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Journal of Clinical Oncology, Vol 23, No 8 (March 10), 2005: pp. 1614-1615 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.016
What Is Targeted Therapy?Indiana University School of Medicine, Indianapolis, IN This Special Series issue of the Journal of Clinical Oncology includes two papers1,2 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 cliché, like the word "paradigm"? At its simplest, targeted therapy implies a therapy with a specific molecular target. This, it must be said, is a very low-level definition. Any therapy that works must have a molecular 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.3 In a related way, with targeted therapy, do we mean 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.4 So the simple equation, "drug + molecular target = 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 be measurable 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.5 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 = targeted therapy), useless (the great majority of treated patients failed to benefit from what the laboratory called "targeted" therapy), and naïve (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 Miller2 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 gene-based, 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 and Miller indicate, this may become a possibility for the breast cancer field in the near future. What are the implications of this approach for laboratory and clinical researchers? Pegram et al1 discuss several important lessons. First, if we are unable to reliably measure the target in the clinic, research into targeted therapies will grind to a halt. Breast cancer clinical trials increasingly enroll larger populations of patients to find smaller differences in outcome. An unselected approach has the real potential for throwing away valuable drugs. Given the huge expense required for bringing a drug to the market, failure to devote real resources to clinical target validation is simply irresponsible. Such validation, requiring the collaboration of laboratory scientists, oncologists, and pathologists, should begin earlier rather than later in the developmental process. Secondly, validation of targeted therapy requires more than the use of a drug in a preselected trial population. Again, this is necessary but not sufficient. We have learned volumes about the biology of the estrogen receptor and HER-2 from the careful analysis of clinical tissues collected in phase III trials. And yet, all too many of the clinical trials performed with targeted agents fail to collect even the simplest of biologic tissues (eg, paraffin-embedded tumor and blood components). Those that do, in turn, rarely receive adequate funding for subsequent laboratory analysis. This shameful starvation of the clinical trials process, whether by government agency or pharmaceutical company, represents a real barrier to the conquest of cancer. I suggested at the start of this editorial that all effective therapies are, by definition, targeted therapy. We have not yet found clinically useful biologic correlates for every current agent, and our patients suffer for this failure. The toxicity of cisplatin in patients with testicular cancer is considered trivial in the grand scheme of things because cisplatin is, in essence, targeted therapy for pluripotent germ cells (routine hematoxylin and eosin staining representing adequate target measurement). Cisplatin is not targeted therapy in breast cancer because we cannot measure whom it benefits. Because it is not targeted, its toxicity is less acceptable to physicians and patients. There is immense potential for improving efficacy and diminishing toxicity through application of genomic, proteomic, and pharmacogenetic technologies. The recent use of multigene reverse transcriptase polymerase chain reaction technology to estrogen receptor–positive, lymph node–negative breast cancer has revealed that even the ancient and nonspecific cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy regimen is strikingly effective for a targeted population of patients.6 CMF now becomes, in essence, targeted therapy. The next decade will see many such surprises. Targeted therapy, as Pegram et al1 suggest, is truly the wave of the future. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Pegram MD, Pietras R, Bajamonde A, et al: Targeted therapy: Wave of the future. J Clin Oncol 23:1776-1781, 2005
2. Schneider BP, Miller KD: Angiogenesis of breast cancer. J Clin Oncol 23:1782-1790, 2005 3. Heidelberger C, Chandhari N: Fluorinated pyrimidines: A new class of tumor inhibitory compounds. Nature 179:663-665, 1957[CrossRef][Medline] 4. Druker B: Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91:1-30, 2004[CrossRef][Medline]
5. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 6. Paik S, Shak S, Tang G, et al: Expression of the 21 genes in the Recurrence Score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20. Breast Cancer Res Treat 88:S15, 2004 (abstr 24)[CrossRef]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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