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May 12, 2022

Does Circulating Tumor DNA Measure Up to Prostate-Specific Antigen?

Author Affiliations
  • 1Sema4, Stamford, Connecticut
  • 2Icahn School of Medicine at Mount Sinai, New York, New York
JAMA Oncol. 2022;8(7):972-974. doi:10.1001/jamaoncol.2022.0511

Circulating tumor DNA (ctDNA) has been making headlines for its potential applications in oncology, including multicancer early detection tests for cancer screening, minimal residual disease (MRD) testing for localized cancers, and treatment selection and response monitoring for advanced cancers. These developments can be understood as diverse applications of a tool that fundamentally expands the spectrum of malignant disease that can be measured and monitored. A prominent example of a similar tool in clinical practice is prostate-specific antigen (PSA), which has fundamentally shaped the management of prostate cancer. The advent of ctDNA has far-reaching implications for the future of solid tumor oncology because, to paraphrase a well-known business aphorism, you can only manage what you can measure.

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1 Comment for this article
Molecular biology and screening of early prostate cancer: A house of cards?
Takeshi Takehashi, M.D, Ph.D | Health and Welfare Bureau, Kitakyushu city office
The authors review potential applications of circulating tumor DNA (ctDNA) in various clinical situations of prostate cancer practice in comparison to PSA.

PSA is an exellent marker in aspects such as minimal residual disease testing and response monitoring. Such markers do not exist in other types of cancer, so there is little room for improvement. Also, PSA is effective for screening, significantly reducing unnecessary diagnostic test. In fact, there has been a lot of controversy about PSA screening, but the most essential problem is overdiagnosis, which stems from a diagnostic test, the pathological diagnosis of a needle biopsy specimen,
not from screening test, PSA.1

Curiously, in reviews and guidelines regarding PSA screening, almost all of the pathological statements are about Gleason score, a prognostic factor used after the diagnosis is confirmed. The diagnostic criteria are “absence of basal cells, prominent nucleoli, and small acinar formation”, and tissue construction is more important than cell atypia. Surprisingly, a look at the history of prostate cancer pathology reveals that the criteria have the origins in the notorious “Bowery series”.2-4 The criteria is only a hypothesis that one of the pathologists, at the request of an ambitious urologic surgeon, tentatively created from the morphological observation of a small number of cases with the technique and knowledge of 1951.4 When PSA screening began in the 1990s, the “Bowery criteria” were adopted as established, ignoring its historical background and scientific validity, and has not been validated until now.4 The USPFTF review could be considered the only verification, and it is stated that PSA screening has the problem of overdiagnosis. In other words, it is not possible to detect “early prostate cancer” by histopathological examination. Perhaps most modern pathologists have never known these articles, but if they read the dialogue between urologist Perry Hudson and pathology expert Arthur Purdy Stout,3 they should be terrified. Pathologists and urologic surgeons have passed the buck to each other and justified the early detection and treatment of prostate cancer, which is an unethical medical practice, since the 1950s to the present.

In addition, at the first stage of research on ctDNA in 1990s and early 2000s, DNA should be extracted from paraffin blocks of radical prostatectomy or needle biopsy specimens by identifying cancer tissue based on pathological diagnosis: “The Bowery criteria”. But there is no scientific evidence that those cells are really cancerous.

The theme of clinical application of molecular biological markers is very interesting and significant. However, the authors should have chosen a more suitable cancer, other than prostate cancer.

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