As reported in the Journal of Clinical Oncology by Louis Fehrenbacher, MD, and colleagues, the phase III NSABP B-47/NRG Oncology trial has shown no invasive disease–free survival benefit with the addition of trastuzumab to adjuvant chemotherapy therapy in patients with HER2-negative breast cancer determined by fluorescence in situ hybridization (FISH) ratio and an immunohistochemistry (IHC) score of 1+ or 2+.

Louis Fehrenbacher, MD

As stated by the investigators, trastuzumab has been shown to be of benefit in patients with HER2-amplified or HER2-overexpressing invasive disease. In addition, a subgroup of patients in landmark adjuvant trials who originally tested HER2-positive but were HER2-negative on central HER2 testing appeared to potentially derive a benefit from trastuzumab.

Study Details

In the trial, 3,270 women with high-risk primary invasive breast cancer were randomly assigned between February 2011 and February 2015 to receive adjuvant chemotherapy with (n = 1,640) or without (n = 1,630) 1 year of trastuzumab therapy. Eligible patients had resected node-positive or high-risk node-negative HER2-low disease; HER2-low was defined as either IHC score of 1+ (FISH not required) or 2+ with negative HER2/chromosome 17 FISH ratio of < 2.0 (if ratio was not performed, then HER2 gene copy number < 4.0).

Investigator-selected adjuvant chemotherapy consisted of docetaxel plus cyclophosphamide every 3 weeks for six cycles, or doxorubicin plus cyclophosphamide every 3 weeks or every 2 weeks for four cycles followed by weekly paclitaxel for 12 doses. Trastuzumab was given every 3 weeks during and after chemotherapy for a total of 1 year, with an 8 mg/kg loading dose followed by 6 mg/kg for remaining doses. The primary endpoint was invasive disease–free survival.

Invasive Disease-Free Survival

Median follow-up was 46 months. Five-year invasive disease–free survival was 89.8% in the trastuzumab group vs 89.2% in the control group (hazard ratio [HR] = 0.98, P = .85). No differences between groups were observed according to the level of HER2 IHC expression, lymph node involvement, hormone receptor status, or selected chemotherapy. Five-year rates were 92.7% vs 93.6% (HR = 1.10, P = .55) for distant recurrence–free interval and 94.8% vs 96.3% (HR = 1.33, P = .15) for overall survival.

Adverse Events

No new adverse events for trastuzumab or chemotherapy were observed, with safety profiles being as expected. Grade 4 toxicity was the highest grade experienced by 4.6% of the trastuzumab group vs 4.1% of the control group; adverse events led to death in seven vs three patients.

The investigators concluded, “The addition of trastuzumab to [adjuvant chemotherapy] did not improve [invasive disease–free survival], distant recurrence–free interval, or [overall survival] in women with non–HER2-overexpressing [invasive breast cancer]. Trastuzumab does not benefit women without IHC 3+ or FISH ratio–amplified breast cancer.”

Priya Rastogi, MD, of NRG Oncology and the University of Pittsburgh Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, Genentech, and F. Hoffmann-La Roche. For full disclosures of the study authors, visit ascopubs.org.