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Morphogenomics and Morphoproteomics A Role for Anatomic Pathology in Personalized Medicine Robert E. Brown, MD I would like to discuss a practice we have implemented in our department (Department of Pathology, Univer- sity of Texas Health Science Center, Houston) and some- plication? Even if we apply trastuzumab, as a single agent, to those cases, what is the response rate? It is approximately 15%. So, there is something else missing here, basically, in terms of its thing that was born at the Geisinger Medical Health Sys- utility in predicting response to trastuzumab, used alone, in a given patient. The story is even a little more disturbing with re- tem (Danville, Pennsylvania) in 2003. Here, I discuss the gard to EGFR. As we heard yesterday, just a little more than 1% application of morphogenomics and morphoproteomics1 of the tumor cells have to show any plasmalemmal expression of as a role for anatomic pathology in personalized medicine. EGFR to be considered a positive result. The sorry truth is that if we have 1 expression, 6% of the MATERIALS AND METHODS patients will respond to cetuximab. If we have 2 expression, The list of immunohistochemical probes and their sources for 13% of patients respond, and if we have 3 expression, no pa- morphoproteomics and the ﬂuorescence in situ hybridization tients respond. So, there is something wrong with this picture. probe for morphogenomics are contained in Table 1. Even patients with ‘‘no expression’’ can respond. We need to do a little better. Deﬁnitions ● Morphogenomics, as it relates to medicine, incorporates mor- Morphogenomics phology plus genomics. Many are familiar with the ﬂuorescence in situ hybridization ● Morphoproteomics comprises morphology plus proteomics. probe, which directs a probe for DNA hybridization to the HER2/ ● Personalized medicine is therapy customized for the individ- neu gene on chromosome 17. This results in a red ﬂuorescent ual patient. signal for the HER2/neu gene. There is also an internal control, where the probe to the centromere on chromosome 17 is used, Morphoproteomics: Evolution of Concept and which results in a green ﬂuorescent signal. We score each cell Historical Perspective and determine the ratio of red to green. Nonampliﬁed expression Most anatomic pathologists are familiar with applying a probe is deﬁned as a ratio of less than 1.8:1, whereas a ratio of HER2/ to detect the presence or absence of estrogen receptor (ER) . We neu (red) to centromere on chromosome 17 (green) signals of have been practicing this process routinely for some time in our more than 2.2:1 is ampliﬁed. The level of ampliﬁcation, as deter- laboratories, looking for the presence of ER-positive breast cancer mined by such numerical ratios, and its predictive value in terms tumors versus ER-negative tumors, so that we can provide some of responsiveness for an individual patient’s tumor to trastuzum- guidance to the clinician with respect to the role of antiestrogenic ab therapy are currently under study. therapy, such as tamoxifen. Then along came immunohistochem- ical testing for human epidermal growth factor receptor 2 MORPHOPROTEOMICS IN GUIDING TARGETED (HER2/neu), c-erb-B2, and many of us have been applying this CANCER THERAPIES: PROOFS OF CONCEPT to assess the level of plasmalemmal (cell membrane) expression When focusing on morphoproteomics in guiding tar- of HER2 total protein as one guide for the application of trastu- geted cancer therapies, we can talk about concepts and zumab therapy. More recently, our clinical colleagues requested that we assess the plasmalemmal expression level of epidermal proofs of concept and then application. But ﬁrst, how do growth factor receptor (EGFR) in carcinoma of the colon as a we deﬁne the clinical application of morphoproteomics? guide to therapy in terms of cetuximab (an antibody that is di- rected against the ectodomain of EGFR). Concept and Deﬁnition However, we have to put the predictive value of these latter The application of morphoproteomics, in its most com- assessments into perspective. If we identify 3 (strong) plas- plete sense, involves the immunohistochemical assessment malemmal expression of HER2/neu, what is the therapeutic im- of the activation of metabolic pathways in cancer cells, and actually, in any diseased cells, to predict susceptibility to Accepted for publication November 7, 2008. small-molecule inhibitors, speciﬁc chemotherapeutic From the Department of Pathology, University of Texas Health Sci- agents, and possibly, differentiating agents. What is the ence Center, Houston Medical School, Houston, Texas. morphologic component of that? Well, the morphologic The author has no relevant ﬁnancial interest in the products or com- component is essential; it is a sine qua non. By using mor- panies described in this article. phologic analysis, we can assess translocation of a protein
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