New anti-HER2 therapies have greatly improved clinical outcomes in HER2-positive breast cancer, but tumor resistance to HER2-directed therapies remains a significant problem that has spurred the development of a number of targeted therapies directed at non-HER2 pathways in this disease. Here we review major mechanisms of resistance to anti-HER2 therapies identified in the preclinical and clinical setting, as well as the preclinical and clinical status of the major categories of novel non–HER2-targeted therapies in clinical development. These include CDK4/6 inhibitors, PI3K/mTOR pathway inhibitors, antiangiogenic agents, inhibitors of bypass signaling through non-HER growth factors, including insulin-like growth factor 1 receptor, fibroblast growth factor receptor, and c-MET, and advances in immunotherapy, including checkpoint inhibitors and cancer vaccines.

HER2+ breast cancer is recognized to be immunogenic. Within the HER2+ breast cancer microenvironment the presence of tumor-infiltrating lymphocytes (TILs) is predictive of response to systemic therapies. Dissection of the TIL content has identified the immunologic components, such as CD8+ T cells, that are critical to such clinical responses. In addition, HER2+ breast cancers influence the local immune response with recent investigation revealing a progressive loss of HER2-specific Th1 immunity through each step of HER2 oncogenesis. Systemic therapies also influence the immune content of HER2+ breast cancers; examples include the partial restoration of HER2-specific immunity with trastuzumab and the suppression of regulatory T cells with cyclophosphamide. Therapeutic agents currently under investigation are seeking to build on these immune responses to standard therapies with the goal of maximizing HER2-specific and antitumor immunity that will improve the clinical outcomes of patients with HER2+ breast cancer.

Therapies for HER2-positive breast cancer have dramatically improved outcomes for this once dismal disease. Trastuzumab revolutionized the management of HER2-positive breast cancer and its discovery led to the development of other very effective HER2-targeted therapies. The optimal length of therapy as well as the sequential and concurrent use of trastuzumab with chemotherapy has been studied. The evidence shows one year in the adjuvant setting is the optimal length of treatment and the concurrent use of trastuzumab with chemotherapy (nonanthracycline) is the preferred regimen. Recently, studies with pertuzumab and neratinib have been reported and documented further improvements in outcomes for subsets of patients with HER2-positive breast cancer. Many patients remain disease free when treated with adjuvant chemotherapy plus trastuzumab for one year. Treatment is generally well tolerated with manageable toxicities. However, a sizeable minority of patients do develop recurrent disease and as such there is room for further improvement in outcomes. Herein we review the adjuvant management of HER2-positive breast cancer and ongoing studies that investigate novel therapies in this setting.

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.

The advent of anti-HER2 cancer therapies has heralded significantly improved survival rates along with decreased recurrence in breast cancer and is being increasingly used in other malignancies, including gastrointestinal tumors. However, a known effect that has been well documented is the onset of cardiomyopathy during treatment, which may potentially alter or delay critical treatment to these patients. This chapter reviews the proposed mechanisms of HER2-related cardiotoxicity, its incidence in major cancer trials and in the postapproval era—much of it related to trastuzumab—and proposed cardioprotective and surveillance strategies to potentially reduce the risk of developing cardiotoxicity.

On the basis of genomic profiling, breast cancer (BC) tumors with amplification or overexpression of human epidermal growth factor receptor 2 (HER2) are highly heterogeneous. Of note, hormone receptor (HR) can be co-expressed with HER2 in approximately half of HER2+ BC patients. Compared with the HR-negative cohort, this particular group has distinct response to conventional therapies based on a variety of chemotherapy and anti-HER2 combinations.

The human epidermal growth factor receptor type 2 (HER2) gene, also known as ERBB2, is amplified/overexpressed in approximately 20% of invasive breast carcinomas and serves as a target for therapeutic intervention. Although it defines a subtype of disease with significantly worse clinical outcomes, treatment of HER2-amplified disease with HER2-targeted therapies, in either the metastatic or adjuvant setting, is associated with significant improvements in both disease-free and overall survival. Therefore, the use of a companion diagnostic assay to identify “HER2-positive” from “HER2-negative” breast cancers is essential. Most companion diagnostic assays, approved by the US Food and Drug Administration (FDA), are either immunohistochemical (IHC) assays for the HER2 protein product or in situ hybridization (ISH) assays for the enumeration of HER2 gene copies in tumor cell nuclei at the DNA level. The FDA has defined interpretative criteria for each of the approved assays based on the data submitted during the approval process. In addition, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have convened panels which recommended standardization of tissue processing and defined criteria for interpretation of these assays. These recommendations, published in 2007, 2013/2014, and 2018, differ variably from the FDA-approved criteria, from one another, and recent published data, especially with regard to ISH. While some of the ASCO-CAP diagnostic criteria are based on published data, others have been based on the opinions of panel members. We summarize these issues and provide our perspectives based on currently available evidence and our experience.

HER2/neu was originally described as an oncogene in rat neuroblastomas in the early era of cancer molecular biology research. In late 1987, the initial description of this alteration in a subset of breast cancers along with the finding that women with HER2-amplified breast cancers had a poorer prognosis than those with a normal HER2 gene copy number was published. This observation led to the development of the initial therapeutic antibody, trastuzumab, that ultimately reversed the poor clinical outcome data for this subtype of the disease. The HER2 receptor belongs to the type 1 receptor tyrosine kinase family that includes epidermal growth factor receptors HER1, HER3, and HER4. This family of receptors form hetero- and homodimers in response to extracellular signals and mediate signaling for proliferation, differentiation, and survival pathways in various epithelia throughout the body. Unlike the other members of the family, HER2 rests in an open conformational state in the absence of ligand, making it the preferential binding partner for dimerization events. With identification of HER2 amplification in 20%–25% of breast cancers and the evidence that their poorer prognosis is due to a pathogenic role the alteration plays in generating this outcome, HER2 targeted agents trastuzumab, pertuzumab, ado-trastuzumab emtansine, and the tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib were developed. These therapeutics are based on our initial understanding of HER2, but their differing clinical efficacies and safety profiles have generated new concepts regarding their mechanisms of action (MOAs) and the patterns of resistance to the MOAs, ultimately contributing to additional insights about HER2 biology and its role in breast cancer.

Central nervous system (CNS) metastases are a common occurrence in patients with HER2-positive metastatic breast cancer and represent a difficult-to-treat complication. Prognosis depends on a number of clinical factors such as age, performance status, burden of systemic disease, and number of brain metastases, among others. Treatment options consist of surgical resection, stereotactic radiosurgery, whole-brain radiation therapy, chemotherapy, and targeted agents. With limited randomized, prospective data to guide treatment selection, the timing and appropriate use of treatment options require multidisciplinary collaboration. This chapter will describe current treatment options for patients with CNS metastases from HER2-positive breast cancer and discuss potential approaches and novel therapies in clinical development.