Clinical Genomics Update: Molecularly Targeted Agents in Personalized Cancer Therapy and Diagnostics

October 30, 2015
Clinical Genomics Update: Molecularly Targeted Agents in Personalized Cancer Therapy and Diagnostics
Stephen Friend has likened pathologists to the shamans of medicine who use technologies similar to the examination of entrails and divining rods to make important decisions. [iStock/duncan1890]

Stephen C. Peiper, M.D.

Zi-xuan Wang, Ph.D.

The dominant paradigm in clinical oncology is personalized (therapeutic) medicine driven by precision diagnostics based on a solid foundation of basic and translational research in oncogenesis and signaling pathways.  It is recognized that malignant transformation occurs through the accumulation of somatic mutations with the ultimate evolution to a malignant tumor that is “addicted” to the signaling programmed by a driver mutation.  Advances in medicinal chemistry have allowed oncologists to directly attack this process with agents specifically targeted to block the oncogenic signaling resulting from the driver mutation, thereby releasing the addiction. 

The success of multiple individual targeted therapies and the inability to make associations between histopathology and somatic genetic mutations has led to an enthusiasm, perhaps quixotic, for genomic diagnosis and has fostered the temptation to consider pathologic diagnoses antiquated.  In fact, Stephen Friend, who cloned the retinoblastoma gene in Robert Weinberg’s laboratory, has likened pathologists to the shamans of medicine who use technologies similar to the examination of entrails and divining rods to make important decisions (He & Friend. Nature Medicine 2001;7:658-9).  The overall result is that current approaches stress aggressive genomic diagnostics and targeted therapies, which are expensive, creating a perfect storm in the current climate of financial efficiency that emphasizes value in medicine.

The critical importance of genomic diagnostics has come to the forefront of clinical research in the form of basket trials in which treatment decisions are based on the detection of actionable driver mutations and are agnostic to pathologic type (including tissue of origin).  Clearly, there have been some therapeutic successes with this approach, such as the effective therapy of hairy cell leukemia (demonstrated in multiple reports, including Dietrich et al. N Engl J Med 2012;366:2038-40) that have the BRAF (V600E) mutation with antagonists that are effective in melanomas that carry this mutation.  There have also been failures, exemplified by the lack of significant clinical responses to these agents in colorectal adenocarcinomas positive for BRAF (V600E).

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