Human epidermal growth factor receptor 2 (HER2)/neu-positive breast cancer has changed from being an aggressive disease with a poor prognosis to a disease that is highly treatable, with prolonged survival possible even in patients with metastatic disease. A better understanding of HER2 biology has led to the development of powerful targeted therapies, and four drugs are already approved by the US Food and Drug Administration for treatment in the metastatic setting (trastuzumab, pertuzumab, lapatinib, and trastuzumab emtansine). Optimizing how these drugs are delivered and in what sequence is an important part of modern management of HER2-positive breast cancer. However, while the prognosis has improved, metastatic disease is still not curable; newer, better drugs are needed. This review will summarize the current standard of care; key issues that arise when treating patients with HER2-positive disease; and developments in novel therapeutics, including small-molecule inhibitors, nanoparticles, immunotherapy, and agents targeting resistance pathways.
Invasive breast cancer is the most frequently diagnosed non- dermatologic cancer in women, with an estimated 234,190 new cases diagnosed in 2015. While disease confined to the breast and local lymph nodes is curable, this is no longer the case when it becomes metastatic, and there were approximately 40,730 breast cancer deaths in 2015. Breast cancer is a heterogeneous disease; while many molecular subtypes have been identified, clinically the disease is categorized according to receptor status. Approximately 20% of breast cancer tumors overexpress human epidermal growth factor receptor 2 (HER2 [ErbB2]), which is associated with a more aggressive clinical phenotype and historically portends poor prognosis. However, the advent of trastuzumab, an immunoglobulin G monoclonal antibody directed against HER2, has changed the treatment paradigm of this disease. There have been great advancements in HER2-targeting therapies since the development of trastuzumab, and the US Food and Drug Administration (FDA) has already approved three additional agents in the metastatic setting—pertuzumab, lapatinib, and trastuzumab emtansine (T-DM1) (Figure 1), converting HER2-positive breast cancer into a highly treatable disease, with extended survival in some patients. The complexity of disease management has likewise increased. Important questions that need to be addressed include the optimal sequence of anti-HER2 agents, how to incorporate anti-HER2 therapies in later-line settings, the appropriateness of combining anti-HER2 agents with endocrine therapy, and how to achieve lower-grade toxicity over a long-term treatment period. Furthermore, despite advances in the management of metastatic HER2-positive breast cancer, the response rate in the first-line setting ranges from 50% to 80%, and from only 20% to 40% in the second-line setting, with most patients eventually succumbing to their disease.[4-8] To improve upon the existing novel therapeutics and to develop new ones requires a better understanding of the intrinsic biology of HER2-positive disease and its interaction with extrinsic biological systems, including the immune system.
HER2 status is the most powerful predictive biomarker with which to determine the effectiveness of anti-HER2 therapy. The primary means of patient assessment is through immunohistochemistry to detect HER2 protein expression on cancer cell membranes. While a score of 0 or 1 is negative and a score of 3 is positive, a score of 2 is considered equivocal and indicates the need for further testing. Fluorescent in situ hybridization (FISH) to assess HER2 gene amplification is the preferred testing method. Typically FISH is used to compare the HER2 gene copy number to the copy number of the chromosome 17 centromere (the HER2/CEP17 ratio) in a sample of the patient’s tumor tissue. Based on a joint update by the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) in 2014, a ratio of 2.0 or greater is considered positive. If the score is below 2.0, the actual HER2 copy number should be assessed. A HER2 copy number of 6 or greater is considered positive, and a copy number less than 4 is considered negative. HER2 copy numbers between 4 and 6 are considered equivocal, in which case further testing should be performed.
Targeting HER2 and HER3
The addition of trastuzumab to chemotherapy increases response rates, progression-free survival (PFS), and overall survival (OS) in patients with HER2-positive metastatic breast cancer, and the regimen of a taxane in combination with trastuzumab was historically considered standard-of-care first-line therapy. However, preclinical studies demonstrated that blockade of both HER2 and human epidermal growth factor receptor 3 (HER3 [ErbB3]) could have synergistic antitumor effects, and pertuzumab, a monoclonal antibody targeting both HER2 and HER3, was developed. Early data on pertuzumab informed the design of the CLEOPATRA trial, in which patients treated with docetaxel, trastuzumab, and pertuzumab (THP) had a median PFS duration of 18.5 months; in comparison, patients randomized to placebo, docetaxel, and trastuzumab (TH), a previous standard of care for first-line therapy, had a median PFS of 12.4 months. The hazard ratio (HR) was 0.62 (95% CI, 0.51–0.75; P < .001). More striking is the OS benefit, which was presented at the European Society for Medical Oncology (ESMO) 2014 Congress: The median OS with TH was 40.8 months, compared with 56.5 months in the THP arm.[7,12] Based on these data, THP is considered the current standard of care for first-line treatment of HER2-positive metastatic breast cancer (Figure 2), as per the National Comprehensive Cancer Network (NCCN) guidelines. As outlined in the CLEOPATRA study design, the taxane portion of treatment should be continued for up to 8 cycles, followed by maintenance trastuzumab and pertuzumab until progression.
Trastuzumab may also be used in later-line therapies, in combination with chemotherapy. Multiple agents have been studied in combination with trastuzumab in second-line and subsequent-line settings. Although continuation of trastuzumab has not been demonstrated to improve OS prospectively, several studies have demonstrated PFS improvements with its use. As a result, and since it does not add significant additional toxicity, it is commonly employed in regimens for patients with HER2-positive disease.[14,15] Regarding pertuzumab, there are no data suggesting that continuation of pertuzumab beyond disease progression provides any benefit.
Second-Line Therapy With Antibody-Drug Conjugates
As previously noted, T-DM1 is an antibody-drug conjugate of emtansine linked to trastuzumab. Emtansine is a derivative of maytansine, which was initially evaluated in phase I studies in the 1970s and found to be too toxic for systemic administration. The development of a linker molecule that attaches emtansine to trastuzumab, however, provides targeted delivery of this drug to HER2-positive tumor cells. The HER2–T-DM1 complex undergoes endocytosis and degradation of the linker, ensuring maximal cytotoxic delivery to the tumor cells while limiting systemic toxicity. The EMILIA study investigated the efficacy of T-DM1 in metastatic HER2-positive breast cancer, comparing T-DM1 with capecitabine and lapatinib in patients previously treated with trastuzumab and a taxane therapy. T-DM1 demonstrated a median 3.2-month PFS benefit (HR, 0.65 [95% CI, 0.55–0.77]; P < .001) and a median 5.8-month OS benefit (HR, 0.68 [95% CI, 0.55–0.85]; P < .001) compared with capecitabine plus lapatinib. This study led to FDA approval of T-DM1 in the second-line setting. T-DM1 was better tolerated than lapatinib, with the most commonly reported grade 3 or 4 adverse events in the T-DM1 group including thrombocytopenia (12.9%) and elevated serum concentrations of both aspartate aminotransferase (4.3%) and alanine aminotransferase (2.9%). While the rate of serious toxicity is low, it should be noted that lower-grade toxicities, including fatigue, nausea, diarrhea, and neuropathy, may occur and can potentially affect quality of life.
Based on this initial success, T-DM1 has also been investigated in the first-line setting. A phase II study comparing T-DM1 vs TH in HER2-positive metastatic breast cancer demonstrated an improved PFS with T-DM1 (14.2 vs 9.2 months, respectively; HR, 0.59 [95% CI, 0.36–0.97]; P = .035), as well as better treatment tolerability with fewer adverse events. These data provided the background for MARIANNE, a phase III randomized controlled trial comparing trastuzumab plus a taxane (docetaxel or paclitaxel) vs treatment with T-DM1 alone or T-DM1 plus pertuzumab. T-DM1 was not compared with the standard of care, THP, in either of these trials. Data from MARIANNE were presented at the 2015 ASCO Annual Meeting; it was demonstrated that treatment arms containing T-DM1 (alone or in combination with pertuzumab) in the first-line setting yielded a non-inferior PFS outcome compared with trastuzumab administered in combination with a taxane. Furthermore, the addition of pertuzumab to T-DM1 did not improve PFS compared with T-DM1 alone. However, T-DM1 was associated with improved health-related quality-of-life measures and fewer high-grade adverse events. Based on these findings, it is reasonable to consider T-DM1 as an alternative in the first-line setting for select patients who are unable to tolerate taxane therapy or who have had rapid disease progression following adjuvant therapy with trastuzumab; otherwise, THP remains the preferred first-line regimen for patients with HER2-positive metastatic breast cancer, as discussed in the current NCCN guidelines.
Small-Molecule Inhibitors and Toxicity
After patients have experienced disease progression on pertuzumab-based therapy and T-DM1, treatment options include trastuzumab with another chemotherapy agent as previously discussed, or with the combination of capecitabine and lapatinib.[5,15] Lapatinib is a small-molecule tyrosine kinase inhibitor (TKI) that reversibly binds to, and inhibits, the intracellular domain of HER2; it was the second anti-HER2 agent approved for management of HER2-positive metastatic breast cancer. A phase III study comparing lapatinib plus capecitabine vs capecitabine alone demonstrated an improvement in time to progression (TTP) with the combination (HR, 0.49 [95% CI, 0.34–0.71]; P < .001), but an OS benefit was not demonstrated (HR, 0.92 [95% CI, 0.58–1.46]; P = .72). As with many other TKIs, off-target toxicity accounted for systemic toxicity, in particular diarrhea (60% any grade) and rash (27% any grade). While high-grade toxicities are less common with TKIs, lower-grade toxicities associated with their use can affect quality of life and long-term tolerability, thus limiting their clinical utility. Until the approval of T-DM1, the combination of lapatinib and capecitabine was the recommended second-line therapy; however, it is now preferable to reserve this combination for later-line treatment (Figure 2).
Moving Away From Chemotherapy: Purely Targeted Approaches
Regimens optimizing survival still require chemotherapy (such as THP); however, for patients who are unable to tolerate chemotherapy or simply wish to avoid it, purely targeted regimens can be considered. As previously discussed, the MARIANNE study provides the rationale for considering T-DM1 in the first-line setting in patients who cannot be treated with standard chemotherapy. In addition, other approaches have been investigated with only targeted therapy, such as the combination of lapatinib with trastuzumab. In patients who progressed on one or more trastuzumab-containing regimens, the combination of lapatinib and trastuzumab yielded improved PFS (from 8 weeks to 11 weeks with the combination; HR, 0.74 [95% CI, 0.58–0.94]; P = .011) and OS (from 10 months to 14 months; HR, 0.74 [95% CI, 0.57–0.97]; P = .026) compared with lapatinib alone, suggesting some clinical benefit. The Translational Breast Cancer Research Consortium (TBCRC) 003 study demonstrated that earlier use of these two agents in combination, such as in patients who have not received trastuzumab in the metastatic setting, has clinical activity, with an associated median PFS of 7.4 months. Nevertheless, in patients previously treated with trastuzumab, PFS decreased to 5.3 months. These studies do not show the robust PFS benefit seen with THP in the CLEOPATRA study (PFS, 18.5 months), or T-DM1 in the MARIANNE trial (PFS, 14.2 months), but combination therapy with lapatinib and trastuzumab could be considered for select patients if there are contraindications to the administration of THP or T-DM1.[6,19]
Certain patients may harbor breast cancers expressing both hormone receptors and HER2 receptors, allowing the opportunity for treatment with targeted therapies directed toward both signaling pathways. A small phase II study to investigate HER2-directed therapy and endocrine therapy in postmenopausal women with both HER2-positive and estrogen receptor (ER)-positive metastatic breast cancer found a trend toward increased TTP when trastuzumab was added to letrozole (TTP was 3.3 months with letrozole alone vs 14.1 months with letrozole plus trastuzumab), but this was not statistically significant (P = .23). The larger Trastuzumab and Anastrozole Directed Against ER-Positive HER2-Positive Mammary Carcinoma (TAnDEM) study was a phase III trial evaluating anastrozole with or without trastuzumab. The investigators found that PFS was improved from 2.4 months to 4.8 months with the addition of trastuzumab (log-rank P = .0016). The addition of lapatinib to letrozole has been shown to improve PFS in patients with ER-positive, HER2-positive breast cancer, from 3 months to 8.2 months. While these data demonstrate that addition of trastuzumab to hormone therapy improves PFS, the results are inferior to those seen with the standard of care, THP. Notably, these studies also demonstrate the very poor PFS that can be expected in patients with ER- and HER-positive metastatic breast cancer treated with endocrine therapy alone. Nevertheless, the combination of anti-HER2 and endocrine therapy may be considered for select patients who are unable or unwilling to receive chemotherapy.
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