with a 5-year DFS of 85.4%. The hazard ratio of 1.15 (95% confidence interval, 0.91-1.46) in favor of the long course crossed the upper limit of the noninferiority margin of 1.29. A significant advantage to the long course was observed in patients with stage III disease compared with stage I or II (hazard ratio, 2.30; P <.001) and in patients with ≥2 positive nodes compared with 0 or 1 positive node (hazard ratio, 2.25; P <.001). “These 2 groups represent about 15% of the entire study population,” said Dr Conte.
A preplanned Bayesian analysis showed that the probability that the short course was not inferior to the long course was 78%. Five-year overall survival rates were 95.1% with the long course and 95.0% with the short course.
A significant decline in mean left ventricular ejection fraction was observed in women assigned to the long course versus the short course (P = .023). There were 122 grade ≥2 cardiac events reported, 90 (14.4%) in the long arm and 32 (5.1%) in the short arm (hazard ratio, 0.32; P <.0001).
1. Conte PF, Bisagni G, Frassoldati A, et al. 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: results of the phase III multicentric Italian study Short-HER. J Clin Oncol. 2017;35(suppl):Abstract 501.