The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer--a systematic review

Abstract

Introduction: This study aimed at evaluating the overall survival (OS) gain associated with human epidermal growth factor receptor 2 (HER2)-directed therapies in patients with metastatic breast cancer (mBC).

Methods: A bibliographic search was conducted in PubMed and Cochrane databases. Only phase III randomized controlled trials (RCTs) including HER2-positive (HER2+) mBC patients were included in this review. OS was defined as time from randomization until the occurrence of death from any cause. Studies have been grouped according to the line of treatment, i.e., first-line or second-line or beyond.

Results: Nineteen RCTs were eligible for inclusion, of which 12 assessed therapies targeting HER2+ mBC in the first-line setting. OS improved from 20.3 months in the first RCT (standard chemotherapy; Slamon et al. (N Engl J Med 344:783-92, 2001)) evaluating HER2-targeting therapies to 48 months in the study of Swain et al. (Lancet Oncol 14:461-71, 2013), with triple combination of pertuzumab, trastuzumab and docetaxel. Seven RCTs evaluated the OS of HER2-targeting therapies in the second-line setting and beyond. The OS in second-line setting improved from 15.3 months (capecitabine; Cameron et al. (Breast Cancer Res Treat 112:533-43, 2008)) to 30.7 months (trastuzumab emtansine; Verma et al. (N Engl J Med 367:1783-91, 2012)). In the third-line setting, the association of lapatinib and trastuzumab has demonstrated to improve OS to 4.5 months compared with lapatinib alone (14 months vs. 9.5 months; Blackwell et al. (J Clin Oncol 30:2585-92, 2012)).

Conclusions: HER2-directed therapies had an undeniable beneficial impact on the OS of patients with HER2+ mBC. The triple combination of docetaxel, pertuzumab and trastuzumab is associated with a survival extent of more than 4.5 years, compared with a life expectancy of 1.5 years achieved 14 years ago.

Fig. 1

Flow of the search strategy. HER2+ human epidermal growth factor receptor 2 positive, mBC metastatic breast cancer, RCTs randomized controlled trials

Fig. 2

Overall survival (blue) and progression-free survival (red) of patients diagnosed with metastatic breast cancer receiving first-line treatment, according to the most effective treatment in each study. Results are displayed from the study with lower OS to the study with higher OS. Results from the study by Inoue et al. [16], Gelmon et al. [31], and Hurwitz et al. [32] are not displayed because OS results were not provided. OS overall survival, PFS progression-free survival

Fig. 3

Overall survival (blue) and progression-free survival (red) of patients diagnosed with metastatic breast cancer receiving second-line treatment, according to the most effective treatment in each study. Results are displayed from the study with lower OS to the study with higher OS. Results from TH3RESA and BOLERO-3 are not displayed because OS results were not provided. GBG 26/BIG 03–05, German Breast Group 26/Breast International Group 03–05 study. OS overall survival, PFS progression-free survival