As reported in the Journal of Clinical Oncology by Cobleigh et al, the phase III NRG Oncology/NSABP B-43 trial did not show a significant reduction in ipsilateral breast tumor recurrence with the addition of adjuvant concurrent trastuzumab to radiotherapy in women undergoing lumpectomy for HER2-positive ductal carcinoma in situ (DCIS).  

Study Details

In the trial, 2,014 women who had undergone lumpectomy were randomly assigned between December 2008 and December 2014 to receive whole-breast radiotherapy with (n = 1,006) or without (n = 1,008) two doses of trastuzumab given concurrently with radiotherapy. The current analysis includes 1,998 women with follow-up data (intention-to-treat population), including 993 in the radiotherapy/trastuzumab group and 1,005 in the radiotherapy group.

Radiotherapy was given with conventional fractionation (25+ fractions) or hypofractionation (16–17 fractions). Radiotherapy boost, including brachytherapy, was given at the radiation oncologist’s discretion. Trastuzumab was given at 8 mg/kg within 1 week before radiotherapy began or within the first 5 days of radiotherapy for patients receiving conventional fractionation, and at 6 mg/kg 3 weeks after the first dose.

The primary endpoint was ipsilateral breast tumor recurrence (ipsilateral invasive breast cancer, ipsilateral skin cancer recurrence, or DCIS), with the hypothesis that the addition of trastuzumab would provide a 36% reduction in ipsilateral breast tumor recurrence. The definitive primary analysis was to be performed when either 163 I ipsilateral breast tumor recurrence events had occurred, or all patients had been on study for ≥ 5 years.

Key Findings

Median follow-up as of December 2019 was 79.2 months. The threshold of 163 ipsilateral breast tumor recurrence events was not reached, with the definitive analysis being triggered by all patients having been on study for ≥ 5 years.

At primary analysis, there were 114 confirmed ipsilateral breast tumor recurrence events, consisting of 51 (5.1%) events in the radiotherapy/trastuzumab group vs 63 (6.3%) in the radiotherapy group (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.56–1.17, P = .26).

Among the 114 ipsilateral breast tumor recurrence events, 38 (33.3%) were invasive, including 20 in the radiotherapy/trastuzumab group vs 18 in the radiotherapy group (HR = 1.11, 95% CI = 0.59-2.10, P = .71). A total of 76 (66.7%) were noninvasive, including 31 in the radiotherapy/trastuzumab group vs 45 in the radiotherapy group (HR = 0.68, 95% CI = 0.43–1.08, P = .11).

Annual ipsilateral breast tumor recurrence event rates were 0.79% per yr in the radiotherapy/trastuzumab group vs 0.99% per year in the radiotherapy group.

Death occurred in 22 patients in the radiotherapy/trastuzumab group vs 26 patients in the radiotherapy group (HR = 0.85, 95% CI = 0.48–1.51, P =.59). Confirmed second primary cancers occurred in 72 vs 78 patients (HR = 0.91, 95% CI = 0.66–1.25, P = .57). Distant recurrence was observed in three patients vs one patient.

Grade 3 adverse events occurred in 4.9% vs 3.9% of patients, and grade 4 events occurred in 0.2% vs 0%. No grade 5 adverse events were reported.

The investigators concluded, “[The] addition of trastuzumab to radiotherapy did not achieve the objective of 36% reduction in ipsilateral breast tumor recurrence rate but did achieve a modest but statistically nonsignificant reduction of 19%. Nonetheless, this trial had negative results. Further exploration of radiotherapy plus trastuzumab is needed in HER2-positive DCIS before its routine delivery in patients with DCIS resected by lumpectomy.”

Melody A. Cobleigh, MD, of Rush University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Cancer Institute and by Genentech. For full disclosures of the study authors, visit ascopubs.org.