Ovarian Cancer: From Precursor Lesion Identification to Population-Based Prevention Programs

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors review the rationale, advantages, and challenges of implementing opportunistic salpingectomy as a mechanism to reduce the incidence of high-grade serous carcinoma.

Comments:

1.       Page 2, line 45. The majority of HGSC show “strong” p53 staining (i.e., diffuse overexpression), but some cases also show null or rarely cytoplasmic staining. “strong” could be changed to “mutant pattern” to account for these other patterns of expression.

2.       Page 2, line 48: “BRCA1 variants increase the risk of ovarian cancer by 39%-44%, and variants in BRCA2 increase a patient's risk by 11%-17% [12].” However, the abstract for reference 12 says “The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers.” That is, those are the cumulative risks, not the increase in risk.

3.       Page 2, line 49: “in ovarian carcinomas, 54% of somatic variants occur in BRCA1, 17% of somatic variants occur in BRCA2, and 56% of germline loss of function variants found in BRCA1 and 19% in BRCA2”. What is the denominator here? I believe in the cited reference these numbers refer to % of HR mutations, but this isn’t clear from the sentence in the manuscript.

4.       Figure 2, “recommended age range to receive bilateral salpingectomy” for BRCA carriers. Where are these ranges from and what is the rational for them? For example, if a 30 year old BRCA carrier does not wish to maintain fertility, why wait 5-10 years before RR salpingectomy?

5.       Although this is a US-specific issue, there are Medicaid related restrictions which may limit the uptake of OS and this should be briefly mentioned (see PMID: 24401047).

6.       Page 5, line 191: should “salpingectomy” be “oophorectomy”?

7.       Gene names should be italicized.

Comments on the Quality of English Language

The paper would benefit from careful proofreading.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In the manuscript “Ovarian Cancer: From precursor lesion identification to population-based prevention programs”, authors discuss opportunistic salpingectomy as primary ovarian cancer prevention strategy, concluding that optimizing access to salpingectomy during other surgeries, e.g. by increasing awareness and improving patient counseling, could help to – indirectly – reduce ovarian cancer risk in selected patients.

Overall, authors provide a comprehensive review, pointing out the unmet clinical need for evidence- based prevention programs for ovarian cancer, discuss the clinical and pathologic background and conclude that targeted salpingectomy in patients at increased risk appears beneficial. Authors thereby somehow point out the obvious, but despite some critical factual errors in the introduction considering clinical considerations, the present review addresses a currently important issue: In times of increasing costs of oncologic therapies – we expect an IO/PARPi/Bev maintenance to become standard of care of advanced EOCs following DUO- data, which will translate in a cost explosion – therefore, every preventable case of EOC has to be of prime interest.

However, there are some important issue to address:

Abstract & Intro, lines 18& 43: The phrase “HGSC are know for their clinical aggressiveness” is as unspecific as clinically useless – aggressive as compared to what exactly? To date, HGSC is the subtype of ovarian cancer we can treat best, and survival estimates for advanced HGSCs doubled in the past 20 years. I suggest to remove these phrases without replacement.

line 40: “Each histotype has unique genomic profiles and treatment targets and can
be considered distinct diseases” does not sound like correct English to me. Apart from that, the only approved treatment target for any subtype is HRD positivity, so I would rephrase this sentence anyway, e.g.: “As each histotype features unique genomic profiles, which translate into specific clinical behaviours, they are to be considered distinct diseases.”

Lines 47-48: “BRCA1 variants increase the risk of ovarian cancer by 39%-44%, and variants in BRCA2 increase a patient's risk by 11%-17%”. These numbers are not relative risk increases, but the absolute risks for carriers. A BRCA1 carrier has a lifetime risk of about 50%, a BRCA2 carrier a lifetime risk of up to 25%. Considering a liftetime risk of ~1% in an unselected population, an RR of 11-44% could almost be considered clinically meaningless. Literature quoted by authors: Kuchenbaecker, JAMA Oncol: „The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers”. Please clarify this accordingly.

Lines 49ff: The deduction regarding PARPi is clinically irrelevant and mirrors our knowledge from about 5 years ago. The current clinical test to select patients who are likely to profit from adjuvant PARPi is NOT BRCA sequencing, but a HRD test.

Lines 58-61: “Although the incidence of ovarian cancer has decreased, largely attributable to a dramatic reduction in risk due to widespread use of oral contraceptives, the 5-year survival rate of less than 50% has not changed substantially over the last two decades [17,18].”

I would at least relativize the information regarding COCs and ovarian cancer risk. To my knowledge, this idea is derived from population-based observations and offers a solid rationale backed by strong statistical association, but we can not prove that this is causative. There are too many potential confounders and other influences around, yet alone that the most commonly accepted idea that HGSC actually originate from STICs/fimbria lesions does not go along well with the COC-theory.

@5year survival: This information is not only factually wrong, but also poorly quoted. Authors just refer to SEER without further information.

In fact:

-          Ray-Coquard, Ann Oncol 2023: 5-Year OS rate in HRD+ disease was 66% with olaparib + bevacizumab versus 48% with placebo + bevacizumab.

-          In 2013, at the dawn of the introduction of bevacizumab, Garcia et al in Ther Adv Med Oncol. estimated the 5y-OS for Ovarian Cancer in high-risk populations to be as low as 27%.

-          If you go back to early 2000, considering e.g. ICON-4, when platinum started to get fully implemented, OS estimates are even lower

Line 158: please write gene symbols like ARID1A in italics whenever mentioned

Line 181: I may recommend against using “OS” as an abbreviation for opportunistic salpingectomy. This is not a well-established abbreviation and would rather remind of “overall survival”

Line 344: proposing a model with almost 5% overestimation is clinically not feasible for population- wide screenings, as its false-positive rate is way too high considering the low incidence of ovarian cancer. Despite low surgical complication risks, yet alone the suspicion of earlier menopause following salpingectomy would result in a loss of healthy life expectancy on a population-wide level. Such models may help clinical decision making in future, but are not fit for clinical routine to date.

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This paper is primarily a review regarding the possible origins of epithelial ovarian cancer epidemiology and the potential strategies regarding ovarian cancer prevention for women with high-risk genetic variants (BRCA mutation carriers). 

The article is well written, and the English language is appropriate and understandable.

The review is clear and comprehensive.

The clinical arguments presented are innovative and of clinical relevance taking into account current evidence for opportunistic salpingectomy in terms of screening, safety, and effectiveness.

The authors reported also data on strategies for scaling ovarian cancer prevention in the future including opportunistic salpingectomy during non-gynecological abdominopelvic procedures such as appendectomy, cholecystectomy, hernia repair, and urological surgeries, as potential targets to increase salpingectomy uptake. 

The conclusions are appropriate focusing on the need for increasing education and awareness of salpingectomy.

The cited references are mostly recent and relevant publications.

Author Response

Thank you for the comments, we greatly appreciate the feedback.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I may thank the authors for adapting the manuscript as suggested - I have no further remarks.