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.

Drug-adapted cancer cell lines as preclinical models of acquired resistance

“…Resistance can be "intrinsic" or "upfront", i.e., cancer cells do not respond to therapy from the outset. Many cancer diseases, however, initially respond well to therapy, but after a temporary response resistant cancer cells emerge leading to "acquired" resistance, ultimately resulting in therapy failure and patient death [8][9][10][11][12][13][14][15][16][17][18][19] . Hence, cancer diseases that have become resistant to the available treatment options represent an unmet clinical need.…”

The evolving role of receptors as predictive biomarkers for metastatic breast cancer

“…Other trials have shown that dual therapy with trastuzumab and a second anti-HER2 agent can lead to superior HER2 signalling blockage and better patient outcome in the neoadjuvant and advanced settings [70][71][72][73]. Research continues to study other anti-HER2 agents such as the pan-HER inhibitor neratinib or HER2-targeted drug delivery and immunotherapy [74].…”

“…Patients with HER2+ MBC can also benefit from targeted treatment, with median survival having more than doubled since the advent of anti-HER2 therapy [74]. The current treatment consensus includes the use of multiple lines of HER2-targeted therapy beyond progression, often using dual blockade with trastuzumab and pertuzumab combined with chemotherapy as first line therapy, followed by treatment with different anti-HER2 agents.…”

“…Patients have also been shown to derive benefit from combination of anti-HER2 drugs with endocrine therapy in ER+/HER2+ MBC cases [75,76,78]. Research continues to assess the potential of treatment strategies that combine anti-HER therapies with agents targeting other pathways and signalling components in the HER network, such as CDK4/6, PI3K and mTOR inhibitors [74,75,[103][104][105].…”

“…Despite the improvement in prognosis of patients with HER2+ breast cancer since the introduction of anti-HER2 therapy (see sections 2.2. and 3.1), challenges remain in the management of these tumours, particularly in the advanced setting where overall response rates are often relatively limited and the high rates of de novo and acquired resistance frequently lead to tumour progression. While researchers continue to investigate alternative anti-HER2 and combination therapies for first and second line treatment [74,76,104,204], there is also a need to identify additional predictors to help improve treatment selection [205]. Most of the research to date has described alterations in associated pathways and downstream effectors of HER2 [206].…”