PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Gene Alterations: Current Evidence Across Ovarian, Breast, Prostate, and Pancreatic Cancers

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors conducted a systematic narrative literature review on “PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Defects: Unlocking potential tar- get Across Ovarian, Breast, Prostate, and Pancreatic Cancers” the interesting topic to cover cross cancers.

Major comments:

1. Lines 28-33: as the authors mentioned in the abstract and methodology sections the study is a systematic review and they have to follow PRISMA guide lines in the manuscript. The authors expected to add a sub-section under the methodology section including search strategies and a registration ID for research strategies.
2. Please re-do the workflow of the manuscript strictly based on the PRISMA guidelines.
3. Please provide the PRISMA check list based on the following PRISMA web address; (https://www.prisma-statement.org).
4. The authors should enhance all the manuscript sections including; Title, Abstract, Methodology, Conclusion. Base on the PRISMA check list.
5. Table 1 in the word file seems is not completed
6. Lines 1172-1180; the authors contribution need to update and remove all default text.

Author Response

• Reviewer 1

Comment 1

Lines 28–33: The authors mentioned that this is a systematic review and therefore should follow PRISMA guidelines, including search strategy and registration.

Response

We appreciate this important observation. After carefully considering the reviewer's comments, we concluded that the manuscript is more accurately classified as a Narrative Review rather than a systematic review. Accordingly, we removed all references to PRISMA compliance, systematic review methodology, and protocol registration throughout the manuscript. The Methods section was completely rewritten to describe the literature search strategy used for this narrative review, including the consulted databases, search approach, and evidence synthesis.

 

Comment 2

Please redesign the workflow according to PRISMA.

Response

Thank you for this suggestion. Since the manuscript has been reclassified as a Narrative Review, a PRISMA flowchart is no longer appropriate. The previous workflow figure was therefore removed and replaced with a schematic illustrating the literature identification strategy consistent with the narrative review methodology.

 

Comment 3

Please provide the PRISMA checklist.

Response

As the manuscript is no longer presented as a systematic review, the PRISMA checklist is no longer applicable and therefore has not been included.

 

Comment 4

Enhance the Title, Abstract, Methodology and Conclusion according to PRISMA.

Response

We have extensively revised these sections. The title now clearly reflects the scope of a narrative review. The Abstract was rewritten to remove systematic review terminology and to accurately describe the narrative methodology. The Methods section now explains the targeted literature search strategy, and the Conclusion has been strengthened to emphasize the current level of evidence supporting individual non-BRCA homologous recombination genes.

 

Comment 5

Table 1 seems incomplete.

Response

Thank you for identifying this issue. Table 1 has been carefully reviewed, completed, and reformatted to improve clarity and consistency.

 

Comment 6

Author contributions should be updated.

Response

The Author Contributions section has been completely revised, and all default template text has been removed.

Reviewer 2 Report

Comments and Suggestions for Authors

This review comprehensively and systematically explored the clinical relevance of non-BRCA homologous recombination gene variants in predicting the sensitivity of ovarian, breast, prostate, and pancreatic cancers to PARP inhibitors. The authors successfully integrated a wealth of evidence, ranging from in vitro preclinical models to 17 important clinical trials, directly addressing how to expand the population benefiting from PARP inhibitors. The article is well-structured and richly illustrated. However, to further enhance the scientific depth and rigor of this review, further revisions are recommended regarding data synthesis methods, heterogeneity analysis, and manuscript verification.

1. Although this is a narrative review, for genes with relatively mature data, extracting objective response rate or hazard ratio data from multiple clinical trials and providing simple forest plots or pooled data analysis would significantly enhance the article's scientific persuasiveness. If a meta-analysis is not feasible, a summary chart is recommended to visually compare the confidence levels of clinical benefits of various genes across different cancer types.

2. Different clinical trials used different testing platforms. The different threshold definitions for LOH or HRD scores on different platforms may be a key factor leading to inconsistencies in cross-trial data. It is recommended to add a dedicated paragraph to discuss the limitations of current HRD companion diagnostic tools in detecting non-BRCA variants.

3. Clinical trial results show that the benefits of non-BRCA genes are highly heterogeneous. It is recommended to explore the underlying molecular mechanisms of this phenomenon in the Discussion section. For example, the difference between monoallelic and bialelic inactivation, the impact of mutation types, and whether the different hierarchical positions of different HR genes in DNA repair pathways determine the differences in sensitivity to PARPi.

In conclusion, the manuscript needs revision before acceptance.

Author Response

• Reviewer 2

Comment 1

A summary chart or pooled comparison of clinical benefit across genes would strengthen the manuscript.

Response

We appreciate this valuable suggestion. Because of the considerable heterogeneity among available studies—including differences in tumor types, study design, enrolled populations, biomarker definitions, and reported endpoints—a formal meta-analysis or pooled quantitative analysis was considered inappropriate.

Instead, we added a new summary table that ranks the current level of clinical evidence for each non-BRCA homologous recombination gene across ovarian, breast, prostate, and pancreatic cancers. This table provides a concise visual comparison of the strength of evidence and highlights the marked heterogeneity observed among different genes and tumor types.

 

Comment 2

Discuss limitations of HRD companion diagnostic assays.

Response

Thank you for this excellent recommendation. A new subsection entitled "Limitations of Current HRD Companion Diagnostic Assays" has been incorporated into the Discussion. This section discusses differences among commercially available HRD assays, including genomic scar scores, loss-of-heterozygosity thresholds, assay variability, historical versus functional HRD, and the limitations of current companion diagnostics in predicting PARP inhibitor sensitivity in tumors carrying non-BRCA homologous recombination gene alterations.

 

Comment 3

Discuss biological mechanisms underlying heterogeneous responses.

Response

We fully agree with the reviewer. The Discussion has been substantially expanded to include a new subsection entitled "Biological Determinants of Heterogeneous PARP Inhibitor Sensitivity." We now discuss the influence of monoallelic versus biallelic inactivation, loss of heterozygosity, mutation type, functional position of individual homologous recombination genes within DNA repair pathways, and known resistance mechanisms such as BRCA reversion mutations and restoration of homologous recombination.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript reviews an important topic on PARP inhibitor sensitivity in tumors with non-BRCA homologous recombination gene defects. The review is useful because the clinical role of non-BRCA HR gene alterations is still not fully clear across ovarian, breast, prostate, and pancreatic cancers.

Overall, the review is good and the authors summarize preclinical evidence, clinical trial data, HRD testing, and ongoing studies. The review also appropriately highlights that PARP inhibitor sensitivity is not the same for all non-BRCA HR genes and that the clinical benefit depends on both the gene and the tumor type.

I recommend minor revisions to improve clarity and presentation.

First, the methodology section should be slightly clearer. The authors state that the review follows PRISMA guidelines, describing it more clearly would help readers understand how the final studies were selected.

Second, the authors should more clearly separate preclinical evidence from clinical evidence. Some genes show PARP inhibitor sensitivity in models, but the clinical response in patients is more variable. This distinction is important and should be emphasized throughout the review.

Third, the conclusions should be a little more precise. The manuscript should avoid grouping all non-BRCA HR genes together. For example, PALB2 appears to have stronger clinical evidence in some settings, while ATM, CHEK2, and CDK12 show more limited or inconsistent benefit. A short summary table ranking the level of clinical evidence by gene and tumor type would be very helpful.

Fourth, the figures and tables should be checked carefully. Some figures are busy and difficult to read. The supplementary tables are useful, but the authors should correct small issues such as duplicated trial IDs, inconsistent terminology, and wording such as “Unknow status.”

Finally, the manuscript needs English editing. The text is understandable, but there are several grammar and spelling issues. The title should also be revised, especially the phrase “Unlocking potential target,” which does not read clearly.

Overall, this is a useful review and I support publication after minor revision. The manuscript would be stronger if the authors improve the methodological clarity, refine the conclusions, and carefully edit the language, figures, and tables.

Comments on the Quality of English Language

The English is generally understandable, but it needs editing for grammar, spelling, and clarity. Some sentences are long or awkward. The authors should also correct spelling and wording issues such as “heterogenous,” “cancer dependant,” “proeminent,” and “Unknow status.” The title should also be revised for clarity.

Author Response

• Reviewer 3

Comment 1

Clarify the methodology.

Response

The methodology has been completely rewritten to accurately describe the literature search strategy used in this narrative review. We also removed all statements suggesting that the study followed systematic review methodology.

 

Comment 2

Separate preclinical from clinical evidence.

Response

We appreciate this suggestion. The manuscript has been reorganized to provide a clearer distinction between preclinical evidence and clinical evidence throughout the Results and Discussion sections, emphasizing that promising preclinical findings do not necessarily translate into clinical benefit.

 

Comment 3

Conclusions should distinguish genes with stronger evidence.

Response

We agree. The Conclusion has been rewritten to emphasize the differences in clinical evidence among individual genes. We specifically highlight the stronger evidence supporting PALB2 and RAD51C/RAD51D alterations, while emphasizing that ATM, CHEK2, CDK12, and several other genes currently demonstrate limited or inconsistent evidence of benefit.

Additionally, a new summary table ranking the level of evidence across genes and tumor types has been incorporated into the manuscript.

 

Comment 4

Figures and supplementary material should be checked.

Response

All figures have been redesigned to improve readability and consistency. Figure legends were revised for clarity, duplicated identifiers in supplementary tables were corrected, inconsistent terminology was standardized, and typographical errors (including "Unknown status") were corrected.

Comment 5

English language requires editing.

Response

The entire manuscript has undergone comprehensive English language editing to improve grammar, readability, scientific style, and consistency. The title was also revised to improve clarity and precision.

Reviewer 4 Report

Comments and Suggestions for Authors

Review of the article by Elizabeth Santana dos Santos et al., "PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Defects: Unlocking potential target Across Ovarian, Breast, Prostate, and Pancreatic Cancers".

This is a valuable and interesting article. I have only a few points to make corrections:

1. In the Introduction is (lines 78-80):
"Therefore, concurrent inhibition of PARP enzymes along with HRD results in an accumulation of DNA damage and genomic instability, which is lethal to cancer cells (Figure 1)."

Genomic instability can also cause genome remodelling, and as a result the cancer cells usually die, but a very small part of the cancer cells can stay alive, often achieving drug resistance.
For this reason, this part of the article and Figure 1 should be thought over and corrected accordingly. This part of your article is also related to treatment effectiveness and conclusions from your work (see my point 3). 

2. In the Figure 1 is:
a) "wild type BRCA tumors".
The meaning of "wild type BRCA tumors" should be presented in the text of the article and also in the description of Figure 1.

b) "??".
The meaning of these two question marks should be presented in the description of Figure 1.

c) In the part "Pre-clinical studies" ("in vivo"), a picture of a rat is presented.
General mechanisms of cancer transformation and progression are similar (or the same) in humans and rats (and other multicellular organisms).
However, the effectiveness of cancer treatment in animals and humans is different.

3. In the Introduction is (lines 101-104):
"The predictive potential of non-BRCA HR PV (e.g. PV in RAD51C, RAD51D, BRIP1, PALB2, NBN, ATM, CHEK2, CDK12) has been evaluated as exploratory analysis of clinical trial data, but no definitive conclusion can be reached so far."

The effectiveness of synthetic lethality therapies depends, among others, on genes and mutations in these genes. Therapies that cause synthetic lethality (for example, PARPi) are the most effective in BRCA-mutated tumors, so the conclusion (lines 1171-1174): "In conclusion, alterations in non-BRCA homologous recombination genes may have clinical relevance as predictive biomarkers of response to PARPi. However, the benefit appears more heterogeneous and generally less pronounced than that observed in BRCA1/2-mutated tumors." is correct.

In the Conclusion part is:
"The main genes with a relevant impact are PALB2, RAD51C and RAD51D." (lines 1174,1175).
It is visible from the article that in the cases of mutations in these genes the therapies that cause synthetic lethality can also be effective.

In the other considered cases in the article, i.e., mutations in the other genes, for example, in ATM/CDK12 and CHEK2 (line 1175), the therapies that cause synthetic lethality may not lead to the death of most cancer cells and may also increase the risk of genome remodelling and, as a result, lead to the emergence of treatment-resistant clones. From this perspective, maybe it is better not to use the therapies that cause synthetic lethality for cancer with mutations in these genes, i.e., ATM/CDK12 and CHEK2 (see my point 1). Please extend your interpretations and discussion accordingly, taking this into account.

4. "Other genes hare more discussed" (line 1175) - "hare" should be corrected to "are".

Author Response

• Reviewer 4

Comment 1

Discuss possible emergence of resistant clones after genomic instability.

Response

We appreciate this insightful observation. The Introduction and Discussion have been revised to clarify that while synthetic lethality generally induces cancer cell death, genomic instability may also promote the emergence of resistant subclones in a minority of tumor cells. We also incorporated discussion regarding known mechanisms of acquired resistance to PARP inhibitors.

 

Comment 2

Clarify Figure 1 ("wild-type BRCA tumors", question marks, animal model).

Response

Figure 1 has been completely redesigned. The meaning of "BRCA wild-type tumors" is now explicitly described both in the main text and in the figure legend. The ambiguous question marks were removed, and the representation of preclinical studies was modified to avoid implying direct equivalence between animal models and human clinical outcomes.

 

Comment 3

Expand discussion regarding ATM, CHEK2 and CDK12.

Response

We appreciate this important suggestion. The Discussion and Conclusion now more clearly emphasize that current evidence supporting PARP inhibitor sensitivity varies considerably among individual homologous recombination genes. While PALB2 and RAD51C/RAD51D demonstrate the strongest clinical evidence outside BRCA1/2, alterations in ATM, CHEK2, and CDK12 have shown inconsistent responses across clinical studies. We discuss possible biological explanations for these differences, including incomplete homologous recombination deficiency, monoallelic alterations, and alternative DNA repair mechanisms. We also acknowledge that these biomarkers currently require further prospective validation before routine clinical implementation.

 

Comment 4

"hare" should be corrected to "are".

Response

This typographical error has been corrected.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I appreciate the authors' effort to address comments.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have addressed all of my previous comments satisfactorily. The revisions made to the manuscript are appropriate and have improved its clarity and quality. I have no further suggestions and recommend the manuscript for acceptance in its current form.

Comments on the Quality of English Language

The English is generally understandable, but it needs editing for grammar, spelling, and clarity. Some sentences are long or awkward. The authors should also correct spelling and wording issues such as “heterogenous,” “cancer dependant,” “proeminent,” and “Unknow status.” The title should also be revised for clarity.