Response to Takahashi

We thank Dr Takahashi for his interest in our work. However, he makes a number of erroneous statements. He references the Bowery series, an infamous violation of research ethics in diagnosing and treating prostate cancer (PC) in homeless men rather than an often-cited illustration of PC epidemiology. The author states that the “Bowery criteria” were used “when PSA screening began,” and “it is necessary to verify the scientific validity” of these criteria. Nonetheless, the currently used Gleason grading system has been demonstrated to be appropriately associated with PC-specific mortality (1).

The main point of our paper is the clinically significant decline in the diagnosis and surgical treatment of Grade Group (GG) 1 PC and a concurrent increase in the incidence of high-grade and metastatic PC (mPC). Although the former results are encouraging, we do not suggest that overdiagnosis has been eliminated. Our findings should be interpreted as evidence that a restrictive screening approach paired with active surveillance for low-grade disease can ameliorate the burden of overdiagnosis and overtreatment.

Dr Takahashi asserts that increasing rates of mPC are explained solely by the relative decrease in the proportion of early-stage disease. Nonetheless, several have demonstrated a statistically significant increase in mPC at diagnosis following the 2012 statement against prostate-specific antigen (PSA) (2,3). Desai et al. (4) showed that the incidence of mPC in men aged 45-74 years increased from 12 to 17 per 100 000 between 2010 and 2018. Most concerning, Burgess et al. (5) used the National Center for Health Statistics database to demonstrate that after years of steady decline, PC-specific mortality flattened or increased since 2014. These changes were observed irrespective of age, race, and location, indicating that the decline in screening that followed the 2012 recommendation was an influential factor.

The balance between early detection of lethal PC and prevention of overdiagnosis must be weighed as these do not exist in isolation. Level 1 evidence shows that PSA screening confers a PC survival benefit but at the expense of biopsy complications and overdiagnosis. Notably, microsimulation models demonstrate that intensifying screening by screening men aged 40-84 years would lead to a PC mortality reduction of 29%-31%, with an increase in overdiagnosis of 112-129 cases per 1000 (6). From a public health perspective, a PC incidence target “not to exceed” benchmark was proposed by Welch et al. (7) to limit overdiagnosis and overtreatment. In this context, we encourage that rates of low-grade and mPC should be carefully monitored to characterize the optimal PC “incidence target” and appropriately steward screening strategies.

Last, we recognize that changes in the pathological criteria to examine PC by GG may affect PC grading at a population level. However, the publication of the 2014 International Society of Urological Pathology consensus was temporally inconsistent with the major decline in GG1 noted in our study, where incidence rates dropped from 52 to 26 cases per 100 000 between 2010 and 2014. Without minimizing these complexities, we argue that the evidence suggests that less PSA screening is associated with a decrease in the incidence of GG1 disease but with the undesired consequences of increasing mPC at diagnosis.

Funding

JCH receives salary support from the National Institute of Health (R01 CA241758, R01 CA259173-01A1), and the Patient-Centered Outcomes Research Institute (CER-2019C1-15682, CER2019C2-17372). This work is supported by a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30-CA008748), a SPORE grant in Prostate Cancer to Dr H. Scher (P50-CA92629), the Sidney Kimmel Center for Prostate and Urologic Cancers and David H. Koch through the Prostate Cancer Foundation.

Notes

Role of the funder: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclosures: All authors declare no support from any organization for the submitted work. Competing interests are reported by 3 authors. JCH and LDB receive salary support from the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust, and JCH receives salary support from the Prostate Cancer Challenge Award. AV is named on a patent for a statistical method to detect prostate cancer that has been licensed to and commercialized by OPKO Health as the 4Kscore. He receives royalties from sales of the test and has stock options in OPKO Health. There are no other relationships or activities that could appear to have influenced the submitted work.

Author contributions: LDB: Conceptualization, Investigation; Visualization; Writing-Original Draft; Writing-Review and Editing. GD: Writing-Review and Editing. XG: Data Curation; Formal analysis, Methodology; Writing, Review and Editing. EC: Writing-Review and Editing. VD: Writing-Review and Editing; ES: Writing-Review and Editing; HN: Writing-Review and Editing. SC: Conceptualization; Supervision; Writing-Review and Editing. AV: Conceptualization; Methodology; Supervision; Writing-Review and Editing. JCH: Conceptualization; Methodology; Supervision; Visualization; Writing-Review and Editing.

Data Availability

No new data were generated or analyzed for this response.