Research Needs for Understanding the Biology of Overdiagnosis in Cancer Screening.

Many cancers offer an extended window of opportunity for early detection and therapeutic intervention that could lead to a reduction in cause-specific mortality. The pursuit of early detection in screening settings has resulted in decreased incidence and mortality for some cancers (e.g., colon and cervical cancers), and increased incidence with only modest or no effect on cause-specific mortality in others (e.g., breast and prostate). Whereas highly sensitive screening technologies are better at detecting a number of suspected "cancers" that are indolent and likely to remain clinically unimportant in the lifetime of a patient, defined as overdiagnosis, they often miss cancers that are aggressive and tend to present clinically between screenings, known as interval cancers. Unrecognized overdiagnosis leads to overtreatment with its attendant (often long-lasting) side effects, anxiety, and substantial financial harm. Existing methods often cannot differentiate indolent lesions from aggressive ones or understand the dynamics of neoplastic progression. To correctly identify the population that would benefit the most from screening and identify the lesions that would benefit most from treatment, the evolving genomic and molecular profiles of individual cancers during the clinical course of progression or indolence must be investigated, while taking into account an individual's genetic susceptibility, clinical and environmental risk factors, and the tumor microenvironment. Practical challenges lie not only in the lack of access to tissue specimens that are appropriate for the study of natural history, but also in the absence of targeted research strategies. This commentary summarizes the recommendations from a diverse group of scientists with expertise in basic biology, translational research, clinical research, statistics, and epidemiology and public health professionals convened to discuss research directions. J. Cell. Physiol. 231: 1870-1875, 2016.