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OPINION

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.

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Fig. 1: Magnitude of the problem of overdiagnosis owing to screening.
Fig. 2: Slow versus rapid progressors — unpredictable tumour growth trajectory.
Fig. 3: Molecular profiling to distinguish indolent from aggressive cancers.

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All authors contributed to the writing of the article. S.S., S.G., P.D.W. and B.S.K. also reviewed and/or edited the manuscript before submission.

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Correspondence to Sudhir Srivastava.

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Public Health England prostate cancer risk management programme: https://www.gov.uk/guidance/prostate-cancer-risk-management-programme-overview

SUMMIT: https://summitstudy.co.uk/

Glossary

Active surveillance

A treatment plan that involves closely watching a patient’s condition but not giving treatment unless there are changes in the test results that show the condition is worsening.

Cohort studies

Research studies that compare a particular outcome (such as breast cancer) in groups of individuals who are alike in many ways but differ in certain characteristics (for example, women who are screened for breast cancer compared with those who are not).

Decision aids

Evidence-based educational tools that facilitate shared decision making, improve knowledge of treatment options, may increase satisfaction with treatment choice and likely facilitate long-term quality of life. They include educational literature, videos and website interactive programmes.

Ecological studies

Observational studies that focus on the comparison of groups rather than individuals. Data are analysed at the population or group level rather than at the individual level.

Gleason pattern

In terms of microscopic appearance of prostatic carcinoma, there are a number of different recognizable patterns that range in number from 1 to 5, with pattern 1 most resembling normal glands and pattern 5 least resembling normal glands.

Gleason score

Prostate cancer is often heterogeneous, with often more than one pattern being present in a given tumour nodule. Gleason score is the sum of the most common and second most common patterns (for example, 3 + 4 = 7) in prostatectomy specimens and the most common and highest pattern in needle biopsy samples. Gleason scores range from 2 to 10.

Grade Group

With modern grading, it was found that almost all prostate cancers range from Gleason score 6 to 10. It is often assumed by many that a Gleason 6 out of 10 is quite aggressive, when in fact this is essentially the lowest grade one can have. Grade groups take this into account by referring to Gleason score 6 tumours as Grade Group 1 (GG1). It also forced a separation of Gleason 7 tumours (which could be either Gleason 3 + 4 = 7 or Gleason 4 + 3 = 7) into two groups because these are known to have a substantially different prognosis.

Incidentalomas

Unanticipated findings that are not related to the original diagnostic inquiry.

Interval cancers

Cancers missed during routine screening but diagnosed between scheduled screening tests.

Overdiagnosis

A condition that fulfils standard diagnostic criteria but would not go on to cause symptoms or death. Cancer overdiagnosis occurs most frequently when a tumour is identified by a screening test but may also be detected as an incidentaloma on images of unrelated target organs.

Reservoir of silent and non-lethal cancers

The existence of a substantial number of subclinical cancers that can be found through routine screening or imaging.

Sigmoidoscopy

A procedure in which a flexible, narrow tube with a light and tiny camera on one end, called a sigmoidoscope or scope, is used to look inside a patient’s rectum and lower colon. During sigmoidoscopy, abnormal growths in the rectum and sigmoid colon can be removed for biopsy.

SPOP

The SPOP gene encodes speckle-type POZ protein, which is thought to modulate the transcriptional repression activities of death-associated protein 6 (DAXX) and is part of an E3 ubiquitin ligase complex that is involved in controlling protein stability of the androgen receptor and some of its transcriptional co-activators.

Thoracotomy

A surgical procedure in which a cut is made between the ribs to see and reach the lungs or other organs in the chest or thorax.

TMPRSS2–ERG

Fusion of the genes ERG and transmembrane protease serine 2 (TMPRSS2) is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate.

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Srivastava, S., Koay, E.J., Borowsky, A.D. et al. Cancer overdiagnosis: a biological challenge and clinical dilemma. Nat Rev Cancer 19, 349–358 (2019). https://doi.org/10.1038/s41568-019-0142-8

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