Content of review 1, reviewed on January 13, 2023

In this study, the authors reviewed the current evidence on the significance of adjuvant radiotherapy in OCCC. The manuscript is straightforward, well written, and concise and has clear results within the scope of a meta-analysis. Definitely deserves to be published and is a valuable contribution to the “Cancer Control” journal. Some comments need to be addressed before publication.

[1] “1. Introduction”, Page 1 of 20, Lines 31-34:
“Almost 70% of patients were not diagnosed until advanced stages (stage III or IV) because of inability to screen. Survival rate for advanced EOC was still poor, despite the great advances in treatment and emergence of novel target therapy[2].”.
At that point, the authors should mention that proteomics has great potential to deliver clinically relevant biomarkers for ovarian cancer diagnosis, as the proteome closely mirrors the dynamic state of cells, tissues and organisms. Technologies of proteomics, such as mass spectrometry and protein array analysis, have advanced the dissection of the underlying molecular signaling events in ovarian cancer. As such proteomics analysis of ovarian cancer can uncover new therapeutic choices, which can reduce the emergence of drug resistance.
Recommended reference: Ghose A, et al. Applications of Proteomics in Ovarian Cancer: Dawn of a New Era. Proteomes. 2022;10(2):16.

[2] “1. Introduction”, Page 1 of 20, Lines 36-40:
“However, EOC should be considered a group of heterogonous diseases included several histological types, the majority was classified as high grade serous (accounting for 30-70%); while, rare subtypes of EOC included: low grade serous, clear cell, endometrioid, mucinous (and undifferentiated types [3–5].”.
The authors should also report that type I ovarian cancers typically arise from recognizable precursor lesions, such as endometriosis or borderline tumors with low malignant potential and are suggested to be relatively indolent and genetically stable. In contrast, type II ovarian cancers are proposed to be biologically aggressive tumors from their outset, with a propensity for metastasis from small-volume primary lesions. High-grade serous – the most common type of ovarian cancer, accounting for approximately 75% of epithelial ovarian cancers – develop according to the type II pathway and present p53 and BRCA mutations.
Recommended reference: Pavlidis N, et al. The outcome of patients with serous papillary peritoneal cancer, fallopian tube cancer, and epithelial ovarian cancer by treatment eras: 27 years data from the SEER registry. Cancer Epidemiol. 2021;75:102045.

[3] “1. Introduction”, Page 2 of 20, Lines 50-53:
“Exclusive randomized clinical trials (RCTs) for OCCC were scare due to its rarity, clinical evidence for specific treatment for OCCC was rare, most RCTs for EOC enrolled a small number of OCCC cases, which was the only evidences for current therapy for OCCC.”.
The authors should highlight that the most frequent genomic alterations in OCCC are mutations in the ARID1A gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches.
Recommended reference: Boussios S, et al. BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside. Cancers (Basel). 2022;14:3888.

[4] “4. Discussion”, Page 12 of 20, Lines 240-242:
“The treatment strategy for EOC had made great progress, anti-angiogenesis and PARP inhibitors had improved the prognosis of certain EOC[47-49] .”.
At that point it should be mentioned the therapeutic strategy of the combinations of PARP inhibitors with immunotherapies, such as anti-CTLA-4 and PD-1/PD-L1 that has partly been based on the hypothesis that BRCA1/2, and wild-type BRCA1/2 homologous recombination (HR) deficiency tumours display a higher neo-antigen load than HR-proficient cancers, producing more effective anti-tumour immune response. In addition, there is evidence that BRCA deficiency may induce a STING-dependent innate immune response, by inducing type I interferon and pro-inflammatory cytokine production.
Recommended reference: Revythis A, et al. Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer. Int J Environ Res Public Health. 2022;19(14):8577.

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    © 2023 the Reviewer.

Content of review 2, reviewed on March 01, 2023

In this article, the authors compare the survival outcome between adjuvant RT/CRT and non-RT during OCCC patients, in order to assess the efficacy of radiotherapy in those patients. The manuscript is straightforward, well written, and concise and has clear results within the scope of a systematic review and a meta-analysis. Definitely deserves to be published and is a valuable contribution to the “Cancer Control” journal. Some comments on the introduction need to be addressed before publication.

[1] “1. Introduction”, Page 14 of 38, Lines 34-37:
“Preclinical studies suggested, new surveillance methods such as liquid biopsy, high-throughput sequencing, proteomics analysis, and so on, might improve the early detection rate of EOC, but they were still immature, not widely adopted in clinical practice yet.”.
At that point, the authors should report the new approaches in proteomics. Targeted proteomics is a key technique that enables the validation and verification of biomarkers that have been discovered. It works with untargeted proteomics to complete the cycle of biomarker discovery and validation. Peptidomics is the second new sub-division of proteomics and can, also, be used to shed light on new biomarkers. It is the study of peptides used to determine the exact form of each peptide. Like proteomics, it is used to identify new peptides that exist within tissue. It utilises quantification techniques to measure the relative level of peptides in varying environments. Finally, exosomes, play a critical role in intercellular communication and they have emerged as a compelling diagnostic and prognostic biomarkers for EOC, as they may transport some tumour-associated proteins.
Recommended reference: Ghose A, et al. Applications of Proteomics in Ovarian Cancer: Dawn of a New Era. Proteomes. 2022;10(2):16.

[2] “1. Introduction”, Page 14 of 38, Lines 39-40:
“Optimal cytoreduction to minimal residual tumor burden combined with platinum-based chemotherapy was the standard protocol for EOC.”.
The authors should clearly mention that when mutations occur within DNA repair pathways, there is an increased risk of chemotherapy resistance. The synthetic lethality of PARP inhibitors is directed against BRCA mutations, which are emerging as novel targets for the treatment of epithelial ovarian cancer. Among PARP inhibitors, olaparib, rucaparib, and niraparib have been approved by the FDA and/or the EMA in EOC in different settings. Olaparib, rucaparib, and niraparib trap PARP approximately 100-fold more efficiently than veliparib.
Recommended reference: Boussios S, et al. BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside. Cancers (Basel). 2022;14(16):3888.

[3] “1. Introduction”, Page 14 of 38, Lines 40-44:
“However, EOC should not be considered a single disease, but a group of heterogonous diseases, according to precursor lesions and genetic background, it could be divided into the less common, slow-growing type I cancers and the more common, aggressive type II cancers”.
At that point, it should be reported that BRCA1/2 germline mutations are the strongest known genetic risk factors for epithelial ovarian cancer and are found in 6–15% of women with epithelial ovarian cancer. The BRCA1/2 status can be used for patients’ counselling regarding expected survival, as BRCA1/2 carriers with EOC respond better than non-carriers to platinum-based chemotherapies. This yields greater survival, even though the disease is generally diagnosed at a later stage and higher grade.
Recommended reference: Shah S, et al. Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes. Int J Environ Res Public Health. 2022;19(13):8113.

[4] “1. Introduction”, Page 15 of 38, Lines 59-61:
“The molecular background of OCCC was unique, since was usually negative for p53 mutations and positive for ARID1A and/or PIK3CA mutations, might served as potential precision oncology approaches”.
Here, it should be reported that since inflammatory and epigenetic processes seem to play a predominant role in the pathogenesis of OCCC, immune checkpoint inhibitors and targeting the PI3K pathway as well as epigenetic treatment approaches may play an important role in the treatment of these tumor entities.
Recommended reference: Samartzis EP, et al. Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets-a narrative review. Ann Transl Med. 2020;8(24):1712.

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    © 2023 the Reviewer.

Content of review 3, reviewed on April 03, 2023

My comments were addressed by the authors.

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    © 2023 the Reviewer.

Content of review 4, reviewed on April 25, 2023

The manuscript is significantly improved and may be a valuable contribution to the “Cancer Control” journal. However, the following references should be added.

[1] “1. Introduction”, Page 27 of 40, Lines 37-41:
“Although peptidomics might identify novel targets and pivotal pathways related to the occurrence and development of cancers, had been regarded as ideal new biomarkers, due to the significant genomic heterogeneity of EOC, lower sensitivity and specificity were the major limiting factors for its application”.
You should definitely add reference.
Recommended reference: Ghose A, et al. Applications of Proteomics in Ovarian Cancer: Dawn of a New Era. Proteomes. 2022;10(2):16.

[2] “1. Introduction”, Page 28 of 40, Lines 62-65:
“Different molecular background might determine different biological behavior, therapeutic sensitivity and prognosis, BRCA1/2 germline mutations were the strongest known genetic risk factors for EOC and were found in 6-15% of women with EOC.”.
Reference is missing.
Recommended reference: Shah S, et al. Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes. Int J Environ Res Public Health. 2022;19(13):8113.

[3] “1. Introduction”, Page 28 of 40, Lines 82-87:
“The molecular background of OCCC was unique, since was usually negative for p53 mutations and positive for ARID1A and/or PIK3CA mutations, might served as potential precision oncological approaches. Immune checkpoint inhibitors and targeting the PI3K pathway as well as epigenetic treatment approaches might play an important role in the treatment of these tumor entities.”.
Again, the reference should be added.
Recommended reference: Boussios S, et al. BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside. Cancers (Basel). 2022;14(16):3888.

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    © 2023 the Reviewer.

Content of review 5, reviewed on May 01, 2023

All my concerns have been adequately addressed by the authors.
The final version can be accepted for publication.
Congratulations on the great work.

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    © 2023 the Reviewer.

References

    Yuan, Z., Hua, Y. 2023. The Significance of Radiotherapy in Ovarian Clear Cell Carcinoma: A Systematic Review and Meta-Analysis. Cancer Control.