EDITORIALS HERe-2 Stay: The Continuing Importance of Translational Research in Breast Cancer

This issue of the Journal contains two important articles that discuss human epidermal growth factor receptor 2 (HER2), also known as c-erbB2 or neu, as a therapeutic target in breast cancer (1,2). The first details preclinical studies that examine the combination of trastuzumab with a number of chemotherapeutic agents. The second applies the knowledge learned in the preclinical studies to the clinical setting and the treatment of patients with HER2-positive metastatic breast cancer. These studies are important with regard to what they tell us about HER2positive breast cancer and its treatment and about a style of research. All have important implications. HER2 is a member of a family of transmembrane receptor tyrosine kinases. To summarize more than two decades of research, HER2 lacks a functioning ligand-binding domain yet represents the preferred dimerization partner for other members of the EGFR family (3,4). Since the late 1980s, HER2 has been known to be overexpressed in the tumors of approximately 20% of patients with breast cancer. Overexpression is typically a consequence of amplification at the DNA level (measurable in the clinic by fluorescence in situ hybridization [FISH]) and is associated with an increased risk of relapse and death for patients with early-stage breast cancer (5). The poor prognosis is the clinical manifestation of the many biologic actions of HER2: increased proliferation, increased cell survival, increased invasion and metastasis, and increased angiogenic activity (6,7). In addition, amplification of HER2 results in impaired response to hormonal manipulations through cross-talk with the estrogen receptor complex (8,9). Although not the subject of this editorial, co-blockade of the estrogen receptor and of either HER2 or EGFR is currently being tested in clinical trials as a potential means of abrogating or preventing hormonal resistance. Similarly, given the role of HER2 as an upstream regulator of vascular endothelial growth factor (VEGF), co-blockade of HER2 and VEGF is also currently under exploration in clinical trials (10). Recognition of the clinical importance of HER2 in breast cancer led to the development in the 1990s of agents that target HER2, in particular, to the development of the humanized monoclonal antibody trastuzumab. In 1998, trastuzumab was approved by the U.S. Food and Drug Administration for clinical use largely on the basis of a randomized clinical trial (11) that compared chemotherapy to chemotherapy plus trastuzumab as a front-line treatment for patients with metastatic breast cancer. This randomized trial demonstrated unequivocally that the addition of trastuzumab to chemotherapy with either doxorubicin plus cyclophosphamide or paclitaxel resulted in increased survival for women with HER2-positive metastatic breast cancer (11). The introduction of any new agent into the breast cancer arena is typically followed by a “feeding frenzy” in which clinical trialists scurry to combine the new agent with existing agents. Such “toothpaste A toothpaste B” combinations litter the medical literature, rarely have any biologic basis, and arguably retard rather than propel the rational development of the new agent. Empiric combination therapy has specific perils beyond mere wastefulness. Indeed, as the HER2 story demonstrates, the combination of trastuzumab with doxorubicin-based chemotherapy was associated with an unacceptably heightened risk of congestive cardiomyopathy (11). This interaction, not detected in initial preclinical toxicology studies, was later found to have a sound biologic basis. HER2 proved to have an important anti-apoptotic role for normal cardiac myocytes, interruption of which leads to increased stress-related cardiac damage (12). This is where the first article by Pegram et al. (1) in this issue of the Journal comes in. At UCLA, Pegram et al. (1) carefully analyzed the combination of trastuzumab with numerous chemotherapeutic agents, using multiple drug effect/combination index isobologram analysis. This approach allows for the demonstration of synergy in the preclinical setting and, as applied in their study, demonstrated synergy in an in vitro model for the two-drug combinations of trastuzumab with carboplatin, 4-hydroxycyclophosphamide (the active metabolite of cyclophosphamide), docetaxel, or vinorelbine. Of these four synergistic compounds, carboplatin was of particular interest. The same authors had previously demonstrated a synergistic interaction between cisplatin and the murine precursor of trastuzumab 4D5 (13). Platinating agents have known single-agent activity in metastatic breast cancer (14–16), combine readily with taxanes (17), and lack the cardiotoxic effects of anthracyclines. Previous work (18) demonstrated that antibodies to the HER2/neu receptor block DNA repair after exposure to cisplatin in HER2-positive human breast cancer cells. Pegram et al. (1) similarly now demonstrate that trastuzumab markedly reduces unscheduled DNA synthesis (a marker of DNA repair) in carboplatin-treated HER2-positive SK-BR-3 breast cancer cells. In addition, they show that the combination of carboplatin with docetaxel was markedly synergistic in the combination index analysis. These in vitro studies led directly to two human in vivo studies, one performed by the Breast Cancer International Research Group (BCIRG) and the other by the UCLA Oncology Research Network (UCLA-ORN) (2). The former trial combined