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the interaction of the tumor with its microenvironment (habitat im- aging). 94 These data can be used for prognostic purposes and can be integrated with genetic features of tumors to provide better un- derstanding of tumor heterogeneity and biology in a spatial context (radiogenomics). 95 The metrics developed by radiomic techniques can assist in distinguishing benign from malignant lesions, in differ- entiating disease grades, and in improving evaluation of treatment response. Ultimately, molecular tumor characterization efforts are likely to use both invasive (tissue-based) and noninvasive features to develop a complete understanding of human tumors at both the level of anatomic architecture and molecular infrastructure. PRECISION PREVENTION Although the concept of precision prevention in oncology has been defined (see earlier discussion), actual interventions that can be applied today to prevent cancer based on a deep molecular un- derstanding of the pathogenesis of premalignant lesions are not as robust as those available for the treatment of established malignan- cies. In part, this is because molecular profiling approaches have not yet been extensively applied in this arena. 96 Limited knowledge of the biology of precancer, including the biology and immunology of populations at high risk of developing cancer, has slowed progress toward developing a better understanding of the molecular charac- teristics of individual subjects requiring preemptive interception. 97 Effective preventive strategies have, most recently, taken ad- vantage of a rapidly developing appreciation of the pathobiology of inherited (germline) cancer susceptibilities. The importance of microsatellite instability and its immune consequences have stim- ulated the growth of screening strategies for the Lynch syndrome, and a better understanding of the role of BRCA1 in the control of replication stress and the hormonal milieu of the breast has helped to explain the mechanistic basis for the utility of tamoxifen as a prevention strategy in BRCA1 -mutant breast cells (that are pre- dominantly ER negative). In like manner, initial large genomic studies of premalignant tissues have begun to develop mutational signatures of DNA repair pathways, the APOBEC family of deam- inases, and oxidative stress that will inform improved diagnostic and interventional strategies. Progress has been notable for pa- tients with Barrett esophagus; this progress has resulted from NGS and transcriptomic studies that have described microbiota-related inflammatory changes and the mutational profile and molecular evolution of this form of precancer. 1. Doroshow JH, Kummar S. Translational research in oncology—10 years of progress and future prospects. Nat Rev Clin Oncol 2014;11(11):649–662. 2. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a mono- clonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11):783–792. 3. Druker BJ. Perspectives on the development of a molecularly targeted agent. Cancer Cell 2002;1(1):31–36. 4. Pharmacogenomics at work. Nat Biotechnol 1998;16(10):885. 5. The Lancet Oncology. Making precision oncology the standard of care. Lancet Oncol 2017;18(7):835. 6. Druker BJ. Perspectives on the development of imatinib and the future of cancer research. Nat Med 2009;15(10):1149–1152. 7. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366(26): 2443–2454. 8. Desmond-Hellmann S, Sawyers CL, Cox DR, et al. Toward Precision Medi- cine: Building a Knowledge Network for Biomedical Research and a New Tax- onomy of Disease . Washington, DC: The National Academies Press; 2011. 9. Doroshow JH. Selecting systemic cancer therapy one patient at a time: is there a role for molecular profiling of individual patients with advanced solid tu- mors? J Clin Oncol 2010;28(33):4869–4871. 10. Tannock IF, Hickman JA. Limits to personalized cancer medicine. N Engl J Med 2016;375(13):1289–1294. 11. DeVita VT Jr, Chu E. A history of cancer chemotherapy. Cancer Res 2008;68(21):8643–8653.

Beyond the remarkable benefits of vaccination against HPV and hepatitis B, understanding of the epigenetics and immune-oncology of premalignancy is at an early stage of devel- opment. It seems likely that an improved comprehension of the microenvironment of premalignant pathologies, particularly in- flammation-related conditions such as inflammatory bowel dis- ease, chronic pancreatitis, and hepatic and/or pulmonary fibrosis, will be necessary to intervene on a patient-specific basis. However, recent studies implicating certain proinflammatory cytokines in cancer etiology (e.g., interleukin-17 in colorectal adenomas and cancer, for which therapeutic antibodies have recently reached the clinic) suggest that novel precision preventive approaches will be forthcoming in the near future. 98 NGS of premalignant tissues could also be used to identify potential neoantigens amenable to vaccine or therapeutic antibody development. Perhaps the most important focus for precision prevention efforts in the future is the development of a “precancer atlas” in which systematic, clinically annotated collections of tissue and blood from patients with premalignant conditions or those who are at high risk of developing cancer are built at scale and sub- jected to intensive, multidimensional molecular characterization. It is the expectation that, in analogy to the NIH-supported Cancer Genome Atlas project, such studies would provide substantively enhanced understanding of the biology of precancer that would stimulate and sustain new approaches to the diagnosis and inter- diction of the malignant process. 97,99 FUTURE PROSPECTS The pace of implementation of precision approaches to cancer treatment and diagnosis has been dramatic over the past 5 years. As genomic technical capabilities continue to improve, the appli- cation of multidimensional approaches to elucidate the dynamics of tumor biology in vivo are likely to become routine components of the therapeutic paradigm of the future. In this way, proteomic, epigenetic, and immunologic profiling of tumors and the tumor microenvironment, as well as pathway molecular imaging, will support development of more precise and more predictive bio- markers for both treatment and preventive interventions. Finally, novel insights into the measurement of tumor heterogeneity in the clinic will permit the application of interventions to preempt ther- apeutic resistance on a patient-by-patient basis, an essential com- ponent of long-term cancer control. 12. Long GV, Eroglu Z, Infante J, et al. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma who received dabrafenib com- bined with rrametinib. J Clin Oncol 2017;36(7):667–673. 13. Zhang B, Wang J, Wang X, et al. Proteogenomic characterization of human colon and rectal cancer. Nature 2014;513(7518):382–387. 14. Shen H, Laird PW. Interplay between the cancer genome and epigenome. Cell 2013;153(1):38–55. 15. Friedman AA, Letai A, Fisher DE, et al. Precision medicine for cancer with next-generation functional diagnostics. Nat Rev Cancer 2015;15(12): 747–756. 16. Garraway LA, Lander ES. Lessons from the cancer genome. Cell 2013; 153(1):17–37. 17. Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014;505(7484): 495–501. 18. Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic can- cer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 2017;23(6):703–713. 19. Robinson DR, Wu YM, Lonigro RJ, et al. Integrative clinical genomics of metastatic cancer. Nature 2017;548(7667):297–303. 20. Borad MJ, LoRusso PM. Twenty-first century precision medicine in oncol- ogy: genomic profiling in patients with cancer. Mayo Clin Proc 2017;92(10): 1583–1591. 21. Conley BA, Doroshow JH. Molecular analysis for therapy choice: NCI MATCH. Semin Oncol 2014;41(3):297–299.

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