In our systematic, cross-sectional investigation of translational research in cancer genetic research in 2007, we find that translational research in cancer genetics accounts for a very small fraction of the overall research portfolio in the field. These findings are consistent with genetic research in general and other fields of translational medicine [12
]. They also clearly indicate the severe constriction in documented translational research after the initial phase of genetic discoveries and especially after the first phase of translation leading to a candidate application.
It is important to acknowledge the inherent strengths and limitations in this type of analysis. Because we relied on reading abstracts of funded NCI research, we acknowledge that these abstracts may reflect an incomplete picture of the scope of actual research that the investigators are performing. It is also important to note that the NCI grants do not reflect all of the cancer genetics research that is being performed (e.g., non-NCI funded research or the NCI intramural program). Finally, the portfolio analysis reflects currently funded cancer genetics research which could potentially predict future research publications. The literature analysis of 2007 reflects the status of publications in the field at a time when genome-wide association studies were just beginning to take off. We expect even greater numbers of genetic discovery publications in 2008 and beyond, thus increasing the numbers of T0 and T1 research. Another limitation is the potential under-ascertainment of T2 and beyond articles in the analysis of the literature. Because we did not read all 20,266 articles, we had to rely on a combination of approaches using medical subject headings, word searches and categories defined by the National Library of Medicine. Nevertheless, we believe our approach paints an overall picture of the status of translational research in cancer genetics in 2007 and of the severe constriction in research on candidate applications for cancer care and prevention. Furthermore, our duplicate coding and quality control review procedures ensured internal consistency in our definitions and classification of translational research phases.
What do these findings tell us and where should we go from here? Clearly, an appropriate emphasis on discovery research in cancer genetics is still needed since the amount and scope of large-scale biological, clinical and epidemiological information continues to emerge. Therefore, we should expect more discovery research in cancer genetics for years to come. Nevertheless, to reap the benefits of gene discoveries, there is a need to facilitate research and to build a research infrastructure that reflects translational clinical and population sciences for current and future discoveries. Such research translation requires a multidisciplinary approach. Even for well-known high penetrance genes that follow Mendelian inheritance patterns such as BRCA1
and Lynch syndrome, which are associated with cancer, we know very little about best ways to implement diagnosis and management of patients and their relatives (T3 research). Furthermore, we have very little data from the real world about the impact of the introduction of these tests on the overall burden of these cancers in the population (T4 research) [24
]. For the more common genetic variants associated with weak to moderate increases in cancer risk, we do not yet know how to assess the clinical implications of these variants, especially their added value compared to more conventional cancer risk predictions (e.g., the Gail model) [25
It is difficult to assess accurately why the distribution of cancer genomic research is skewed away from translation. This may reflect a combination of factors, although we have no direct data to assess their relative importance. These factors include the relative dearth of investigator applications for funding, the preferences of peer-review panels and the absence of infrastructure to conduct large-scale population research in epidemiology and multidisciplinary research such as behavioral sciences. An additional but unmeasured factor is that such translational research could be sponsored by other federal agencies and industry. Additionally, it is possible that some downstream therapeutic and diagnostic research is being performed by industry and thus would not be reflected in such a portfolio analysis. However, since the literature analysis did not ascertain more translation papers, we feel that this is unlikely to explain the large translational research gap. Certainly, the perception that more discovery is needed before embarking on translational research among researchers and peer reviewers may contribute to the mismatch between discovery and translational research.
Despite the present lack of translational research, we are already seeing the emergence of genetic profiles for susceptibility to several cancers, including prostate (http://www.decodediagnostics.com/PC-general.php
) and breast cancers (http://www.myriad.com/products/bracanalysis.php
). Many such markers are viewed as candidate health applications for risk assessment and cancer prevention. Some are even sold directly to consumers (e.g., https://www.23andme.com/
). As recommended in an NIH-CDC multidisciplinary workshop on personal genomics in December 2008 by Khoury et al. [26
], a multidisciplinary translational research agenda is needed to move genetic applications into practice and to document clinical benefits, costs and harms through observational studies and clinical trials. Additional research in behavioral and social sciences is needed to assess how genetic information impacts patients, providers, family members and the population at large [27
]. Communication sciences will play an important role in determining the best way to educate and inform individuals about rapidly changing genetic information. Finally, outcomes research in the health services settings will be critical in documenting the impact of these technologies in practice and surveillance research to document their impact on population health. It is important to consider that translational research categories T1 to T4 correspond to the phase of translation and not to the type of research conducted. For example, behavioral and communication research can be done in T1 and T2 even before a specific genomic application is ready for implementation, and later in T3 and T4 as part of implementation and measuring population health outcomes.
In a time of rapidly escalating healthcare costs, it is becoming absolutely essential to document the added value of genetic information in cancer control and treatment beyond traditional approaches that do not use genetic information. This is particularly needed in the field of pharmacogenomics, where promising genetic tests may be able to tailor cancer therapeutics to minimize side effects and maximize drug response. Although very few clinical trials have been conducted in pharmacogenomics, the results of such trials have far reaching effects. For example, the Children's Oncology Group recently found through a clinical trial that alteration of IKZF1
, a gene that encodes the lymphoid transcription factorIKAROS, is strongly associated with recurrence in pediatric acute lymphoblastic leukemia [28
The chasm between discovery research and translational research in cancer genetics is contributing to our ‘evidence dilemma’ in genomic and personalized medicine [29
]. A series of articles by Khoury et al. [29
], Woodcock [30
] and Hudson [31
] recently discussed the widening gap between discoveries and practice in genomic medicine and the need for a more robust applied research infrastructure that includes observational studies and randomized clinical trials. Even for genomic applications currently in practice, we lack highly needed information on how validated genome technologies (such as HER2 testing) actually work in practice [32
] and whether or not they lead to ‘real world’ net benefits in clinical outcomes. In fact, over the past 7 years, independent panels such as the U.S. Preventive Services Task Force and the EGAPP Working Group only made a few evidence-based recommendations for use of genomic applications in practice [33
]. Two recent evidence reviews of promising genomics applications yielded inconclusive evidence of clinical utility for their use in practice [35
Although it can be argued that not all genetic factors and gene-environment interactions related to cancer are currently known, it is important to enhance the current translational research infrastructure to assess emerging applications. As discussed by Califf and Ginsburg, this will require enhancing the clinical epidemiology capacity through multidisciplinary teams, integration of clinical, molecular databases and population records, use of interoperable electronic health records and centralized biobanking [37
]. Furthermore, even though most genetic risk factors are not ready for translation into practice, translational research in the form of assessing impact of genetic information on behavior can and should be done in proof-of-principle investigations. An example of this type of study is the ‘multiplex’ project conducted by McBride et al. [27
]. The goal of this project, an example of T3 research, is to evaluate the impact of information from multiple variants that can spur individuals to seek additional risk assessments (e.g., family history and behavioral risk assessments) and/or additional health services (e.g., well care visits), even though the genetic markers used for the study will not be ones that are used in clinical practice in the future.
For validated genetic applications already in use, it is important to evaluate how we are doing in practice and whether or not all segments of the population are benefiting from these applications. The ‘lost in translation’ phenomenon has been described in other fields of medicine [38
], where most basic science discoveries do not make it into clinical applications, and those that do take a very long time to get there [39
], contributing to exacerbations in health care costs and disparities in our population. In summary, this paper clearly documents the present lack of a robust translational research agenda in cancer genetics. A translational research infrastructure is urgently needed to fulfill the promise of gene discoveries for cancer care and prevention in the 21st century.