2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial Aron Goldhirsch, Richard D Gelber, Martine J Piccart-Gebhart, Evandro de Azambuja, Marion Procter Lancet : R2 박현영 / Prof. 백선경 R2 박현영 / Prof. 백선경

Introduction Trastuzumab Trastuzumab About 15–20% of breast cancers exhibit overexpression or amplification of the HER2 oncogene About 15–20% of breast cancers exhibit overexpression or amplification of the HER2 oncogene Trastuzumab substantially reduces disease recurrence and death in patients with HER2 oncogene type of early breast cancer Trastuzumab substantially reduces disease recurrence and death in patients with HER2 oncogene type of early breast cancer Initial trials compared 1 year of trastuzumab treatment with a no trastuzumab control group Initial trials compared 1 year of trastuzumab treatment with a no trastuzumab control group persistent benefit of 1 year of treatment compared with observation alone persistent benefit of 1 year of treatment compared with observation alone

Introduction The HERceptin Adjuvant (HERA) trial The HERceptin Adjuvant (HERA) trial Included randomisation of patients to 2 years of trastuzumab to allow comparison of two different durations of treatment Included randomisation of patients to 2 years of trastuzumab to allow comparison of two different durations of treatment Aim of study Aim of study Comparison of 2 years versus 1 year of adjuvant trastuzumab Comparison of 2 years versus 1 year of adjuvant trastuzumab Comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years Comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years

RESEARCH DESIGN AND METHODS Between Dec 7, 2001, and June 20, 2005, a total of 5102 patients were randomly allocated to three groups Between Dec 7, 2001, and June 20, 2005, a total of 5102 patients were randomly allocated to three groups Observation Observation trastuzumab for 1 year trastuzumab for 1 year trastuzumab for 2 years trastuzumab for 2 years All patients included had locally assessed HER2-positive early-stage invasive breast cancer All patients included had locally assessed HER2-positive early-stage invasive breast cancer Left ventricular ejection fraction (LVEF) Left ventricular ejection fraction (LVEF) 55% or higher after completion of chemotherapy with or without radiotherapy 55% or higher after completion of chemotherapy with or without radiotherapy

RESEARCH DESIGN AND METHODS The comparison of 2 years versus 1 year of trastuzumab 12- month landmark analysis of the 3105 women The comparison of 2 years versus 1 year of trastuzumab 12- month landmark analysis of the 3105 women Remained alive and disease-free for at least 12 months (366 days) after randomisation to one of the two trastuzumab treatment groups Remained alive and disease-free for at least 12 months (366 days) after randomisation to one of the two trastuzumab treatment groups initial dose of 8 mg/kg, followed by a maintenance dose of 6 mg/kg every 3 weeks for 1 year or 2 years. initial dose of 8 mg/kg, followed by a maintenance dose of 6 mg/kg every 3 weeks for 1 year or 2 years.

RESEARCH DESIGN AND METHODS Cardiac monitoring Cardiac monitoring Clinical assessments and measurements of LVEF Clinical assessments and measurements of LVEF A primary cardiac endpoints A primary cardiac endpoints Defined as New York Heart Association (NYHA) class III or IV Defined as New York Heart Association (NYHA) class III or IV Significant LVEF drop of at least 10 percentage points from baseline Significant LVEF drop of at least 10 percentage points from baseline Absolute LVEF below 50%, or cardiac death Absolute LVEF below 50%, or cardiac death A secondary cardiac endpoint A secondary cardiac endpoint Asymptomatic (NYHA class I) or mildly symptomatic (NYHA class II) with a significant LVEF drop of at least 10 percentage points below baseline and to an absolute LVEF below 50%, confirmed by repeat assessment Asymptomatic (NYHA class I) or mildly symptomatic (NYHA class II) with a significant LVEF drop of at least 10 percentage points below baseline and to an absolute LVEF below 50%, confirmed by repeat assessment

RESEARCH DESIGN AND METHODS The primary endpoint The primary endpoint Disease-free survival Disease-free survival the 12-month landmark the 12-month landmark Secondary endpoints Secondary endpoints Overall survival Overall survival Sites of first relapse Sites of first relapse Adverse events (particularly cardiac safety) Adverse events (particularly cardiac safety)

Statistical analysis A log-rank test p value of or less was required for statistical significance in this final analysis A log-rank test p value of or less was required for statistical significance in this final analysis χ2 tests χ2 tests Kaplan-Meier curves Kaplan-Meier curves The Cox proportional hazards model The Cox proportional hazards model

Result

Discussion Patients with HER2-positive early breast cancer given adjuvant trastuzumab have shown substantial improvements in disease-free and overall survival outcomes compared with those given no trastuzumab Patients with HER2-positive early breast cancer given adjuvant trastuzumab have shown substantial improvements in disease-free and overall survival outcomes compared with those given no trastuzumab The HERA trial tested the hypothesis that continuation of trastuzumab treatment beyond 1 year would be superior to 1 year of such treatment The HERA trial tested the hypothesis that continuation of trastuzumab treatment beyond 1 year would be superior to 1 year of such treatment No additional benefit, and a small but real increase in adverse events, leading to an unfavourable benefit–risk ratio for 2 years of adjuvant trastuzumab No additional benefit, and a small but real increase in adverse events, leading to an unfavourable benefit–risk ratio for 2 years of adjuvant trastuzumab

Discussion The FinHER investigators The FinHER investigators Benefit in terms of disease-free survival from 9 weeks of trastuzumab treatment compared with no trastuzumab Benefit in terms of disease-free survival from 9 weeks of trastuzumab treatment compared with no trastuzumab PHARE investigators PHARE investigators A direct randomised comparison of 6 versus 12 months of trastuzumab A direct randomised comparison of 6 versus 12 months of trastuzumab 6 months of trastuzumab is non-inferior to 12 months 6 months of trastuzumab is non-inferior to 12 months PERSEPHONE trial PERSEPHONE trial

Discussion Trastuzumab treatment is associated with an increased risk of cardiac toxicity Trastuzumab treatment is associated with an increased risk of cardiac toxicity the incidence of cardiac toxicity was low, particularly in comparison with the recently reported population based cohort study the incidence of cardiac toxicity was low, particularly in comparison with the recently reported population based cohort study

Conclusions Our results showed an unfavourable benefit–risk ratio for 2 years of trastuzumab therapy, and thus support the continuation of the 1 year standard duration of treatment. Our results showed an unfavourable benefit–risk ratio for 2 years of trastuzumab therapy, and thus support the continuation of the 1 year standard duration of treatment.