Cancer overdiagnosis: a biological challenge and clinical dilemma

Abstract

For cancer screening to be successful, it should primarily detect cancers with lethal potential or their precursors early, leading to therapy that reduces mortality and morbidity. Screening programmes have been successful for colon and cervical cancers, where subsequent surgical removal of precursor lesions has resulted in a reduction in cancer incidence and mortality. However, many types of cancer exhibit a range of heterogeneous behaviours and variable likelihoods of progression and death. Consequently, screening for some cancers may have minimal impact on mortality and may do more harm than good. Since the implementation of screening tests for certain cancers (for example, breast and prostate cancers), a spike in incidence of in situ and early-stage cancers has been observed, but a link to reduction in cancer-specific mortality has not been as clear. It is difficult to determine how many of these mortality reductions are due to screening and how many are due to improved treatments of tumours. In cancers with lower incidence but high mortality (for example, pancreatic cancer), screening has focused on high-risk populations, but challenges similar to those for general population screening remain, particularly with regard to finding lesions with difficult-to-characterize malignant potential (for example, intraductal papillary mucinous neoplasms). More sensitive screening methods are detecting smaller and smaller lesions, but this has not been accompanied by a comparable reduction in the incidence of invasive cancers. In this Opinion article, we focus on the contribution of screening in general and high-risk populations to overdiagnosis, the effects of overdiagnosis on patients and emerging strategies to reduce overdiagnosis of indolent cancers through an understanding of tumour heterogeneity, the biology of how cancers evolve and progress, the molecular and cellular features of early neoplasia and the dynamics of the interactions of early lesions with their surrounding tissue microenvironment.

Fig. 1 |. Magnitude of the problem of overdiagnosis owing to screening.

This schematic illustrates that only a small proportion of a screened population will have cancer that is lethal. However, screening for asymptomatic cancers, preneoplastic lesions or risk factors has the potential to label very large numbers of people as at risk , including those who were not destined to develop life-threatening disease.

Fig. 2 |. Slow versus rapid progressors — unpredictable tumour growth trajectory.

This schematic illustrates the large variability in growth rates and lethal potential of malignant cells. Overdiagnosis occurs when screen-detected cancers are either non-growing or so slow- growing that they would never cause medical problems before death from other causes. Therefore, the prerequisites of overdiagnosis are a reservoir of silent disease and a screening or detection activity that leads to detection of subclinical disease within the reservoir. Adapted with permission from REF., Oxford University Press.

Fig. 3 |. Molecular profiling to distinguish indolent from aggressive cancers.

The schematic illustrates the use of validated molecular aberrations, including cellular and phenotypic changes, that could help develop decision criteria for clinical management. This hypothetical workflow assumes that there is a screening process in place, overdiagnosis occurs and validated molecular assays exist to stratify screen-detected lesions as low-risk , intermediate-risk or invasive cancer. The schematic is not intended to be the only possible workflow , and other clinical scenarios may require additional diagnostic work-ups at any stage of this workflow. CNV, copy number variation; seq, sequencing.