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The Role of Pathologists in the Era of Personalized Medicine Eric E. Walk, MD A lthough the ﬁeld of oncology has made signiﬁcant progress in improving the duration and quality of life for patients with cancer, response rates to traditional agnostic, there may be no utility for the drug. Thus, while targeted therapies often demonstrate dramatic responses in diagnostic-driven patient subsets, the therapy’s efﬁcacy chemotherapeutic agents remain unacceptably low when in unselected patient cohorts is typically too low for reg- compared with response rates in other disease areas.1 This ulatory approval. The US Food and Drug Administration situation, combined with the disturbing trend of decreas- has published a guidance document in draft form on the ing annual new drug applications despite increasing drug codevelopment of drugs and diagnostics.3 A major point development spending,2 has accelerated the adoption of of emphasis in that document is the need to begin devel- the personalized medicine concept in several areas of opment of the diagnostic assay early in the drug devel- medicine but most signiﬁcantly in oncology. In this ﬁeld, opment process, ideally in the preclinical stage, to best in the past 5 to 10 years, the terms personalized medicine, ensure that a robust assay can be approved by the US biomarkers, and translational medicine have gone from being Food and Drug Administration and be commercialized in hypothetical concepts to being widespread actualities in conjunction with the pharmaceutical compound. drug development, basic and clinical research, and clinical If one considers the large and growing number of mo- practice. Once obscure points of discussion at cancer con- lecularly targeted therapies that are either available com- ferences, these topics now dominate many congresses and mercially or in development,4 as well as the enormous have spawned dozens of biomarker meetings around the amount of ongoing translational research in oncology, it world each year. becomes clear that the personalized medicine concept is In its simplest form, personalized medicine seeks to do not going to be a short-lived trend but rather a true par- away with the cancer treatment paradigms of ‘‘one drug adigm shift and a new way of diagnosing and treating ﬁts all’’ and ‘‘trial and error,’’ replacing them with a mod- cancer as a disease. el centered on the pairing of molecularly classiﬁed cancer At the same time, the personalized medicine concept subgroups with new generations of chemotherapeutic faces a number of signiﬁcant challenges before its poten- molecules targeting the speciﬁc pathogenic mechanisms tial can be fully realized. At the scientiﬁc level, although that drive the respective neoplastic processes in each sub- our knowledge surrounding the molecular underpinnings group. The objective is to administer the right drug to the of cancer continues to expand at a rapid pace, we are a right patient at the right time and at the right dose. This long way from having a complete understanding of how model is entirely dependent, however, on a new genera- cancer cells are driven, how they evolve over time, how tion of cancer tests that accurately and comprehensively they interact with the host microenvironment and how characterize patients’ tumors at the DNA, RNA, and pro- they react to therapeutic intervention. In drug develop- tein levels, thereby allowing physicians to identify likely ment, we face the challenges of developing therapies responders before beginning treatment. against targets we do not completely understand and of These tests have been designated companion diagnostics selecting optimal trial designs, clinical endpoints, and bio- to acknowledge that, in the personalized medicine model, marker strategies. In the clinic, we need to deal with the the pharmaceutical compound and the diagnostic assay reality of acquired drug resistance, even in patients who become inexorably linked. That is, without the drug, there have had dramatic initial responses, and with a previously is no need for the companion diagnostic; and perhaps underestimated degree of intrapatient and intratumoral more conceptually provocative, without the companion di- heterogeneity. Although the combination of targeted ther- apies appears to be one solution to the latter challenges, Accepted for publication October 31, 2008. clinical trials that include adaptive designs and combina- From Ventana Medical Systems, Inc, a member of the Roche Group, torial approaches have only recently been initiated, and it Tucson, Arizona. remains to be seen whether toxicity will be a limiting fac- Presented in
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