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The Role of Pathologists in the Era of Personalized Medicine


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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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