HER2-Positive Breast Cancer

Sara Hurvitz, Kelly McCann

• Publisher: Elsevier
• Year: 2018
• ISBN:
  9780323581233
• Topic: Medizin
• Subtopic: Onkologie

Get a quick, expert overview of clinically-focused topics and guidelines that are relevant to testing for HER2, which contributes to approximately 25% of breast cancers today. This concise resource by Drs. Sara Hurvitz, and Kelly McCann consolidates today's available information on this growing topic into one convenient resource, making it an ideal, easy-to-digest reference for practicing and trainee oncologists.

Section II

Advanced Disease

Outline

Chapter 3. Optimal First-Line Treatment of Advanced HER2-Positive Breast Cancer

Chapter 4. HER2-Positive Breast Cancer: Second Line and Beyond

Chapter 5. Central Nervous System Metastases in HER2-Positive Breast Cancer

Chapter 6. Neoadjuvant Treatment of HER2- Positive Breast Cancer–A Review

Chapter 7. Adjuvant Therapy

Chapter 8. Hormone Receptor and Human Epidermal Growth Factor Receptor 2 Co-expressing Tumors: Overview of Clinical Practical Implications and Treatment Strategies

Chapter 9. Deescalating Treatment in the Adjuvant Setting in Low-Risk HER2-Positive Breast Cancer

Chapter 3

Optimal First-Line Treatment of Advanced HER2-Positive Breast Cancer

Ruta Rao, MD, and Melody Cobleigh, MD

Abstract

Approximately 20% of breast cancers have overexpression of the HER2 protein and/or amplification of the HER2 gene and are associated with aggressive tumor behavior and poor disease-free survival and overall survival (OS) rates. Treatment options and outcomes for this disease have been revolutionized with the introduction of targeted HER2 therapies. The pivotal trial showed that the addition of trastuzumab, a monoclonal antibody against HER2, to chemotherapy significantly improved progression-free survival (PFS) and OS compared with chemotherapy alone as first-line therapy for metastatic disease [2]. In the CLEOPATRA trial, the addition of pertuzumab, another monoclonal antibody, to trastuzumab and docetaxel significantly improved the PFS and OS, with a median OS of 56.5 months [19,20]. This combination of dual antibodies and a taxane is considered standard first-line therapy for HER2-positive, advanced breast cancer. Ongoing clinical trials are evaluating novel compounds to further improve upon these results.

Keywords

Lapatinib; Neratinib; Pertuzumab; Trastuzumab; Trastuzumab emtansine

Introduction

Approximately, 20% of breast cancers have overexpression of the HER2 protein and/or amplification of the HER2 gene, which has been associated with aggressive tumor behavior and poor disease-free survival (DFS) and overall survival (OS) rates. A seminal study by Slamon and colleagues published in 1987¹ reported on 189 primary human breast cancers, 30% of which had HER2 gene amplification. HER2 gene amplification was a significant predictor of decreased time to relapse and decreased OS. A number of subsequent studies confirmed the correlation of HER2 status with disease outcomes.

Treatment options and outcomes for this disease have been revolutionized with the introduction of HER2-targeted therapies, including monoclonal antibodies against HER2, tyrosine kinase inhibitors, and antibody-drug conjugates (ADCs). These therapies have improved the prognosis of women with HER2-positive (HER2+) metastatic disease in terms of progression-free survival (PFS) and OS. The subsequent use of these targeted therapies in the early-stage setting has led to significant improvements in DFS and OS for these patients. In this chapter, we will outline the options for first-line treatment of metastatic HER2+ breast cancer.

Trastuzumab

Trastuzumab is a recombinant monoclonal antibody directed against subdomain IV of the extracellular portion of the HER2 receptor. Trastuzumab affects the HER2 receptor in a number of ways; but its major mechanism of action is thought to be antibody-dependent cellular cytotoxicity (ADCC). It can also trigger HER2 receptor internalization and degradation. Finally, trastuzumab interferes with dimerization of the HER2 receptor, which is required for activation. By doing so, it leads to inhibition of the downstream MAPK (mitogen-activated protein kinase) and PI3K (phosphatidylinositol 3-kinase)/AKT (a serine/threonine kinase also known as protein kinase B) pathways, culminating in suppression of cell growth, proliferation, differentiation, motility, and survival.

The Addition of Trastuzumab to Chemotherapy

Before targeted therapies, chemotherapy was the mainstay of treatment for HER2+ metastatic breast cancer (MBC). A pivotal trial published by Slamon et al. in the New England Journal of Medicine in 2001 showed that treatment with trastuzumab, in addition to chemotherapy, significantly improved PFS and OS when compared with chemotherapy alone.² This trial enrolled women who had breast cancers that overexpressed HER2, defined as 2+ or 3+ on immunohistochemistry (IHC), and had received no prior chemotherapy for metastatic disease. They were randomized to receive chemotherapy alone or chemotherapy plus trastuzumab (Fig. 3.1). Chemotherapy consisted of either an anthracycline (doxorubicin 60 mg/m² or epirubicin 75 mg/m²) and cyclophosphamide (600 mg/m²) or paclitaxel (175 mg/m²) if they had previously received anthracycline in the adjuvant setting. They were treated every 3 weeks for six cycles with additional cycles given at the investigator's discretion. Trastuzumab was given at a loading dose of 4 mg/kg followed by a dose of 2 mg/kg weekly until disease progression. The primary endpoints of the study were time to disease progression and the incidence of adverse events. Secondary endpoints were response rate (RR), duration of response, time to treatment failure, and OS. The study enrolled 469 patients and was published with a median follow-up of 30 months. The median time to tumor progression (TTP) was improved for the patients receiving chemotherapy and trastuzumab versus those who received chemotherapy alone (7.4 months vs. 4.6 months; P < .001). This difference was seen in both the subgroup that received anthracycline a...