Current Therapies for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Patients

Abstract

The median survival of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) has more than doubled, since the discovery of HER2-targeted treatments: it rose from less than 2 years in 2001 (prior introduction of trastuzumab) to more than 4 years in 2017. The initial generation of HER2-targeted therapies included trastuzumab with taxanes in the first line, followed by the addition of lapatinib and by a switch to another cytotoxic agent after progression. Results of CLEOPATRA, EMILIA, and TH3RESA trials have changed this clinical practice. The current consensus includes horizontal dual blockade (trastuzumab + pertuzumab) with taxanes or vinorelbine in the first line, followed by trastuzumab-emtansine (T-DM1) in the second line, with addition of lapatinib in the later lines of treatment. However, the fast and simultaneous development of new drugs led to a relative shortage of clinical evidence to support this sequence. Triple-positive breast cancers (TPBC), which express both hormonal receptors and HER2, constitute nearly half of HER2-positive cases. For these tumors, the current consensus is to add endocrine therapy after completion of cytotoxic treatment. Again, this consensus is not fully evidence-based. In view of the recent progress in treatment of estrogen-receptor positive breast cancers, a series of trials is evaluating addition of CDK4/6 inhibitors, aromatase inhibitors or fulvestrant to HER2-targeted and cytotoxic chemotherapy in TPBC patients. Despite the remarkable progress in treatment of HER2-positive breast cancer, metastatic disease is still incurable in the majority of patients. A wide range of novel therapies are under development to prevent and overcome resistance to current HER2-targeted agents. This review discusses pivotal clinical trials that have shaped current clinical practices, the current consensus recommendations, and the new experimental treatments in metastatic HER2-positive breast cancer.

Keywords: HER2; lapatinib; metastatic breast cancer; pertuzumab; therapies; trastuzumab; trastuzumab-emtansine; triple-positive breast cancer.

Figure 1

Human epidermal growth factor receptor 2 (HER2) signaling. (A) HER2 hetero-dimerization and HER2 targeting. (B) Signaling downstream of HER2 and its targeting.

Figure 2

Selected trials supporting current practices in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Abbreviations: T, trastuzumab; P, pertuzumab; L, lapatinib; Tx, taxanes; Cp, capecitabine; Ac, anthracyclines; Ph Ch, physician choice. (a) Difference between arms is not significant. (b) In the sequential arm Tx is added after progression on T alone. Median progression-free survival (PFS) is shown for T alone phase only. (c) Median overall survival (OS) is in favor of T + Tx, median OS not reached. (d) OS not reported. (e) After 3 T-containing lines on average. (f) After at least 2 metastatic lines. Median PFS and OS are indicated in months.

Figure 3

Triple positive breast cancer trials. Abbreviations: T, trastuzumab; P, pertuzumab; L, lapatinib; AI, aromatase inhibitor. (a) Mixed first line and later lines; median progression-free survival (PFS) and median overall survival (OS) for patients with centrally confirmed estrogen receptor. (b) OS trend not significant. (c) OS not reported. Median PFS and OS are indicated in months.