How we treat patients with metastatic HER2-positive breast cancer

Abstract

HER2-positive breast cancer represents 15%-20% of breast malignancies and is characterized by an aggressive behavior and high recurrence rates. Anti-HER2-directed agents represent the mainstay of treatment of patients with HER2-positive metastatic breast cancer (MBC). In this review we propose a treatment algorithm for patients with HER2-positive MBC based on the currently available literature on the topic. The combination of trastuzumab, pertuzumab and a taxane (THP) remains the preferred first-line therapy in most scenarios. Results of trials recently presented at the European Society for Medical Oncology (ESMO) Congress 2021 might have direct clinical impact in the second- and later-line settings. The randomized DESTINY-BREAST03 study compared trastuzumab deruxtecan (T-DXd) with trastuzumab emtansine (T-DM1) in patients previously treated with trastuzumab and a taxane. T-DXd significantly improved progression-free survival and showed a trend towards improved overall survival, establishing this agent as preferred second-line therapy. Treatment with T-DM1, or the combination of tucatinib, trastuzumab and capecitabine, are considered reasonable options after second-line therapy. For subsequent lines, trastuzumab duocarmazine, neratinib plus capecitabine or the continuation of trastuzumab with different chemotherapy partners are valid options. For patients experiencing disease relapse up to 6 months after completion of adjuvant therapy, as well as for those relapsing within 12 months from the completion of pertuzumab-based adjuvant treatment, we recommend T-DXd as preferred first-line option. For those relapsing between 6 and 12 months after non-pertuzumab-based adjuvant treatment, we recommend first-line THP. Finally, for patients with active brain metastasis, tucatinib-based combination represents a suitable second-line option.

Comparative Efficacy of Tyrosine Kinase Inhibitors and Antibody–Drug Conjugates in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A Systematic Review and Network Meta-Analysis

“…Particularly, the HER2CLIMB trial also included patients with active (progressive and/or untreated) BCBM [ 27 ]. In view of the gratifying outcomes, neratinib plus capecitabine and the tucatinib–trastuzumab–capecitabine triplet are recommended for the later-line treatment for HER2-positive BC in metastatic setting, especially for patients with CNS disease [ 53 ]. In this NMA, we focused on the BCBM subgroup of the original studies.…”

Systemic Treatments for Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Old Certainties and New Frontiers

“…Based on these premises, the most updated international guidelines recommend the dual blockade with trastuzumab – pertuzumab plus docetaxel as the first-line standard in treatment-naïve HER2-positive BC patients with metastatic disease, regardless of hormone receptor status. 14 , 15 Docetaxel should be given for at least 6 cycles, if tolerated, followed by maintenance trastuzumab and pertuzumab until disease progression; after completing at least 6 cycles of upfront concomitant chemotherapy, endocrine treatment may be added to trastuzumab and pertuzumab maintenance therapy for patients with HER2-positive, hormone-receptor positive tumors. 14 , 15 In case of significant comorbidities, advanced age, and/or poor performance status in BC patients with hormone-receptor positive disease, endocrine treatment combined with a HER2-targeted therapy may be used.…”

“… 14 , 15 Docetaxel should be given for at least 6 cycles, if tolerated, followed by maintenance trastuzumab and pertuzumab until disease progression; after completing at least 6 cycles of upfront concomitant chemotherapy, endocrine treatment may be added to trastuzumab and pertuzumab maintenance therapy for patients with HER2-positive, hormone-receptor positive tumors. 14 , 15 In case of significant comorbidities, advanced age, and/or poor performance status in BC patients with hormone-receptor positive disease, endocrine treatment combined with a HER2-targeted therapy may be used. Lastly, the use of single-agent endocrine therapy without an anti-HER2 agent is not routinely recommended unless cardiac disease could preclude the safe use of HER2-directed treatments.…”

Endocrine resistant breast cancer: brain metastasis

“…HER2+ BCBM may be endocrine resistant and consequently immune to therapies that target hormone receptor-positive breast cancer, such as tamoxifen and fulvestrant. One first-line treatment for HER2+ BCBM is taxane, trastuzumab, and pertuzumab [ 60 , 61 ]. Trials have indicated that while the monoclonal antibody pertuzumab may have a low blood-brain barrier (BBB) permeability, the concentration in the central nervous system (CNS) is enough to produce a significant therapeutic effect [ 61 , 62 ].…”

“…One first-line treatment for HER2+ BCBM is taxane, trastuzumab, and pertuzumab [ 60 , 61 ]. Trials have indicated that while the monoclonal antibody pertuzumab may have a low blood-brain barrier (BBB) permeability, the concentration in the central nervous system (CNS) is enough to produce a significant therapeutic effect [ 61 , 62 ].…”