Emerging Biomarker-Guided Therapies in Prostate Cancer

Round 1

Reviewer 1 Report

The authors have submitted a review of the rapidly changing landscape of prostate cancer treatments and associated bio-markers. The focus is the biomarkers ability to predict treatment effect. Overall the review is clear cut, comprehensive and easily understood. The review, if published will potentially be of help for health professionals involved in prostate cancer care albeit not directly involved in the research field. There are several helpful (and beautiful) illustrations throughout the manuscript further facilitating for the reader to understand various mechanisms.   Minor comments Line 176-180: The development of more aggressive tumours in a low testosterone environment have been assessed and mechanisms have been suggested. The authors can consider acknowledging this research.   The associations between the biomarkers and the different outcomes are inconsistently reported. The first couple of markers are simply reported as predicting this or that whereas the later associations are reported with both central estimate, confidence intervals and p values.  

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

The structure of the article should reflect the logic of the title: it should emphasize the role of the biomarkers, in every therapy class.

Row #49: The therapy of nmCRPC includes now, along ADT, other classes of drugs, including second generation antiandrogens, or abiraterone.

Row #89: The methodology of the literature search should be better described, including all the search terms related to the therapy options and to the corresponding biomarkers.

Row #97: Please rephrase the first sentence – the association of “unfortunately eventually” is not so relevant for the development of the resistance to castration/ADT.

Row #106: Please give more details about the mechanism of action of abiraterone.

Row #120: Please number the subsection about NLR as 2.1.1

Row #128: Please create a new section, dealing with testosterone, numbered as 2.1.2

Row #136: Please number the subsection about AR-V7 as 2.1.3

Row #149: Please number the subsection about ctDNA and cfDNA as 2.1.4; moreover, please develop this subsection and give more information regarding liquid biopsies

Row #175: Please number the subsection about low testosterone as 2.2.1.1

Row #182: Please number the subsection about ERG as 2.2.1.2.

Row #207: Please number the subsection on DNA repair genes mutations as 2.2.2.1         

Row #211: Please number the subsection on SLFN11 as 2.2.2.2

Row #232: Please number the subsection on Lu-PSMA as 2.4.1.1

Row #238: Figure 2, describing PSMA binding, is missing.

Row #241: Please number the subsection on Ga-PSMA as 2.4.1.2

Row #254: Please number the subsection on Ac-PSMA as 2.4.1.3

Row #262: Please number the subsection on BiTE as 2.4.2.1

Row #267: Please number the subsection on CAR-T as 2.4.2.2

Row #280: Please number the subsection on HRR mutations as 2.5.1.1

Row #337: I suggest to move the whole paragraph to the Limitations/Discussion section.

Row #400: Please mark CTLA-4, PD-1, PDL-1, MSI, dMMR, and tumor mutational burden with bold (or bold italic) letters, to emphasize their role as biomarkers.

Row #463: Please mark prostatic acid phosphatase with bold (or bold italic) letters, to emphasize its role as a biomarker.

Row #480: Please expand the section LIMITATIONS, considering the actual limitations of the mentioned biomarkers, and also the strategies being developed to overcome these limitations, together with some new research ideas in the field.

The Figures should be placed in the text right after their first mention.

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

 

 

In this review Deluce et al., sumarised new potential biomarkers driving treatments for advanced human prostate cancer. For this work the authors conducted a fine literature search based on Clinical Trials and retrieved English article published between 2015-2022.

Minor concerns:

Please improve the structure of the first part of the manuscript. From Methods to chapter 2.5 (PARP section) there is a lot of repetition and in reading the purpose of the review is lost.

All figures: please provide explanation of the figure contents also in the legend.

There is confusion between figure 2 and 3/4. Line 229-238, refers to fig 2 but there is not any correspondence between the figure and the text, while I found some correspondence with what shown in fig 3. Again, fig 4 shows the mechanism of action of Lutetium-177, which would make sense to me think that fig 4 is actually the fig 2.

Figure 1: Panel A and B: are not clear. It is difficult link what is described in the text (line 50-52) with what shown in panel A. Pathways shown in panel B should be better explained in the text. Please review the figure consistently with what reported in the text.

Line 149: please explain what the differences are between ctDNA and cfDNA

Line 152-53: the sentence is unclear

Line 153-58: text is unclear and also somewhat confusing.

Line 202-203: repetition of what was already typed in the text above

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

The Authors fully responded and revised the manuscript as requested. I have nothing to add, I am satisfied with the revision