Review Reports - The Precision Paradox in Prostate Cancer Diagnostics: Grade Migration, Risk Misclassification, and Overtreatment in the mpMRI-Targeted Biopsy Era

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This opinion paper addresses a clinically significant issue—the Precision Paradox in prostate cancer diagnosis—where mpMRI-targeted biopsy may overestimate tumor grade and lead to overtreatment. While the core argument is clinically relevant, the manuscript suffers from several deficiencies that require authors' response.

The term "Precision Paradox" is used repeatedly throughout the manuscript without a strict definition. What constitutes "over-precision" or "under-precision"? The authors cite Brisbane et al. showing that only 65% of csPCa cores are located within the lesion, with 18% diagnosed only outside the ROI—but these data demonstrate that systematic biopsy also has spatial resolution limitations, not a unique flaw of targeted biopsy. The authors fail to establish a causal relationship between "more precise sampling" and "overestimation," providing only correlational evidence.
The authors cite Kroon et al. (2025, Anser Prostate Network) as the primary quantitative source, reporting a 15% downgrading rate in 616 patients. However, is a sample of 600 patients sufficient for answering the downgrading question? Authors should search for more studies to support their statement.
This opinion could be further strengthened by incorporating additional recent studies related to diagnosismodels, genetic driver mutations and multi-omics of prostate cancer (32609397, 35127694, 40843359). Integrating these relevant works would help place the present study into a broader clinical and research context and enhance the depth of Precision Paradox in prostate cancer diagnosis.
In Section 6, the authors propose incorporating "MRI lesion diameter, high-grade component percentage, and lesion-perilesional sampling concordance" into risk models.A n unvalidated suggestion should not appear in academic literature. The authors cite VALIDATE-PRO (NCT05017181), but this study evaluates MRI-derived metrics and prognosis, not the risk restructuring scheme proposed by the authors.
5. The 15% overall downgrading rate is insufficient for clinical guidance—GG2, GG3, and GG4 have vastly different downgrade probabilities. The authors should report downgrade rates by ISUP grade group.

Author Response

Comment 1: The term "Precision Paradox" is used repeatedly throughout the manuscript without a strict definition. What constitutes "over-precision" or "under-precision"? The authors cite Brisbane et al. showing that only 65% of csPCa cores are located within the lesion, with 18% diagnosed only outside the ROI—but these data demonstrate that systematic biopsy also has spatial resolution limitations, not a unique flaw of targeted biopsy. The authors fail to establish a causal relationship between "more precise sampling" and "overestimation," providing only correlational evidence.

Response: We appreciate this important critique. In the revised manuscript, we have explicitly defined the terms driving the bidirectional diagnostic tension. We define "over-precision" as the scenario where the biopsy needle directly targets the absolute peak of cellular atypia within an index lesion. Conversely, we define "under-precision" as undersampling.

Regarding the citation of Brisbane et al., we agree that spatial resolution limitations are not exclusively a flaw of targeted biopsy (TBx). We have revised the text to clarify that findings regarding the perilesional "penumbra" must be interpreted with consideration of the potential error margin inherent to fusion biopsy platforms. We have also explicitly stated that our goal is not to present TBx as inherently flawed or to merely blame it for grade inflation. Instead, the contemporary diagnostic challenge is to reconcile the spatial sensitivity of MRI with biologically meaningful grading across the entire prostate.

Comment 2: The authors cite Kroon et al. (2025, Anser Prostate Network) as the primary quantitative source, reporting a 15% downgrading rate in 616 patients. However, is a sample of 600 patients sufficient for answering the downgrading question? Authors should search for more studies to support their statement.

Response: We completely agree. To strengthen our quantitative evidence, we have incorporated additional, larger-scale studies into Section 3. We now cite a comprehensive meta-analysis by Weinstein et al., which encompasses 6,638 patients across 19 studies. Furthermore, we have included data from a robust multicenter study by Baboudjian et al., which evaluated 1,020 biopsy-naïve patients.

Comment 3: This opinion could be further strengthened by incorporating additional recent studies related to diagnosis models, genetic driver mutations and multi-omics of prostate cancer. Integrating these relevant works would help place the present study into a broader clinical and research context and enhance the depth of Precision Paradox in prostate cancer diagnosis.

Response: We thank the reviewer for highlighting these crucial areas and providing the suggested literature. Guided by these recommendations, we have significantly expanded Section 6, now titled "The Role of Biomarkers, Genomics, and Multi-Omics". We have integrated discussions on how multi-omics (transcriptomics, proteomics, and metabolomics) provide deeper insights into tumor behavior beyond mere morphological grading.

Comment 4: In Section 6, the authors propose incorporating "MRI lesion diameter, high-grade component percentage, and lesion-perilesional sampling concordance" into risk models. An unvalidated suggestion should not appear in academic literature. The authors cite VALIDATE-PRO (NCT05017181), but this study evaluates MRI-derived metrics and prognosis, not the risk restructuring scheme proposed by the authors.

Response: We agree with the reviewer's assessment regarding the inclusion of unvalidated risk schemes and the misapplication of the VALIDATE-PRO citation. In the revised manuscript (now addressed in Section 5), we have removed the specific unvalidated parametric proposal and the citation to VALIDATE-PRO. Instead, we have adopted a much more cautious tone, noting that while it is reasonable to suggest older models require updating, established risk frameworks are not entirely invalidated by mpMRI, but rather require recalibration.

Comment 5: The 15% overall downgrading rate is insufficient for clinical guidance—GG2, GG3, and GG4 have vastly different downgrade probabilities. The authors should report downgrade rates by ISUP grade group.

Response: We thank the reviewer for this excellent point, which adds necessary clinical nuance to the manuscript. We have revised Section 3 to explicitly state that the risk of pathological downgrading is not uniform across all risk strata and is highly dependent on the initial biopsy Grade Group (GG). We have added specific data indicating that while the probability of downgrading is remarkably low for GG 2 (approximately 2.7%), it becomes highly pronounced for cases assigned a GG 4 following targeted biopsy, where up to 61% of specimens are subsequently downgraded upon comprehensive analysis of the radical prostatectomy specimen.

Reviewer 2 Report

Comments and Suggestions for Authors

With great interest, I reviewed the manuscript entitled “The Precision Paradox in Prostate Cancer Diagnostics: Grade Migration, Risk Misclassification, and Overtreatment in the mpMRI-Targeted Biopsy Era.” The topic is clinically relevant and timely. The manuscript raises an important question: whether highly focal MRI-targeted biopsy may, in selected cases, overrepresent the biological significance of limited high-grade components and thereby contribute to risk inflation and overtreatment. This is a worthwhile discussion point. However, in its current form, the paper remains too assertive for an opinion article, relies on a relatively narrow and selectively framed evidence base, and at times presents a conceptual concern as though it were already a broadly established paradigm.

Major comments:

The main limitation is conceptual overstatement. The manuscript presents the “precision paradox” as a fairly coherent and clinically dominant problem, whereas the available literature appears more heterogeneous and context-dependent. MRI-targeted biopsy can indeed contribute to grade discordance and risk reclassification, but the paper currently underemphasizes the opposite risk: undersampling, undergrading, or missing clinically relevant extension outside the index lesion. The argument would be stronger if the manuscript more clearly acknowledged that this is a bidirectional diagnostic tension rather than a one-directional overtreatment mechanism.
The manuscript repeatedly moves from biopsy-to-prostatectomy discordance to overtreatment, but that causal bridge is not sufficiently substantiated. Downgrading at prostatectomy does not automatically mean that treatment was inappropriate, nor does it prove that MRI-targeted biopsy caused clinically meaningful overtreatment. This distinction is especially important in an opinion paper submitted to Cancers. The text should more carefully separate pathological discordance, prognostic uncertainty, and actual overtreatment.
The evidence base is somewhat selective and not fully balanced. Several studies are used to support the central thesis, but the manuscript does not sufficiently integrate broader data showing the overall clinical value of mpMRI-targeted pathways, including improved detection of clinically significant disease and reduced diagnosis of low-risk disease compared with systematic biopsy alone. Without that balance, the paper risks sounding corrective in a way that may overstate the clinical harm of MRI-targeting.
The concept is interesting, but the paper would benefit from a clearer genre definition. At present it is presented as an opinion article, yet parts of the text read like a mini-review with selective supporting literature, while other parts move into normative recommendations. The authors should decide more clearly whether this is primarily a conceptual commentary, a critical perspective, or a structured narrative discussion. That would help align tone, scope, and evidentiary expectations.
Several clinical recommendations are currently broader than the paper’s evidentiary base supports. Statements regarding the need to update risk models, reinterpret Grade Group in the MRI era, or systematically reframe counseling are directionally reasonable, but they should be phrased more cautiously. The current manuscript sometimes implies that established risk frameworks are already substantially invalidated by MRI-targeted biopsy, which is too strong.
The discussion of mitigation strategies would be stronger if it were more specific and practical. At present, the manuscript argues for more nuanced interpretation, tumor-volume integration, and combined/perilesional sampling, but without enough detail on how these strategies should realistically alter decision-making in different clinical scenarios. A more explicit clinical framework would improve usefulness.

Minor comments:

The title is attractive, but “Precision Paradox” may sound more established than the current evidence justifies. A slightly more cautious formulation could be considered.
There are multiple stylistic and grammatical issues throughout the manuscript, including awkward phrasing, spacing inconsistencies, and occasional imprecise wording. Further language editing is needed.
Figure 1 and Figure 2 are relevant, but their legends are somewhat long and could be tightened.
Some references and formatting details should be checked carefully. For example, there are visible inconsistencies in citation style and language in the reference list.

Author Response

Comment 1. The main limitation is conceptual overstatement... The argument would be stronger if the manuscript more clearly acknowledged that this is a bidirectional diagnostic tension rather than a one-directional overtreatment mechanism.

Response: We entirely agree with this assessment. We have restructured the manuscript to explicitly address this dual challenge, dedicating Section 2 to "The Bidirectional Diagnostic Tension: Overestimation vs. Undersampling". We clearly state that the precision paradox is not a one-directional mechanism leading solely to overtreatment. To provide balance, we discuss the concept of "under-precision" or undersampling , acknowledging that targeted biopsy also suffers from severe spatial resolution limitations, and targeting too narrowly can miss clinically relevant disease extensions.

Comment 2. The manuscript repeatedly moves from biopsy-to-prostatectomy discordance to overtreatment, but that causal bridge is not sufficiently substantiated... The text should more carefully separate pathological discordance, prognostic uncertainty, and actual overtreatment.

Response: This is an excellent point, and we have carefully revised our terminology to prevent unwarranted leaps from discordance to overtreatment. We now explicitly advise readers to separate pathological discordance from actual clinical overtreatment. We clearly state that downgrading at prostatectomy does not automatically imply that the radical treatment was inappropriate. To substantiate this, we integrated findings from Baboudjian et al., demonstrating that while the overall downgrading rate in their study was 17%, the actual overtreatment rate—defined as patients who could have been safely managed with active surveillance—was only 2.7%.

Comment 3. The evidence base is somewhat selective and not fully balanced... the manuscript does not sufficiently integrate broader data showing the overall clinical value of mpMRI-targeted pathways...

Response: We appreciate this important critique regarding the tone and balance of the paper. We have added explicit acknowledgment of the bidirectional nature of prostate cancer diagnostics and firmly state that the integration of mpMRI and targeted biopsy provides meaningful clinical value. We highlight that this approach effectively reduces the diagnosis of indolent, low-risk prostate cancer and improves the detection of clinically significant disease compared to systematic biopsy alone.

Comment 4. The concept is interesting, but the paper would benefit from a clearer genre definition... The authors should decide more clearly whether this is primarily a conceptual commentary, a critical perspective, or a structured narrative discussion.

Response: Thank you for pointing out this ambiguity. We have clarified the aim and intent of the manuscript early in the text. We now explicitly define the paper as a "conceptual commentary" that aims to provide a "critical perspective" on this diagnostic issue. We hope this helps align the reader's expectations regarding the tone and structure of our arguments.

Comment 5. Several clinical recommendations are currently broader than the paper’s evidentiary base supports... The current manuscript sometimes implies that established risk frameworks are already substantially invalidated by MRI-targeted biopsy, which is too strong.

Response: We concur that our previous assertions regarding established risk models were too aggressive. We have adopted a much more measured tone in the revised manuscript. We now state that while it is reasonable to suggest that these models require updating, such recommendations must be phrased cautiously. We explicitly clarify that established risk frameworks are not entirely invalidated by mpMRI; rather, they require recalibration.

Comment 6. The discussion of mitigation strategies would be stronger if it were more specific and practical... A more explicit clinical framework would improve usefulness.

Response: To make our proposed mitigation strategies more actionable, we have expanded our discussion on patient-physician counseling and practical data integration. We recommend transparently discussing all findings—including PSA density, the total number of positive systematic and targeted cores, and the PI-RADS score—to contextualize focal biopsy grades. Furthermore, we suggest future models and clinical decisions should integrate focal grade data with spatial volume, PSA density, and perilesional sampling outcomes to refine patient allocation without reflexively assuming that all upgraded cancers are overtly dangerous.

Response to Minor Comments:

Title and terminology: While we have retained the title "The Precision Paradox in Prostate Cancer Diagnostics" , we have softened the introduction of the term within the text, framing it cautiously as a phenomenon "which could be called the 'Precision Paradox'" rather than an absolute, established doctrine.
Stylistic and grammatical issues: The manuscript has undergone a thorough round of proofreading and language editing to resolve unwieldly phrasing, spacing inconsistencies, and imprecise wording.
Figure legends: We have reviewed and tightened the legends for both Figure 1 and Figure 2 to make them more concise while retaining essential descriptive information.
References and formatting: We have carefully reviewed the reference list to correct visible inconsistencies in citation style and language, ensuring full compliance with the journal's formatting guidelines.

Reviewer 3 Report

Comments and Suggestions for Authors

This opinion paper raises a clinically relevant and timely perspective on the interpretive limitations of mpMRI-targeted biopsy in prostate cancer. The proposed “precision paradox” is thought-provoking and worthy of discussion.

Major Comments

The manuscript overstates the link between pathological downgrading and overtreatment: The concern is valid, but the current evidence more directly supports grading discordance than actual overtreatment. Downgrading at radical prostatectomy does not, by itself, prove that treatment was inappropriate. Unless stronger evidence is provided, the authors should soften the wording throughout and frame overtreatment as a potential consequence rather than an established outcome.
The discussion should better acknowledge the potential relevance of minor high-grade components: While the manuscript appropriately warns against overinterpreting focal high-grade findings on targeted biopsy, it should also state more clearly that small-volume high-grade disease, particularly tertiary pattern 5, should not be considered clinically irrelevant. A more balanced discussion is needed to avoid an overly one-sided message.
Figure 1 should be improved: The lesion shown in Figure 1 is too small and not sufficiently clear for an illustrative figure in an opinion paper. The authors should enlarge the lesion, add clearer annotation, or replace the image with a more representative case.

Minor Comments

The manuscript should more clearly distinguish among grade overestimation, downgrading, risk misclassification, and overtreatment, as these are related but not equivalent concepts.
The practical recommendations should be framed more cautiously. Some proposed implications for risk stratification remain conceptual and are not yet supported by validated clinical models.

Comments on the Quality of English Language

Minor language and typographical editing is needed.

Author Response

Comment 1. The manuscript overstates the link between pathological downgrading and overtreatment: The concern is valid, but the current evidence more directly supports grading discordance than actual overtreatment. Downgrading at radical prostatectomy does not, by itself, prove that treatment was inappropriate. Unless stronger evidence is provided, the authors should soften the wording throughout and frame overtreatment as a potential consequence rather than an established outcome.

Response: We completely agree with this fundamental distinction. In the revised manuscript, we have explicitly advised readers to separate pathological discordance from actual clinical overtreatment. We have softened our wording throughout the text, clarifying that downgrading at the time of prostatectomy does not automatically imply that radical treatment was inappropriate. To provide stronger, contextual evidence, we have incorporated data from Baboudjian et al.. This study reported an overall downgrading rate of 17%; however, when defining strict "overtreatment" as cases downgraded to Grade Group 1 or low-burden Grade Group 2 (which could have been safely managed with active surveillance), the actual overtreatment rate was only 2.7%. We now frame overtreatment as a theoretical exposure or potential consequence of grade migration rather than an absolute outcome.

Comment 2. The discussion should better acknowledge the potential relevance of minor high-grade components: While the manuscript appropriately warns against overinterpreting focal high-grade findings on targeted biopsy, it should also state more clearly that small-volume high-grade disease, particularly tertiary pattern 5, should not be considered clinically irrelevant. A more balanced discussion is needed to avoid an overly one-sided message.

Response: We appreciate this crucial point, which greatly enhances the balance of our commentary. We have dedicated a portion of Section 4 to explicitly discussing the relevance of minor high-grade components. We now clearly state that the presence of a small-volume high-grade disease focus detected via targeted biopsy should not be summarily dismissed as a mere statistical artifact or clinically irrelevant over-precision. We emphasize that advanced histopathological features, such as tertiary Gleason pattern 5, intraductal carcinoma (IDC), and invasive cribriform carcinoma, are predictive of adverse oncologic outcomes, including biochemical recurrence and metastatic progression. We further note that detecting these components should be viewed as the successful targeted detection of an aggressive subclone rather than a failure leading to overtreatment.

Comment 3. Figure 1 should be improved: The lesion shown in Figure 1 is too small and not sufficiently clear for an illustrative figure in an opinion paper. The authors should enlarge the lesion, add clearer annotation, or replace the image with a more representative case.

Response: Thank you for pointing this out. We have revised Figure 1 to ensure the illustrative value of the case is clear. Specifically, we have magnified the primary regions of interest, including the index lesion in Panel A and the focal gadolinium hypointensity at the needle tip in Panel C. Furthermore, clearer annotations, such as white arrows, have been added to facilitate the identification of these key features. We believe these enhancements ensure that the figure effectively demonstrates the targeted biopsy procedure as intended.

Response to Minor Comments:

The manuscript should more clearly distinguish among grade overestimation, downgrading, risk misclassification, and overtreatment, as these are related but not equivalent concepts.

Response: We have carefully reviewed the manuscript to ensure that these concepts are distinctly categorized. We describe "grade migration" and "overestimation" as the initial biopsy-level risk of inflating the overall tumor grade compared to whole-gland histology. We separate this from "pathological downgrading," which occurs at the time of radical prostatectomy. We frame "risk misclassification" as the resulting prognostic uncertainty that complicates risk stratification for downstream management, such as active surveillance or focal therapy. Finally, we explicitly state that these phenomena must be distinguished from "true clinical overtreatment," noting that the absolute risk of overtreatment remains relatively low.

The practical recommendations should be framed more cautiously. Some proposed implications for risk stratification remain conceptual and are not yet supported by validated clinical models.

Response: We concur that our recommendations regarding risk stratification must reflect the current evidentiary base. We have heavily revised Section 5 to adopt a more cautious tone. We now explicitly state that "While it is reasonable to suggest that these models require updating, such recommendations must be phrased cautiously". We clarify that established risk frameworks, such as the D'Amico classification or NCCN guidelines, are not entirely invalidated by multiparametric MRI; rather, they simply require recalibration.

Reviewer 4 Report

Comments and Suggestions for Authors

The abstract and the opening of section 1 are duplicates (same sentence). The introduction should expand on, not restate, the abstract.
The argument across Sections 2 and 3 relies almost entirely on one study (Kroon et al.). For an opinion paper making clinical claims about overtreatment risk, an elaborative and holistic approach-based synthesis and analysis of existing meta-analyses and systematic reviews (such as Weinstein et al. [5] and Goel et al. [11]) would substantially strengthen the manuscript.
The manuscript clearly advocates for refined risk stratification without once mentioning validated tissue-based biomarkers (e.g., Decipher, Prolaris, Oncotype DX GPS), which are already used clinically to adjudicate precisely the low-volume, high-grade cases the authors describe. This is an important gap that undermines the practical clinical impact of the proposed framework.
The keyword list includes "focal therapy," yet the text contains no discussion of how the precision paradox affects focal therapy candidacy or outcomes. The authors should either address this directly or remove the keyword.
No AI tool disclosure.
Sections 8 and 9 are underdeveloped. The patient counseling section (lines 222-236) largely repeats points already made in Section 5, and the conclusion (lines 237-243) is only five sentences with no discussion of the proposed mitigation strategies. Both sections need substantive expansion or consolidation.
Typos: Line 150 section "Overtratment" (missing 'e'); line 207 "measurment" (missing 'e').
Grammatical error in line 102: "According ISUP criteria" is missing the preposition.
"Paradigm shift" appears at lines 28 and 45; "meticulously" appears at line 241; "excels" at line 229. All three are clearly AI-generated phrases that weaken the writing in an opinion piece aiming for precision.
PI-RADS is used throughout the manuscript (lines 67-68, Figure 2 legend), csPCa appears at line 128, TRUS appears in Figure 2's caption, and EAU is used at lines 47 and 210; none of these are included in the abbreviations list.
What is the source of Figures 1 and 2? Please include it.

Author Response

Comment 1. The abstract and the opening of section 1 are duplicates (same sentence). The introduction should expand on, not restate, the abstract.

Response: We agree that the opening was repetitive. We have revised the text to ensure the introduction expands upon the abstract rather than duplicating it. The abstract now introduces the significant evolution of the diagnostic field with the widespread integration of multiparametric magnetic resonance imaging (mpMRI) and mpMRI-targeted biopsies (TBx). Meanwhile, the introduction elaborates on how this diagnostic pathway has been fundamentally transformed by the introduction of standardized reporting systems such as the Prostate Imaging Reporting and Data System (PI-RADS).

Comment 2. The argument across Sections 2 and 3 relies almost entirely on one study (Kroon et al.). For an opinion paper making clinical claims about overtreatment risk, an elaborative and holistic approach-based synthesis and analysis of existing meta-analyses and systematic reviews (such as Weinstein et al. and Goel et al.) would substantially strengthen the manuscript.

Response: We entirely agree that relying heavily on a single study was a limitation. We have substantially expanded Section 3 to include a broader synthesis of quantitative evidence. Specifically, we now prominently feature the comprehensive meta-analysis by Weinstein et al., which encompasses 6,638 patients across 19 studies. We also incorporated the findings from Goel et al., demonstrating that systematic biopsy has a much higher likelihood of upgrading relative to TBx, confirming that TBx effectively targets the highest-grade disease but leaves room for potential grade overestimation.

Comment 3. The manuscript clearly advocates for refined risk stratification without once mentioning validated tissue-based biomarkers (e.g., Decipher, Prolaris, Oncotype DX GPS), which are already used clinically to adjudicate precisely the low-volume, high-grade cases the authors describe. This is an important gap that undermines the practical clinical impact of the proposed framework.

Response: Thank you for highlighting this critical omission. We have added a new section (Section 6: "The Role of Biomarkers, Genomics, and Multi-Omics") dedicated entirely to this topic. We now explicitly discuss how validated tissue-based genomic classifiers, such as the Oncotype DX Genomic Prostate Score (GPS), the Prolaris Cell Cycle Progression (CCP) score, and the Decipher Genomic Classifier, have demonstrated significant clinical utility. We elaborate on how utilizing tests like Decipher on biopsy cores can stratify patients, helping identify those who may safely continue active surveillance despite a focal high-grade finding.

Comment 4. The keyword list includes "focal therapy," yet the text contains no discussion of how the precision paradox affects focal therapy candidacy or outcomes. The authors should either address this directly or remove the keyword.

Response: We chose to address this directly, as focal therapy is highly relevant to the concept. We have expanded Section 5 (now titled "Implications for Risk Stratification and Focal Therapy") to include a robust discussion on the topic. We explain that the success of Focal Therapy depends on the precise spatial and histological characterization provided by mpMRI and TBx. We also discuss how overestimating the histological grade of a small index lesion could erroneously redirect excellent candidates for organ-sparing therapies toward radical surgery.

Comment 5. No AI tool disclosure.

Responste: We appreciate this reminder. We have reviewed the journal's guidelines and confirm that the intellectual conception, synthesis, and primary drafting of this manuscript were entirely human-driven by the listed authors. We have ensured that any necessary disclosures regarding the use of basic grammar-checking software comply with the publisher's policies.

Comment 6. Sections 8 and 9 are underdeveloped. The patient counseling section (lines 222-236) largely repeats points already made in Section 5, and the conclusion (lines 237-243) is only five sentences with no discussion of the proposed mitigation strategies. Both sections need substantive expansion or consolidation.

Response: We have significantly restructured and expanded these final sections, consolidating them into Section 7 (Patient-Physician Counseling and Shared Decision Making) and Section 8 (Conclusions).

Section 7 has been revised to provide concrete clinical guidance rather than repeating earlier concepts. We now recommend transparently discussing all findings—including PSA density, the total number of positive systematic and targeted cores, and the PI-RADS score—to help patients understand their personalized risk.
Section 8 (Conclusions) has been expanded to synthesize the core arguments and explicitly discuss mitigation strategies, emphasizing that combining targeted biopsies with perilesional or regional sampling offers a highly effective method to capture the true disease extent.

Response to Minor Comments:

1.Typos: Line 150 section "Overtratment" (missing 'e'); line 207 "measurment" (missing 'e').

Response: We apologize for these oversight. Both typographical errors have been corrected in the final manuscript.

Grammatical error in line 102: "According ISUP criteria" is missing the preposition.

Response: This has been corrected. The text now properly refers to the "grading protocols established by the International Society of Urological Pathology (ISUP)".

"Paradigm shift" appears at lines 28 and 45; "meticulously" appears at line 241; "excels" at line 229. All three are clearly AI-generated phrases that weaken the writing in an opinion piece aiming for precision.

Response: We appreciate your keen eye for stylistic precision. We have thoroughly reviewed the manuscript and rephrased these expressions to ensure a more academic, precise, and authentic authorial voice throughout the text.

PI-RADS is used throughout the manuscript (lines 67-68, Figure 2 legend), csPCa appears at line 128, TRUS appears in Figure 2's caption, and EAU is used at lines 47 and 210; none of these are included in the abbreviations list.

Response: We have updated the abbreviations list to ensure it is comprehensive. The table now formally includes PI-RADS (Prostate Imaging Reporting and Data System), csPCa (Clinically Significant Prostate Cancer), TRUS (Transrectal Ultrasound), and EAU (European Association of Urology).

What is the source of Figures 1 and 2? Please include it.

Response: We have clarified that both figures are original clinical images provided by our institution. Figure 1 represents a direct MRI-guided targeted biopsy procedure from our imaging department, and Figure 2 is a post-procedural report sourced directly from our MRI/TRUS software-fusion transperineal prostate biopsy platform.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The revised manuscript is substantially improved and addresses the main previous concerns appropriately.

The remaining issues are minor and mainly relate to further softening of a few statements and slight tightening of the biomarkers/multi-omics section.

Author Response

Dear Reviewer,

Thank you for your favourable comments.

We have softened the relevant statements.

In view of the minor tightening required, we did not further shorten the multi-omics section, as we felt that doing so would have led to a loss of information and potentially compromised the quality of this Opinion paper, while providing only a limited improvement in readability.

Kind regards

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have adequately addressed the previous concerns. The revised manuscript now provides a more balanced discussion regarding pathological downgrading, risk misclassification, and overtreatment, with appropriately softened conclusions and improved supporting evidence.

The expanded discussion on the clinical relevance of minor high-grade components, including cribriform architecture and tertiary pattern 5, further strengthens the manuscript. The distinction among grade migration, downgrading, and true overtreatment is now considerably clearer. The revised figures are also improved.