Trastuzumab with Adjuvant Chemotherapy Reduces Risk of Relapse in HER2+ Breast Cancer

The combination use of tailored, dose-dense adjuvant chemotherapy and trastuzumab (Herceptin) was found to decrease the relative risk of relapse by 32% for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to a protocol-predefined secondary analysis of the randomized phase III Pan-European Tailored Chemotherapy (PANTHER) trial.

“To our knowledge this is the first report of phase III data from randomized allocation to (dose-dense) adjuvant chemotherapy and trastuzumab versus standard interval chemotherapy and trastuzumab, for HER2-positive (breast cancer),” the authors wrote in the study, published in Cancer. “The demonstrated effect in favor of (tailored, dose-dense chemotherapy) in PANTHER, even though formal statistical significance was not reached, may have important implications.”

In the study, 342 aged 65 or older with HER2-positive breast cancer were randomized 1:1 to receive either of the following:

• standard therapy with 3 cycles of 5-fluorouracil (100 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (500 mg/m²) every 3 weeks followed by 3 cycles of docetaxel at 100 mg/m² every 3 weeks

• tailored, dose-dense epirubicin (38-120 mg/m²; starting at 90 mg/m²) and cyclophosphamide (450-1200 mg/m²; starting at 600 mg/m²) every 2 weeks for 4 cycles followed by tailored, dose-dense docetaxel (60-100 mg/m²; starting at 75 mg/m²) every 2 weeks for 4 cycles.

The primary endpoint of the study was breast cancer recurrence-free survival (BCRFS). Secondary endpoints included overall survival (OS), event-free survival (EFS), distant disease-free survival, and toxicity. Median follow-up was 5.3 years. 

The 5-year BCRFS rate was not statistically significant in the trastuzumab arm, compared with the standard treatment group (89.1 % vs 85.3%; 95% CI, –3.7% to 11.0%).

The researchers also presented a substudy related to the cardiac safety of trastuzumab treatment. The patients with HER2-positive breast cancer underwent repeated assessments of cardiac function at baseline as well as at 4, 6, and 10 years after the end of chemotherapy. Of the 153 patients for which 4-year data was available, 77 were HER2-positive, and 76 were HER2-negative. For the HER2-positive group, there was no clinical or statistical difference in left ventricular ejection fraction (LVEF) decline between the experimental and standard treatment. For the HER2-negative group, both treatment groups showed LVEF decline (P = .009 for tailored, dose-dense chemotherapy, and P = .004 for standard chemotherapy) at 4 years, with the tailored, dose-dense chemotherapy group showing LVEF decline at 6-year follow up (P < .001).

“In PANTHER, dose tailoring according to the intrapatient pharmacokinetic variabilities with the hematologic nadirs used as a biomarker could have potentially contributed to the low cardiotoxicity rates despite the significantly higher epirubicin dose in the experimental treatment group,” noted the researchers. “It should be mentioned, however, that patients treated in the experimental arm did not receive 5-fluorouracil, which is also associated with cardiotoxicity.”

There were several limitations to the study, including the sample size of the substudy. “The small number of patients in the cardiac safety substudy could have introduced a bias,” noted the authors. “And the relatively short follow-up of 6 years could have potentially masked clinically important differences in heart-related adverse events.”

Additionally, as the study was not designed to detect differences in efficacy in the HER2-positive subgroups, the authors suggested that the analysis be considered exploratory in nature. 

While the overall analyses showed promise, the authors cautioned that further research in the form of a properly designed randomized trial is needed to validate the use of adjuvant tailored, dose-dense chemotherapy with trastuzumab before it can be considered a standard of care.

References:

Papakonstantinou A, Matikas A, Bengtsson NO, et al. Efficacy and Safety of Tailored and Dose-Dense Adjuvant Chemotherapy and Trastuzumab for Resected HER2-Positive Breast Cancer: Results from the Phase 3 PANTHER Trial. Cancer. doi:10.1002/cncr.32653.