LAUSR

Survival improves when cancer is detected early. However, ~50% of cancers are at an advanced stage when diagnosed. Early detection of cancer or precancerous change allows early intervention to try to slow or prevent cancer development and lethality. To achieve early detection of all cancers, numerous challenges must be overcome. It is vital to better understand who is at greatest risk of developing cancer. We also need to elucidate the biology and trajectory of precancer and early cancer to identify consequential disease that requires intervention. Insights must be translated into sensitive and specific early detection technologies and be appropriately evaluated to support practical clinical implementation. Interdisciplinary collaboration is key; advances in technology and biological understanding highlight that it is time to accelerate early detection research and transform cancer survival. Description Detecting cancer early Many types of cancer are detected at an advanced stage, when treatment options are limited and prognosis is poor. Being able to detect cancers early can substantially improve survival, but this approach comes with challenges, including the possibility of overdiagnosis and overtreatment, which can harm people who would not have developed overt malignancy. In a Review, Crosby et al. discuss the importance of cancer early detection and the main challenges that need to be overcome to better understand the early events in tumorigenesis that are detectable in screening tests. The results of these tests can then be reliably interpreted to determine whether an individual requires treatment. —GKA A review discusses approaches to enable early detection of cancer and allow earlier intervention and increase survival. BACKGROUND When cancer is detected at the earliest stages, treatment is more effective and survival drastically improves. Yet ~50% of cancers are still only detected at an advanced stage. Improved earlier detection of cancer could substantially increase survival rates. Although recent advances in early detection have saved lives, further innovations and development of early cancer detection approaches are needed. The field is evolving rapidly, owing to advances in biological understanding and an increasing pace of technological progress. ADVANCES We highlight five challenges facing the field, current work in those areas, and where more research is needed to make early detection a reality. The first challenge is to build a greater understanding of the biology and behavior of early disease. This will help identify ways to distinguish between consequential, aggressive lesions and inconsequential lesions that will not cause harm. Such insight will be crucial to realizing the potential for early detection to inform treatment decisions and improve survival, while minimizing the risk of overtreatment. Alongside studies in human samples, better models of disease are enabling identification of early signals of tumorigenesis and clarifying the contributions of the immune system and microenvironment to tumor development. The second challenge is determining the risk of developing cancer. How can we use germline genomic susceptibility, family history, exposures, demographic, and behavioral data to build nuanced risk models to identify who should be tested for cancer and how test results should be interpreted and followed up? Progress is being made to address this challenge through improved understanding of the genomics of cancer risk, integration of that insight with other risk factors, and the development of large-scale population cohorts where risk models can be developed and validated. The third challenge is finding and validating biomarkers of early cancer. There is considerable difficulty in finding accurate signals of early cancer (which usually exist in very small amounts) amid the noise of normal human physiology. Although progress has historically been slow, many promising early detection markers are emerging, including circulating tumor DNA, circulating tumor cells, proteins, exosomes, and cancer metabolites. Advances in data analysis methodologies (such as machine learning) and integration across marker types in multimodal tests are also accelerating progress. The fourth challenge is technological. It involves both the iterative improvement of existing approaches and the development of disruptive detection technologies that can very sensitively and specifically identify early biological changes, whether in tissue structure, biochemistry, or function. Powerful molecular analytical technologies and advanced imaging and histopathological methods are increasing the ability to sensitively find earlier tumors, while the use of synthetic markers may help to amplify their signal. The fifth challenge is how to appropriately evaluate early detection approaches. Translation of biological insights into new diagnostic technologies and execution of clinical trials to validate those advances require substantial time and money. We discuss ways in which that process might be improved. OUTLOOK For early detection to deliver transformative progress in cancer survival, wider skill sets beyond cancer biology are essential, including engineers, chemists, physicists, technology developers, and behavioral and computer scientists. Integrated, interdisciplinary collaboration is key to bringing new ideas to address the challenges of early cancer detection. We believe that early detection of cancer is approaching a tipping point, as biological insight and technological capacity are increasing at an unprecedented rate and as public and private funders of research are increasingly willing to invest. This Review discusses the current state of the field and suggests constructive ways forward that build on current progress to deliver effective earlier detection of cancer and appropriate intervention. The early detection of cancer—challenges and ways forward. This figure summarizes challenges that impede the early detection of cancer and the areas of current research that are helping to overcome them.