Adjuvant Trastuzumab Benefit Elucidated in Small HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer that was ≤2 cm experienced a substantial improvement in disease-free and overall survival when treated with adjuvant trastuzumab, according to a meta-analysis of data from 5 clinical trials that was published in the Journal of Clinical Oncology.

In the analysis, which looked at data from the HERA, N9831, NSABP-B31, PACS-04, and FinHER trials, a total of 2588 patients with HER2-positive breast cancer were treated with adjuvant trastuzumab while 1632 were not. Endocrine therapy was administered to a majority (94.1%) of patients with hormone receptor (HR)-positive disease (n = 2263). Overall, 1957 patients had HER2-positive and HR-negative breast cancer. Across both groups, a majority of patients had T1c disease (~80%).

Eight-year disease-free survival (DFS) was improved by 9.4% for patients with HER2-positive and HR-negative tumors ≤2 cm treated with trastuzumab compared with those who did not receive HER2 inhibition (hazard ratio [HR], 0.66; 95% CI, 0.49-0.88; P <.001). In this same group, overall survival (OS) at 8 years was increased by 8.8% with trastuzumab versus without (HR, 0.59; 95% CI, 0.47-0.74; P <.001).

The 8-year DFS was 7.0% higher for patients with HER2-positive and HR-positive tumors ≤2 cm treated with trastuzumab (HR, 0.70; 95% CI, 0.59-0.85; P <.001). In this same group, the 8-year OS rate was 3.8% higher with trastuzumab versus without (HR, 0.68; 95% CI, 0.52-0.89; P = .006).

"Patients with HER2-positive tumors ≤2 cm derive significant benefit from the addition of trastuzumab to their treatment regimens, although the majority of patients included in our analyses had T1c, node-positive disease and were thus a selected group," wrote lead author Ciara C. O'Sullivan, MD, from the National Cancer Institute, and colleagues. "The proportional benefit was similar for patients with HR-positive and HR-negative disease, although timing of relapses and absolute magnitude of benefit seemed to differ over time."

In the trials, trastuzumab was given sequentially to chemotherapy in HERA and PACS-04 and concurrently in FinHER and NSABP-B31. In the N9831 trial, patients may have received chemotherapy either sequentially or concurrently with trastuzumab. Chemotherapy regimens varied across trials, with 96% of patients receiving anthracycline-based therapy. Trastuzumab was administered for 1 year in 73% of patients (range, 9 weeks to 2 years).

Study-to-study heterogeneity in treatment effects was not statistically significant for those with HR-positive disease (P = .76). However, there was significant heterogeneity seen for those with HR-negative breast cancer (P = .01).

Cross over between arms was a primary cause for heterogeneity in treatment effect across the trials, the authors theorized. In the HERA trial, 55% of patients crossed over from the placebo arm to receive trastuzumab, as compared with 12% in N9831 and 13% in NSABP-B31.

"In our meta-analysis, the majority of patients received sequential trastuzumab, and for patients with HR-positive disease, testing for study-to-study heterogeneity did not reach statistical significance. By contrast, testing for study-to-study heterogeneity in patients with HR-negative disease did reach statistical significance," the authors wrote. "There was clear evidence of heterogeneity between trials, and a diminished treatment effect was noted over time in HERA."

For patients with HR-positive disease and ≤1 positive lymph node (n = 1040), there was a 5.9% gain in DFS with trastuzumab versus without (HR, 0.77; 95% CI, 0.59-1.00; P = .05). At 8-years, 91.8% of patients treated with trastuzumab remained alive versus 87.8% who did not receive the HER2 inhibitor (HR, 0.69; 95% CI, 0.46-1.04; P = .084).

For those with HR-positive disease and ≤1 positive lymph node (n = 1092), at 8 years 12.7% treated with trastuzumab remained disease-free versus 19.4% who did not receive the medication (HR, 0.64; 95% CI, 0.47-0.83; P = .003). In this group, OS was improved by 2.1% with trastuzumab (HR, 0.68; 95% CI, 0.42-1.10; P = .11).

"Overall, subgroup analyses on the large adjuvant trastuzumab clinical trials suggest that patients with small, node-negative, HER2-positive tumors also derive benefit from adjuvant trastuzumab, a finding that is supported by the results of our meta-analysis," the authors wrote. "Across the five trials studied in our meta-analysis, only 75 patients had T1a-b node-negative disease, likely because they had other adverse biologic features. Therefore, it would be difficult to extrapolate the DFS and OS results to every patient with T1a and T1b node-negative HER2-positive disease seen in the clinical setting."

With the illumination of treatment outcomes across subtypes, more can be done to improve DFS and OS for patients while reducing treatment-related morbidity, the authors noted. This could be particularly true for those with HR-positive, HER2-positive breast cancers measuring ≤2 cm with ≤1 positive; however, a clinical trial in this space would be difficult to assess using standard endpoints.

O'Sullivan CC, Bradbury I, Campbell C, et al. Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2—Positive Early Breast Cancer and Tumors ≤ 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials. J Clin Oncol. 2015;33(24):2600-2608.