What Is Targeted Therapy?
Authors: George W. Sledge
Journal: Journal of Clinical Oncology (2005)

This Special Series issue of the Journal of Clinical Oncology includes two papers discussing new targeted therapies for breast cancer. Clinical and laboratory investigators interested in breast cancer will find these subjects both appropriate and timely. Targeted therapies in breast cancer (especially those targeting the estrogen receptor and HER-2) have transformed the face of this disease over the past generation. The very term ‘‘targeted therapy’’ raises questions deserving of our consideration. What do we mean by targeted therapy? Functionally, how do we ensure the success of targeted therapy in the clinic? Is the phrase anything more than another medical cliche, like the word ‘‘paradigm’’? At its simplest, targeted therapy implies a therapy with a specificmolecular target.This, itmustbesaid, is avery lowlevel definition. Any therapy that worksmust have amolecular target. In some cases (trastuzumab), we discover the target first, while in others (aspirin), we discover the drug before the target. In its day, fluorouracil was held up as targeted therapy, and appropriately so. In a related way, with targeted therapy, do wemean that the therapy has only one target? Some of our best targeted therapies (eg, imatinib) have more than one molecular target, so we cannot even claim that targeted therapy requires an exacting degree of specificity. So the simple equation, ‘‘drug molecular target Z targeted therapy,’’ is essentially meaningless. At best, it can be considered necessary but not sufficient. Breast cancer supplies a better functional definition of targeted therapy. In addition to the existence of a target (the estrogen receptor for tamoxifen, HER-2 for trastuzumab), the breast cancer story tells us what we should require of targeted therapies. A targeted therapy should attack a biologically important process (usually, though not necessarily, a single molecule), preferably one central to a hallmark of cancer. The target should bemeasurable in the clinic, and measurement of the target (in either quantitative or qualitative terms) should correlate with clinical outcome when the targeted therapy is administered. Using this approach, gefitinib moved into the realm of targeted therapy only in the clinic. That is to say, its inclusion in the targeted therapy club required the discovery of epidermal growth factor mutations correlating with therapeutic outcome in lung cancer patients. Translational science is often thought of in terms of an arrow directed from the lab to the clinic. As I have argued, this unidirectional arrow is simplistic (ie, gefitinib epidermal growth factor receptor Z targeted therapy), useless (the great majority of treated patients failed to benefit from what the laboratory called ‘‘targeted’’ therapy), and naive (a generation of cell-line work having failed to detect the existence of epidermal growth factor mutations in clinical lung cancer specimens). Targeted therapy requires clinical validation, or it is not targeted therapy. Similarly, it is reasonable to suggest that agents targeting vascular endothelial growth factor do not yet pass the bar of targeted therapy. As Schneider and Miller demonstrate, we are currently unable to measure a target (in breast cancer or any other disease) correlating treatment with outcome. We are not even certain at present whether the cells being attacked are endothelial cells, cancer cells, or both. At present, antiangiogenic therapy remains something less than targeted therapy in a functional sense. This is not to say that antiangiogenic therapy may not yet become targeted therapy: multiple surrogate markers of the angiogenic process are currently under investigation at the message, protein, and organ level (with genebased, immunohistochemical, and molecular imaging approaches). No doubt we will discover a great deal more about therapeutic targeting of antiangiogenic agents in coming years; our impatience in this regard should not blind us to the reality that the first definably antiangiogenic agent (bevacizumab) received US Food and Drug Administration approval (for colorectal cancer) in the very recent past. Indeed, if what I have said regarding a definition of targeted therapy is correct, it is premature to consider a therapy functionally targeted unless, and until, large positive studies become available. As Schneider VOLUME 23 d NUMBER 8 d MARCH 1