ABSTRACT: The outlook for patients with HER2-positive breast cancer was revolutionized by the development of trastuzumab(Drug information on trastuzumab) (Herceptin), a humanized murine monoclonal antibody. Use of this agent led to improved overall survival when it was added to chemotherapy for the treatment of metastatic breast cancer. Improved understanding of mechanisms of resistance to trastuzumab has facilitated the development of novel agents for HER2-positive breast cancer, and also resulted in superior outcomes when added to chemotherapy in the adjuvant setting. This review explores the use of several such agents, including lapatinib (Tykerb), HSP90 inhibitors, T-DM1, and other tyrosine kinase inhibitors. Emerging data from trials of these agents indicate that the HER2 pathway remains a valid therapeutic target following disease progression on trastuzumab, and suggest a promising role for combined HER2 blockade with two or more agents.
The human epidermal growth factor receptor 2 (HER2) gene encodes a transmembrane glycoprotein receptor belonging to a family of growth factor receptors (the ErbB or HER family) with intrinsic tyrosine kinase activity. The initial descriptions of HER2 focused on the negative prognostic implications of amplification of the gene and/or overexpression of its product.1,2 The outlook for patients with HER2-positive breast cancer was revolutionized by the development of trastuzumab (Herceptin), a humanized murine monoclonal antibody targeting an extracellular domain (domain IV) of the receptor.3 This antibody led to improved outcomes, including overall survival, when added to chemotherapy for the treatment of metastatic breast cancer.4 It was subsequently explored in several large adjuvant studies, in which the addition of trastuzumab to chemotherapy for early breast cancer was found to reduce the risk of recurrence and death.5 The results of these studies have led to the incorporation of trastuzumab as an integral component of chemotherapy regimens for early and advanced breast cancer.
Despite the major advance in the therapy of HER2-positive breast cancer represented by this agent, nearly all patients treated with trastuzumab for advanced breast cancer will ultimately experience progression, while a significant proportion of patients receiving this treatment in the setting of early breast cancer will experience disease recurrence. Some may receive further trastuzumab in the metastatic setting, but again, will likely experience progression despite this treatment. Accordingly, a large volume of research has centered on identifying mechanisms of resistance to trastuzumab, and developing novel agents to target the aberrant growth signaling pathway represented by HER2. Key components of the HER2 pathway are illustrated in Figure 1, along with the sites of action of novel agents targeting this pathway.
Mechanisms of Resistance
Potential mechanisms underlying trastuzumab resistance include blocking of the interaction of trastuzumab with the HER2 receptor, interaction of the receptor with other growth factor receptors, and downstream activation of signaling pathways. Trastuzumab binding may be physically prevented by increased expression of the membrane glycoprotein MUC46 or by shedding of the extracellular domain of the receptor containing the trastuzumab-binding site.7 Crosstalk or heterodimerization between HER2 and IGF-1R or other HER family members may be a mechanism of resistance to trastuzumab, allowing activation of interlinked signaling pathways and resulting in cell proliferation.6,8 Trastuzumab's inhibition of HER2 signaling along the PI3K/AKT pathway may be bypassed by activating mutations of AKT and decreased expression of PTEN, a negative regulator of this pathway.9,10 Another potential mechanism of resistance involves transcriptional upregulation of HER2 gene expression.11
Tyrosine Kinase Inhibitors: Lapatinib
By targeting the intracellular tyrosine kinase moiety of HER2, mechanisms of resistance affecting the extracellular component (including increased glycoprotein expression, shedding of the extracellular domain, etc) may be countered. Lapatinib (Tykerb) was the first such agent to be approved for HER2-positive breast cancer. This is an orally available, reversible small molecule tyrosine kinase inhibitor (TKI) that targets not only HER2 but also the epidermal growth factor receptor (HER1/EGFR). Results for this agent as monotherapy in heavily pretreated patients with HER2-positive metastatic breast carcinoma were disappointing, with response rates of 5% or less.12,13 In the first-line setting, lapatinib monotherapy yielded a more promising overall response rate of 24%,14 which is comparable to the outcome for trastuzumab monotherapy in the first-line setting.15
Lapatinib Plus Chemotherapy
EGF100151 was an open-label phase III study that investigated the addition of lapatinib to capecitabine(Drug information on capecitabine) (Xeloda) in patients with HER2-positive advanced breast cancer previously treated with an anthracycline, a taxane, and trastuzumab.16 The control arm consisted of capecitabine at 2,500 mg/m2 daily for 14 out of every 21 days, which is the US Food and Drug Administration (FDA)-approved dosing regimen. The investigational arm received lapatinib at 1,250 mg daily continuously with a lower dose of capecitabine (2,000 mg/m2 daily). Study accrual was discontinued after a prespecified event analysis on 324 patients demonstrated a significant improvement in time to progression for the combination treatment (hazard ratio [HR] = 0.49; 95% confidence interval [CI] = 0.34–0.71; P < .001).
Updated analysis of the total accrued population of 399 patients confirmed a significant improvement in time to progression and overall response rate with the combined treatment. There was no difference in survival. The most common toxicity for the combination was diarrhea (occurring in 60%, with G3 in 12% and grade 4 in 1%). A second upfront phase III study randomized 579 patients with advanced breast cancer to lapatinib (1,500 mg daily) or placebo in addition to paclitaxel(Drug information on paclitaxel) every 3 weeks.17 No patients with known HER2-positive disease were enrolled, although central HER2 testing was performed as part of the study. This revealed 86 patients with HER2-positive disease. In this subgroup of patients, time to progression, event-free survival, overall response rate, and clinical benefit rate were all significantly improved with the combination, whereas no improvement in any of the efficacy endpoints was seen in the HER2-negative population.
Toxicities seen more commonly with the combination included rash, diarrhea, sepsis, and vomiting. In addition, there was an increased rate of fatal adverse events in the combination arm (2.7% vs 0.6%), including three cases of sepsis related to diarrhea. This highlights the importance of early and effective antidiarrheal management in patients treated with lapatinib, as well as the potential of other agents to potentiate this toxicity.
In the years following the incorporation of trastuzumab into the routine treatment of HER-positive metastatic breast cancer, a prevailing debate has centered on the appropriateness of continuing trastuzumab in the setting of disease progression. The experience with conventional cytotoxic agents suggests that it is futile to continue therapy beyond progression, but whether this dictum applied to novel biologic agents was unknown. In practice, many oncologists continued trastuzumab into second and greater lines of therapy, while changing the chemotherapy partner drug. This practice was not based on any prospective evidence, however.
Two recent randomized studies have finally answered this debate. In the first, patients progressing after trastuzumab-based therapy were randomized to capecitabine with and without trastuzumab.18 Accrual was halted early after 156 of 482 patients were enrolled, when a preplanned interim analysis indicated a significant improvement in progression-free survival (PFS) from 5.6 to 8.2 months (P = .03) in the patients continuing trastuzumab.
A second study investigated the role of continuing trastuzumab in the setting of lapatinib monotherapy.19,20 A total of 296 patients who had received a median of three prior trastuzumab-containing regimens for HER2-positive metastatic breast cancer were randomized to lapatinib at 1,500 mg daily or lapatinib at 1,000 mg daily plus weekly trastuzumab treatment. Despite a built-in crossover to the combination for patients progressing on lapatinib monotherapy, a significant improvement in overall survival was demonstrated with the combination therapy (HR = 0.74; 95% CI = 0.57–0.97; P = .026). Continued trastuzumab led to an improvement in PFS and clinical benefit rate, with a trend for improved overall survival despite a built-in crossover to the combination for patients progressing on lapatinib monotherapy (HR = 0.75; 95% CI = 0.53–1.07; P = .106). As well as validating the common practice of continuing trastuzumab after progression, this study confirmed a role for combined HER2 blockade, which is a feature of many current studies evaluating novel HER2-targeting agents.