Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives

Abstract

Amplification and/or overexpression of ERBB2, the gene encoding HER2, can be found in 15-20% of invasive breast cancers and is associated with an aggressive phenotype and poor clinical outcomes. Relentless research efforts in molecular biology and drug development have led to the implementation of several HER2-targeted therapies, including monoclonal antibodies, tyrosine-kinase inhibitors and antibody-drug conjugates, constituting one of the best examples of bench-to-bedside translation in oncology. Each individual drug class has improved patient outcomes and, importantly, the combinatorial and sequential use of different HER2-targeted therapies has increased cure rates in the early stage disease setting and substantially prolonged survival for patients with advanced-stage disease. In this Review, we describe key steps in the development of the modern paradigm for the treatment of HER2-positive advanced-stage breast cancer, including selecting and sequencing new-generation HER2-targeted therapies, and summarize efficacy and safety outcomes from pivotal studies. We then outline the factors that are currently known to be related to resistance to HER2-targeted therapies, such as HER2 intratumoural heterogeneity, activation of alternative signalling pathways and immune escape mechanisms, as well as potential strategies that might be used in the future to overcome this resistance and further improve patient outcomes.

Fig. 1:. Timeline of the evolution of HER2 as biomarker in breast cancer and approval of therapeutic agents for HER2+ metastatic breast cancer.

Abbreviations: ADC, antibody-drug conjugate; mAb, monoclonal antibody; TKI, tyrosine kinase inhibitor. * FDA approval for HER2+ advanced breast cancer; ** FDA approval for HER2-low advanced breast cancer; *** pyrotinib is currently approved in China only.

Fig. 2:. Treatment algorithm for patients with advanced/metastatic HER2+ breast cancer.

^a For patients with disease-free interval 6–12 months who did not receive pertuzumab in the early setting, consider THP as first-line regimen. ^b Paclitaxel or nab-paclitaxel can be used to replace docetaxel as chemotherapy backbone. The use of vinorelbine instead of taxanes can be considered in selected cases where the administration of taxanes is deemed to be not safe. ^c Consider adding local intervention (radiotherapy or surgery) depending on brain metastases characteristics. ^d No data after tucatinib- and T-DXd-based regimens. * Bilateral arrows indicate that T-DXd and tucatinib-capecitabine-trastuzumab can be used interchangeably in patients with active brain metastases after progression to first-line therapy. Abbreviations: BM, brain metastases; ER, estrogen receptor; ET, endocrine therapy; MBC, metastatic breast cancer; THP, trastuzumab-pertuzumab-taxane.

Fig. 3:

Incidence of selected treatment-related adverse events of clinical interest in clinical trials testing anti-HER2 therapies in HER2-positive breast cancer.

Fig. 4:

Heterodimerization of HER family members and downstream intracellular pathways that can mediate resistance to anti-HER2 therapy.