HER2 in Prostate Cancer—a Viable Target or Innocent Bystander?

Extract

The promise of molecular medicine is that clinical outcomes will be improved by directing therapy toward the mechanisms and targets associated with the growth of an individual patient's tumor. In practice, the targets are not static and change as the disease progresses (1–3). For prostate cancer, the framework to address this dynamic is provided by a model that considers the disease as a series of states from diagnosis to death (Fig. 1). Therapeutic aims and trial hypotheses are defined by determining the clinical and biologic factors associated with tumor growth at the state a given patient resides. Factors determined to be present on the majority of cancers within a state can be targeted without profiling an individual patient's tumor. Those present at a lower frequency, or that change over time, would require individual profiling so that those patients most likely to benefit from a specific approach are treated (3).

The paradigm for therapy directed to a biologic determinant on a solid tumor is exemplified by trastuzumab (Herceptin™; Genentech, South San Francisco, CA), an antibody that targets the extracellular domain of the HER2 gene product (Her-2), in advanced breast cancer. Trastuzumab is believed to induce growth arrest by decreasing the expression of activated Her-2 receptors on the cell surface. Antibody-dependent cell-mediated cytotoxicity may also contribute to tumor response. Antitumor effects correspond with the level of expression: Tumors that do not express Her-2 or do so at low levels are insensitive to trastuzumab (4). In clinical trials, trastuzumab was active as a single agent and was shown to prolong life when it was added to two standard chemotherapy regimens in patients with advanced disease (5). The Her-2 target was credentialed by the demonstration that clinical benefit was restricted to patients with tumors that overexpressed the HER2 gene product (6), which led to the approval by the U.S. Food and Drug Administration (FDA) of a diagnostic test for expression that is now considered to be part of the “routine” management of breast cancer (7,8).