Foreword

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Cancer biomarkers, companion diagnostics and personalized oncology

emergence of exciting other technologies ... are causing unprecedented changes in modern healthcare.
The introduction of targeted therapeutics into clinical oncology practice has created major opportunities for further development of cancer biomarkers in the hope that they could evolve into companion diagnostics. The approvals of trastuzumab, for the treatment of HER2 overexpressing breast cancer and imatinib, for the treatment of chronic myelogenous leukemia featuring a bcr/abl translocation and gastrointestinal stromal tumors with selective c-KIT oncogene activating mutations, at the turn of the last century heralded the start of the era of anticancer therapy focused on the genetic targets of the cancer cells [1,2] . The molecular diagnostics industry is in a state of rapid evolution, featuring continuous technology developments and new clinical opportunities for drug selection, predicting efficacy and toxicity, and monitoring disease outcome. The in vitro diagnostics industry is now believed to consist of a near US$40 billion market of which molecular diagnostics has become a major component [3] . Gene-based and molecular diagnostics testing is growing at a 3050% rate and it is currently believed that as many as 1500 genes and 5000 proteins may be candidates for new molecular test targets [3] . It is widely held that in the next 510 years the clinical application of molecular diagnostics will further revolutionize the drug discovery and development process, customize the selection, dosing, route of administration of existing and new therapeutic agents, and truly personalize medical care [4] . changes in modern healthcare. The emergence of rapid communication, social networking and electronic information sharing has created a better-informed and more demanding consumer. The era of phenotypically derived pharmaceuticals that show limited efficacy in as many as 70% of treated patients is no longer acceptable to the public [5,6] . Furthermore, adverse drug reactions caused by the failure to predict individual drug toxicity or toxic drugdrug interactions now account for 100,000 patient deaths, 2 million hospitalizations and $100 billion in healthcare costs in the USA every year [5,6] .

The discovery of the human genome, expansion of proteomics research and the

Jeffrey S Ross
Albany Medical College, Department of Pathology, Mail Code 81, 47 New Scotland Avenue, Albany, NY 12208, USA Tel.: +1 518 262 5461 Fax: +1 518 262 8092 rossj@mail.amc.edu

By applying the principles of personalized oncology, including discovery and application of novel biomarkers and companion diagnostics, it should be possible to significantly enhance the productivity of drug discovery and development.
Personalized oncology Personalized oncology includes the concepts that each individual solid tumor and hematologic malignancy in each person is unique in cause, rate of progression and responsiveness to surgery, chemotherapy and radiation therapy [7] . In the past, personalized oncology relied on nonspecific clinical signs. However, emerging genomic and proteomic technologies are now allowing for the subclassification of diseases on an individual basis. For example, expanded knowledge of the molecular basis of cancer has shown that significant differences in gene sequence and/or expression patterns can guide therapy for a variety of solid tumors such as breast cancer (HER2 testing), colorectal cancer (KRAS and BRAF testing), lung cancer (EGF receptor gene [EGFR] testing) and melanoma (BRAF testing), as well as for malignant lymphoma and both lymphoid and nonlymphoid leukemias.
Biomarkers Med. (2011) 5(3), 277279
ISSN 1752-0363

Forces driving unprecedented change in healthcare The discovery of the human genome, expansion of proteomics research and the emergence of exciting other technologies, including next-generation DNA sequencing, PET scanning and functional imaging, in vivo microscopy, biosensors, evolving nano-technologies and enhanced computational biology, are causing unprecedented
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Foreword

Ross

Goals of personalized oncology The ultimate goals of personalized oncology are to take advantage of a molecular understanding of disease, both to optimize therapy for individuals already stricken with the disease (Box 1) and to direct preventive resources and therapeutic agents at the right population of people while they are still well. Genetic sequence variants can be used to predict the predisposition of an individual for future cancer development. Productivity & personalized oncology By applying the principles of personalized oncology, including discovery and application of novel biomarkers and companion diagnostics, it should be possible to significantly enhance the productivity of drug discovery and development. Through the identification of the right gene, the right pathway and the right target in the pathway, the right drug can be developed to treat the right patient. Reductions of 20% in the number of new compounds tested in Phase II and III human clinical trials, of 50% in the number of patients in Phase II trials, of 10% in the number of patients in Phase III trials and of 20% in the length of Phase III trials may well be within reach [7] .
Prediction of drug toxicity One of the earliest applications of germline genotyping in cancer management was the discovery of variations in drug metabolism associated with genomic variations in drug metabolizing enzymes, such as the cytochrome system [8] . Other detoxification pathways associated with single nucleotide polymorphism-based variations in drug metabolism have been described [8] ; however, compared with the cytochrome gene system, these markers have not achieved significant clinical utility. The potential clinical value of the pharmacogenetics approach for predicting drug toxicity will be uncovered as more candidate polymorphisms can be discovered. Prediction of drug efficacy The application of gene sequencing strategies to predict anticancer drug efficacy has recently
Box 1. Cancer drug development and personalized oncology goals.
Select optimal drug targets Select optimal drug dosage Predict which individuals will respond to specific drugs at high rates and who will be less likely to suffer toxic side effects Select and monitor patients for shorter less expensive advanced clinical trials Reduce the overall cost of drug development, and increase drug value Improve and provide more effective healthcare for patients

emerged in a variety of clinical settings including KRAS and BRAF sequencing to detect responsiveness to anti-EGFR antibody therapeutics in colorectal cancer [9] , EGFR sequencing to determine responsiveness to anti-EGFR tyrosine kinase inhibitors [10] and EML4-ALK translocation determination to predict benefit of ALK inhibitors in non-small cell lung cancer [11] , and BRAF sequencing to predict response to BRAF inhibitors in metastatic melanoma [12] . In addition, the development of printed and spotted genomic microarrays and continuing development of multiplex real-time PCR techniques have allowed for the rapid accumulation of new information concerning gene expression in human malignancies. Gene expression profiling has been linked to resistance and responsiveness to standard-of-care chemotherapy in some studies. This approach to personalize the treatment of newly diagnosed cancer patients, especially when combined with gene sequencing strategies, mRNA profiling and epigenomic testing, shows great promise towards the true individualization of cancer treatment in the future [13,14] .

The realization of the integration of diagnostics with therapeutics and the transition to personalized medicine are not without challenges, yet many of these challenges are being addressed.
Conclusion The traditional trial and error practice of medicine is progressively eroding in favor of more precise marker-assisted diagnosis, and safer and more effective treatment of disease. For the cancer therapeutics industry there appears an equally desirable outcome of this approach: increased efficiency, productivity and product lines. For the diagnostics industry this represents an unprecedented opportunity for integration, increased value and commercial opportunities for molecularly derived tests. The realization of the integration of diagnostics with therapeutics, and the transition to personalized medicine are not without challenges, yet many of these challenges are being addressed. As patients continue to take on more and more of the burden of their own health and well being, educational forums must be developed for patients and providers alike to understand the complex nature of the genomic and proteomic information that is now driving biomarker-based drug development, and the future introduction of integrated diagnostics and therapeutics.
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Biomarkers Med. (2011) 5(3)

Cancer biomarkers, companion diagnostics & personalized oncology

Foreword

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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