Trends in the Utilization of BRCA1 and BRCA2 Testing After the Introduction of a Publicly Funded Genetic Testing Program

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This paper explores the impact of population based brca1amd 2 testing over time - critically it identifies that testing is occurring at older ages and is not impacting on identifying patients prior to cancer development - the paper is well written and presented , the discussion is excellent and insightful - the study has wider implications in other jurisdictions and on the need to realign our testing to maximise its impact 

Author Response

We thank the reviewer for these positive comments highlighting the implications and impact of these findings

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

 

I would like to congratulate for the idea of this study. The significance and the implication  of the BRCA1,2 testing is still controversial. Your paper need to be improved as follow:

• state clear the type of the study : for example- retrospective, cohort - but essential is if the study was a population based or for patients that has already diagnostic of cancer- since there are two different population that cannot be mixed.
• the objective of the study have to be clear stated- it is very important for the relevance, impact for readers
• the material and methods have to be more descriptive and the information here are insufficient
• the type of genetic testing and results have to be clear. Was taking into account also the VUS variant, the benign variant of BRCA mutation or just the pathogenic one? Was collected data about other mutation than BRCA- ex TP53, PALB2..etc?
• the conclusion have to be relevant and have to clarify the practical application of the results of this study and also to give some future direction of the research need on this field of genetic testing.

Author Response

Comment 1: State clear the type of the study: for example- retrospective, cohort – but essential is if the study was a population based or for patients that has already diagnostic of cancer- since there are two different population that cannot be mixed

Response: Thank you for this comment. We now clarify in the abstract that this was a retrospective near population-based study. Our methods explain that this study captures 70% of all women tested in the province of Ontario (hence, near population-based). Furthermore, we have now included in the inclusion criteria within our Methods that we included all women tested, including those with or without a cancer diagnosis.

 

Comment 2: the objective of the study have to be clear stated- it is very important for the relevance, impact for readers

Response: We agree with the reviewer on the need to clearly state the study objective. This is written at the end of our introduction section, “The aim of this study was to evaluate trends in utilization of BRCA1 and BRCA2 testing in Ontario since the inception of this program and to identify gaps in testing in order to inform targeted strategies for cancer risk reduction.”

 

Comment 3: the material and methods have to be more descriptive and the information here are insufficient.

Response: We have followed the STROBE guidelines for observational studies in our description of the study methods. We additionally reference the study protocol paper, which details how this cohort was created (despite this, we have attempted to include all relevant methods within this manuscript so that it can stand alone). If there are other specific details that the reviewer thinks would be necessary to include, we would welcome these comments and would be happy to incorporate these elements

 

Comment 4: the type of genetic testing and results have to be clear. Was taking into account also the VUS variant, the benign variant of BRCA mutation or just the pathogenic one? Was collected data about other mutation than BRCA- ex TP53, PALB2..etc?

Response: Thank you for this comment. In our methods, we explain the type of testing performed – “Genetic testing type was categorized as predictive/familial testing (for a specific gene variant known to be carried by a family member), Ashkenazi founder testing (testing for the three variants carried in highest frequency among the Ashkenazi Jewish population), and complete analysis (sequencing of coding region of the BRCA1 and BRCA2 genes and split cites, +/- 15 base pairs from the exon junction, as well as deletion duplication analysis.”

In our protocol paper we detail exactly how results were characterized (variants categorized by ACMG 2007 guidelines into pathogenic, likely pathogenic, VUS, likely benign, and benign) and provide the details of the classification based on the exact type of testing performed. Given that the focus of this manuscript is not the result of testing but rather the number of tests and types of tests (predictive/non-predictive), we did not include those details in this manuscript.

As noted in our methods and captured in the study title, this cohort includes only women who underwent BRCA testing. For the time period of cohort capture (2007-2016), genetic panel testing was not being performed in Ontario and, as such, individuals were not commonly undergoing testing for alternate mutations such as TP53, PALB2, etc.

 

Comment 5: The conclusion have to be relevant and have to clarify the practical application of the results of this study and also to give some future direction of the research need on this field of genetic testing.

Response: Thank you for this comment. Regarding the practical applications of the study’s results, we have highlighted:

• Shortcomings in identifying individuals *prior* to cancer development – and further discussing that prioritization of women *with* cancer for genetic testing is important but can be viewed as a lost opportunity in identifying high-risk women who could benefit from cancer risk-reduction
• Issues with reliance on family history in setting genetic testing criteria and the potential implications of having broad testing criteria
• Need for greater focus on cascade testing, proposing strategies for improving this

With respect to future directions, we have now added our perspective on this to the manuscript’s discussion section: “Future studies of testing trends among individuals undergoing panel testing and an exploration of the barriers to testing among high-risk, cancer-free individuals are needed.”

Furthermore, we state that “Our study demonstrated that a publicly funded genetic testing program can be successfully utilized to identify individuals with pathogenic variants near the time of cancer diagnosis, when this information can inform treatment decision-making. However, to truly reduce cancer burden more broadly, efforts need to shift toward utilizing such programs to identify individuals prior to cancer development…To have real impact on cancer prevention, strategies focused on increasing genetic test utilization prior to cancer development, including by broadening testing criteria and targeting individuals eligible for cascade testing, require prioritization and implementation”

Reviewer 3 Report

Comments and Suggestions for Authors

Using the data generated by the Ontario public-funded BRCA screening program in over 15000 cases, the study traced the general temporal treads of the tested individuals. The most striking result is that the participants of asymptotic individuals were not changed, regardless the free-testing policy and the increased public awareness of genetic factors contributing to hereditary cancer. This is highly contradictive to the expectation that identification of mutation carriers before cancer occurs is the most effective cancer prevention approach. The study indicates the major factor contributing to the issue is the highly conserved nature of current screening guidelines that exclude the eligibility of the potential individuals into the screening program. This is the same concerns for the proposed population screening approach under current screening guidelines, which must be modified in order to fully release the power of population screening to prevent cancer.

Author Response

We thank the reviewer for these positive comments on the implications of this study