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Genetic testing for germline cancer susceptibility genes is widely available. The Ask2Me.org (All Syndromes Known to Man Evaluator) tool is a clinical decision support tool that provides evidence-based risk predictions for individuals with pathogenic variants in cancer susceptibility genes.
The aim of this study was to understand the search behavior of the Ask2Me.org tool users, identify the patterns of queries entered, and discuss how to further improve the tool.
We analyzed the Ask2Me.org user-generated queries collected between December 12, 2018, and October 8, 2019. The gene frequencies of the user-generated queries were compared with previously published panel testing data to assess the correspondence between usage and prevalence of pathogenic variants. The frequencies of prior cancer in the user-generated queries were compared with the most recent US population–based cancer incidence.
A total of 10,085 search queries were evaluated. The average age submitted in the queries was 48.8 (SD 16.5) years, and 84.1% (8478/10,085) of the submitted queries were for females.
The patients entered in the Ask2Me.org tool are a representative cohort of patients with pathogenic variants in cancer susceptibility genes in the United States. While a majority of the queries were on breast cancer susceptibility genes, users also queried susceptibility genes with lower prevalence, which may represent a transformation from single gene testing to multigene panel testing. Owing to these changing tides, more efforts are needed to improve evidence-based clinical decision support tools to better aid clinicians and their practice.
Since the commercialization of
One major challenge for clinicians in dealing with positive genetic testing results is to provide patients with accurate cancer risk estimates. Following genetic testing, patients usually rely on their providers to interpret results and assess cancer risk. However, literature regarding the magnitude of cancer risk for specific pathogenic variants (ie, penetrance) often varies in quality and study design. It is almost impossible for busy providers to keep up with the rapidly growing literature, carefully evaluate each study, and select the most reliable risk estimate [
The Ask2Me.org (All Syndromes Known to Man Evaluator) tool is a clinical decision support tool used for providing a summary of the major cancer susceptibility genes and the associated absolute cancer risk predictions [
The Ask2Me.org tool allows users to enter patient information that includes their age and sex, prior surgical (bilateral mastectomy, hysterectomy, and oophorectomy) and cancer history, and select a gene with a pathogenic variant. In return, this tool provides a summary of that gene along with the patient’s future risk for each type of cancer associated with a pathogenic variant in the selected gene. A total of 35 genes can be queried in the Ask2Me.org tool, which covers most of the commonly tested cancer susceptibility genes such as
To assess the correlation between the frequency of genes entered by users in the Ask2Me.org tool and the frequency of pathogenic variants among patients who undergo panel testing (ie, the targeted user group of this tool), we used a large multigene cancer panel cohort reported by LaDuca et al [
Continuous data were expressed as mean (SD) and median (IQR). Categorical data were expressed as percentages. Pearson correlation coefficients were used to evaluate the degree of correlation between both user-generated queries and published gene frequencies and user-generated queries and population-based cancer incidence. A linear regression model was fitted to visualize the results. As the default setting of the Ask2Me.org tool—a 25-year-old female with no cancer or surgical history as a likely test case—a sensitivity analysis was performed by excluding these entries and re-evaluating the correlations.
From December 12, 2018 to October 8, 2019 (300 days), 10,085 queries were submitted to the Ask2Me.org tool. The average age submitted in the query was 48.8 (SD 16.5) years (median 49 [IQR 37-61] years), and 84.1% (8478/10,085) of the submitted queries were for females.
Correlation between frequencies of genes entered by the Ask2Me.org tool users and frequencies of pathogenic variants in panel testing results reported by LaDuca et al [
Of the 10,085 queries, 5343 queries (52.9%) entered a prior history of cancer, comprising 56.3% (4771/8478) of the queries on females and 35.6% (572/1607) of the queries on males. The frequencies of the type of prior cancer in the queries on females have a strong linear correlation with the corresponding US cancer incidences (
Correlation between frequencies of prior cancers in the Ask2Me.org user queries on females and corresponding US cancer incidences. The blue line represents the results from the regression model.
Correlation between frequencies of prior cancers in the Ask2Me.org user queries on males and corresponding US cancer incidences. The blue line represents the results from the regression model.
In this study, by analyzing over 10,000 user queries, we characterized the search behaviors of Ask2Me.org tool users and identified the patterns of pathogenic variants and cancer history among the queries. We found that breast cancer susceptibility genes were the most commonly searched genes in both males and females. There was a strong linear correlation between the frequencies of genes entered by Ask2Me.org users and the prevalence of pathogenic variants in panel testing results recently reported by LaDuca et al [
Hart et al [
Over half of queries entered in the Ask2Me.org tool included a personal history of cancer, with around 10% of them having multiple cancers. These results show that queries with prior cancers accounted for a considerable portion of the Ask2Me.org tool user queries. Similarly, in LaDuca et al’s 165,000-patient cohort, 72.5% of patients had a personal history of cancer [
The indications for germline genetic testing have been expanded in recent decades. In addition to testing for hereditary breast and ovarian cancer, germline genetic testing has also been recommended to manage other cancers such as colorectal cancer, pancreatic cancer, and prostate cancer. It is essential to incorporate high-quality, evidence-based, and easy-to-access clinical decision support tools into the interpretation of testing results and the personalization of disease prevention and clinical management plans. One purpose of studying search behavior is to understand user needs and further improve the Ask2Me.org tool. Since this tool became available in 2016, efforts have been made to optimize and improve this clinical decision support tool. A natural language processing algorithm was developed to classify medical literature on cancer susceptibility genes [
This study has several limitations. First, search queries are likely to correspond to not only real patients but also test cases or research purposes. Although we performed sensitivity analyses by removing the queries with default settings, there is still no way to explicitly distinguish them. Second, the frequencies of genes and prior cancers were only reflective of the search queries of the Ask2Me.org tool but may not represent the actual prevalence of the pathogenic variants and cancers at the population level. Third, as the vast majority of users are in the United States, the current findings in the searching behavior may not be generalized to users from other countries. The Ask2Me.org tool has become an increasingly recognized clinical decision tool that provides risk predictions for patients with pathogenic variants in cancer susceptibility genes. There is a strong linear relationship between the frequencies of genes entered by the Ask2Me.org tool users and the frequencies of pathogenic variants in panel testing results reported by LaDuca et al [
All Syndromes Known to Man Evaluator
DB and KSH conceived and designed the research; KY collected and analyzed the data; KY, JZ, PS, JW, and DB interpreted the results; KY and JZ drafted the manuscript; and DB and KSH made critical revisions of the manuscript. Data are available upon reasonable request. All authors approved the submission of the final manuscript.
KSH receives Honoraria from Hologic (surgical implant for radiation planning with breast conservation and wire-free breast biopsy) and Myriad Genetics and is a founder of and has a financial interest in CRA Health (Formerly Hughes RiskApps, cancer risk assessment software), which was recently acquired by Volpara (breast density and cancer risk assessment company). KSH is the cocreator of Ask2Me.org (a genetic risk KnowledgeBase), which Mass General Brigham licenses to MedNeon (a cancer risk assessment company). KSH’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham Healthcare in accordance with their conflict of interest policies. DB coleads the BayesMendel laboratory, which licenses software for the computation of risk prediction models. She does not currently derive any personal income from these licenses. All revenues are assigned to the laboratory for software maintenance and upgrades. The other authors declare that they have no conflict of interest.