Current and Future Management of HER2-Positive Metastatic Breast Cancer

Olga Martínez-Sáez, MD; Aleix Prat, MD


J Oncol Pract. 2021;17(10):594-604. 

In This Article

Abstract and Introduction


Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 20% of breast cancers, conferring an aggressive tumor behavior but also an opportunity for targeted therapies. In the advanced setting, the prognosis of patients suffering from this disease has greatly improved after the introduction of new anti-HER2 drugs beyond trastuzumab. For most patients, a taxane combined with trastuzumab and pertuzumab in the first-line setting, followed by trastuzumab-emtansine in second line, should be considered the standard of care today. However, chemo-free anti-HER2 strategies in hormone receptor-positive, HER2-positive breast cancer could also be considered in selected patients. In the third-line setting and beyond, several emerging anti-HER2 therapies are becoming available, including tucatinib, fam-trastuzumab deruxtecan-nxki (DS-8201a), neratinib, and margetuximab-cmkb. In addition, new compounds and combinations are showing promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, active drugs such as pertuzumab and trastuzumab-emtansine are moving to early-stage, many biomarkers, including quantification of HER2 itself, are being explored to improve patient selection, and patient populations with specific needs are emerging, such as those with brain metastasis. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer.


Advanced breast cancer with overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) is a clinically aggressive subtype with poor survival outcomes.[1,2] However, with the introduction of trastuzumab, the survival rates have greatly improved.[1] Trastuzumab binds to the extracellular domain IV of HER2 preventing its activation.[3] In addition, other mechanisms have been proposed to explain its efficacy such as blocking various intracellular signaling pathways, increasing HER2 degradation, and activating an immune response through antibody-dependent cellular cytotoxicity.[4] Trastuzumab monotherapy has low efficacy but the addition of chemotherapy is synergistic and thus trastuzumab is generally combined with chemotherapy-based approaches.[1,5] Beyond trastuzumab, the incorporation of other anti-HER2 drugs in daily clinical practice, such as pertuzumab, trastuzumab-emtansine (T-DM1), and lapatinib, has achieved median overall survival (OS) of approximately 5 years, and a substantial proportion of patients (approximately 30%-40%) are alive at 8 years.[6]

Despite major improvements, many challenges lie ahead. For instance, the optimal sequence of available HER2-targeted therapies is currently unknown and will depend on previously administered therapies in the adjuvant setting, patient's relapse-free interval, benefit obtained from previous therapies in the advanced setting, amount of tumor burden, patients' preferences and quality of life, as well as drug availability and cost in each country. Finally, predictive biomarkers for the management of HER2-positive advanced breast cancer will be needed. This review analyzes the current and future standard of care for patients with HER2-positive advanced breast cancer and discusses the clinical and research gaps that exist.