Factors that influence the management recommendations breast surgeons provide to women with pathogenic variants in moderate penetrance breast cancer susceptibility genes

Pathogenic variants in moderate penetrance breast cancer susceptibility genes, such as ATM and CHEK2, confer a two‐ to five‐fold increased lifetime risk for breast cancer. The National Comprehensive Cancer Network has guidelines for breast surgeons to utilize when counseling women with pathogenic variants in these genes; however, previous studies indicate that other factors impact breast surgeons' recommendations to patients. This study investigated factors influencing management recommendations presented by breast surgeons to women with pathogenic variants in moderate penetrance breast cancer susceptibility genes. Focus groups and interviews were conducted with breast surgeons practicing in Ohio, Kentucky, and Indiana. A total of 15 breast surgeons from eight different hospitals participated in five focus groups and three individual interviews. Participants discussed factors they consider when making management recommendations for risk reduction in women with pathogenic variants in moderate penetrance breast cancer susceptibility genes. Participants provided risk management recommendations for given scenarios. Patient motivation/opinion, family history, patient current health status, patient personal preference, and patient anxiety level were among the most common factors mentioned. It appeared that how these factors are valued and applied in practice varies. There was no consensus among breast surgeons on which risk‐reducing management options they would recommend in each scenario. There are many factors breast surgeons take into consideration when making recommendations for this patient population. This information could inform future research on decision making around treatment for individuals with pathogenic variants in moderate penetrance breast cancer susceptibility genes.


| INTRODUC TI ON
Although most breast cancers occur sporadically, a significant proportion are caused by an inherited genetic predisposition, through either multifactorial inheritance or hereditary cancer syndromes (Hollestelle et al., 2010). Breast cancer susceptibility genes can be divided into two major categories: high and moderate penetrance.
High penetrance genes, such as BRCA1, BRCA2, PTEN, and TP53, confer a greater than five-fold increased lifetime risk of breast cancer, and moderate penetrance genes, such as ATM and CHEK2, confer a two-to five-fold increased lifetime risk of breast cancer (Couch et al., 2017;Hollestelle et al., 2010;Weiss et al., 2018). Previously, moderate penetrance breast cancer genes included ATM, CHEK2, CDH1, NBN, NF1, PALB2, and STK11; however, in recent years the specific breast cancer risks conferred by pathogenic variants in these genes have been better established, with some of these genes now being classified as high risk, such as PALB2, CDH1, and STK11, and others now no longer being associated with breast cancer, such as NBN (Hu et al., 2021;Wood et al., 2020;Zuntini et al., 2021).
The risk of primary breast cancer is well established for high penetrance and some moderate penetrance breast cancer susceptibility genes; pathogenic variants in BRCA1 and BRCA2 confer a 5-to 20fold increased risk, PTEN confer a six-fold increased risk, and CHEK2 and ATM each confer a three-fold increased risk (Kurian et al., 2011;Weiss et al., 2018).
The risk for a second primary breast cancer is well established for individuals who carry a pathogenic variant in either BRCA1 or BRCA2, while this risk for women with pathogenic variants in a moderate penetrance breast cancer susceptibility gene is less well defined; Weiss et al. (2018) noted that a specific truncating variant in CHEK2, c.1100delC, confers a relative risk of 2.77 for second primary breast cancer. Hollestelle et al. (2010) suggested the reason rates of second primary diagnosis have not been established for moderate penetrance breast cancer susceptibility genes may be due to the polygenic inheritance of these genes, meaning that several different genes all contribute to the same trait or cancer risk. This complicates risk calculations for moderate penetrance breast cancer susceptibility genes.
There are also genes that were previously described as potentially conferring an increased risk of breast cancer without a quantified risk figure. These genes were previously described as "unknown risk genes" and include BARD1, BRIP1, RAD51C, and RAD51D (National Comprehensive Cancer Network, 2019). Recent studies are now adding evidence to support the increased risk of breast cancer associated with some of these genes, and their quantified risk figures are no longer unknown; one large case-control study published in 2021 reported a significant association of breast cancer with protein-truncating variants in BARD1, RAD51C, and RAD51D (Breast Cancer Association Consortium et al., 2021).
Another study by Hu et al. (2021) demonstrated pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer. The current National Comprehensive Cancer Network (NCCN) recommendations for breast cancer risk management for BARD1, RAD51C, and RAD51D include annual mammogram and consideration of breast MRI (age depending on the specific gene) with insufficient evidence for risk-reducing mastectomy (RRM) and to manage patients based on family history (National Comprehensive Cancer Network, 2023). The NCCN recommendations for BRIP1 state "insufficient data; managed based on family history" (National Comprehensive Cancer Network, 2023).
The recommendations for these previously "unknown risk" genes are rapidly changing as new data emerges quantifying conferred breast cancer risk.
In 2019, during the time frame of this study, for the moderate penetrance genes NCCN recommended annual mammogram and consideration of breast MRI (age depending on the specific gene) with insufficient evidence for risk-reducing mastectomy (RRM) and to manage patients based on family history ( Previous literature has demonstrated that the course of treatment a patient pursues is influenced by surgeon recommendation; a study conducted by Napoli et al. (2020) investigated the factors that impact management decisions for women with pathogenic variants in moderate penetrance breast cancer susceptibility genes, and while numerous influencing factors were identified in this study, physician opinion was the only factor identified by all participants (Napoli et al., 2020). Taylor et al. (2019) investigated what factors affect breast surgeon recommendation for contralateral prophylactic mastectomy (CPM), confidence in this recommendation, as well as awareness of the American Society of Breast Surgeons guidelines regarding CPM. It was noted that recommendation of CPM and confidence in this recommendation was higher in younger patients, higher-stage disease, triple-negative, and human epidermal growth factor receptor 2 (HER2) positive relative to estrogen receptor (ER) positive, and in women with a family history of breast cancer (Taylor et al., 2019). This study demonstrates that many factors can influence the course of treatment a breast surgeon recommends.
While guidelines exist to aid clinicians in their management recommendations for individuals who carry pathogenic variants in moderate penetrance breast cancer susceptibility genes, it is unknown what additional factors breast surgeons utilize when making recommendations to these patients. We aimed to identify factors that influence breast surgeon management recommendations for women with pathogenic variants in moderate penetrance breast cancer susceptibility genes associated with hereditary breast cancer; breast surgeon comfort level with moderate penetrance breast cancer susceptibility genes; how breast surgeons discuss management options with these patients; as well as possible barriers to making medical management recommendations for these patients.

| Participants
Breast surgeons employed at hospitals in Ohio, Indiana, and Kentucky were contacted via email and asked to participate in a focus group or individual interview. Participants were preferentially scheduled for focus groups; however, when only one surgeon at a hospital volunteered to participate or the surgeon schedules prevented organizing a focus group, individual interviews were offered as an alternative. The same questions were asked in both the focus groups and individual interviews. Focus groups and individual interviews were scheduled as requested.

| Procedures
All participants were given a brief presentation reviewing the genetics of breast cancer; general information on moderate penetrance breast cancer susceptibility genes and associated breast cancer risks; and the NCCN screening guidelines for moderate penetrance breast cancer genes. The NCCN guidelines provided to the participants were from 2019, as this is when this research was conducted ( Table 1). The genes discussed as moderate penetrance breast cancer susceptibility genes were ATM, CHEK2, CDH1, NBN, NF1, PALB2, and STK11, as at the time this research was conducted all of these genes were considered to be "moderate breast cancer risk" genes.
While not all genes discussed in the focus groups are still considered moderate penetrance breast cancer susceptibility genes, the themes and content of the discussions remain applicable to current moderate penetrance breast cancer susceptibility genes.
During the focus group, participants were asked questions regarding confidence in their ability to provide management recommendations to women with pathogenic variants in moderate penetrance breast cancer susceptibility genes; what factors they consider to be important when making management recommendations; and how they would rank the importance of these factors.
Participants were then given specific scenarios and asked what they would recommend and how different factors would change their recommendations ( Table 2).
Finally, participants were asked about barriers that impact their recommendations; their discussion with patients about management for moderate penetrance breast cancer susceptibility gene variants; their comfort level with genes that confer an increased but unknown risk of breast cancer; and additional information that would help them to make medical management recommendations for women with pathogenic variants in moderate penetrance breast cancer genes.

| Data analysis
Transcripts of focus groups and interviews were coded by two separate members of the research team, using a codebook that was developed from themes that were predicted to occur, such as family history, patient opinion, and NCCN guidelines. Additional codes were added as novel themes were identified during the coding process. Inter-coder reliability was used for consistency with a cutoff value of 0.7 (Landis & Koch, 1977). The final value for inter-coder reliability was Cohen's K = 0.895.
Coding and analysis were completed at the level of focus group or interview rather than individual participant. It was not possible to separate out individual surgeon opinions in each focus group, because the surgeons within each focus group influenced one another's answers and each surgeon in the focus groups did not answer every question. In some instances, multiple and sometimes contradictory opinions were coded within the same transcript.
Factors that influence risk management recommendations were organized into thematic groups.  Table 3). All of the participants identified as white and female.

| Study participants
There were three participants (20%) who identified as Hispanic or Latino. All of the participants reported that they currently see patients in a clinical setting with a personal or family history of breast cancer and that they currently utilize a genetic counseling service in their practice or refer out to a genetic counseling service.
The average number of years spent practicing as a breast surgeon was 9.4 years (range from 6 months to 23 years). The participants were asked which moderate penetrance breast cancer susceptibility genes they had encountered in their patients; 93.3% of the surgeons had encountered a patient with a pathogenic variant in 46.7% in NBN, and 13.3% in STK11.

| Influencing factors
Participants named a wide variety of factors that they believe are important to consider when making recommendations for women with pathogenic variants in moderate penetrance genes ( Table 4).
Factors mentioned in all focus groups/interviews were patient motivation/opinion, family history, and patient overall health status.
Patient motivation/opinion had several subthemes, including patient preference and anxiety.

| Barriers to managing patients with pathogenic variants in moderate penetrance genes
The participants were asked if they have encountered barriers that prevented them from making a preferred recommendation or barriers that prevented patients from following their specific recommendations, regarding management for moderate penetrance breast cancer genes. The most common barrier

| Topics of discussion for patients with pathogenic variants in moderate penetrance genes
The majority of participants stated that when discussing management options with these patients they provide education on moderate penetrance genes and their associated cancer risks, NCCN and other management guidelines for the specific gene, and management options available in general. All of the participants reported that they recommend these patients see a genetic counselor, either before or after speaking with the breast surgeon.

| Unknown risk genes
We asked participants about their experiences and comfort level with genes that confer an increased, but unknown, risk of breast cancer, such as pathogenic variants in BRIP1, BARD1, and RAD51C. As there is insufficient evidence to guide management, we wanted to know more about the breast surgeons' experiences with these genes (National Comprehensive Cancer Network, 2019). We heard a wide variety of views on these genes from our participants. An overarching theme regarding the unknown risk genes is that there is not enough data available, which can make it challenging to

TA B L E 5 Examples of responses given by participants for each scenario
give recommendations regarding what is appropriate for management of women with pathogenic variants in these genes.

| DISCUSS ION
The surgeons that participated in this study identified multiple factors that influence recommendations provided to women with pathogenic variants in moderate penetrance breast cancer susceptibility genes. These findings are consistent with established literature (Katz et al., 2018;Morrow et al., 2009). For example, Katz et al. (2018) found that attending surgeon preference for CPM explained more of the observed variation in CPM rates than patient clinical factors.
Similar to the present study, Katz et al. (2018) showed that a woman with breast cancer could see two different surgeons and receive two very different treatment recommendations. Katz et al. (2018) also reported variation in breast surgeon discussion with patients in regard to whether or not the surgeon endorsed breast conservation as the best surgery option, brought up CPM as an option, or tried to discourage a woman from pursuing CPM (Katz et al., 2018). Our study found similar trends when surgeons were asked to make recommendations for women with pathogenic variants in moderate penetrance breast cancer genes. Katz et al. (2018) reported that common reasons breast surgeons performed CPM include requested by a patient for patient peace of mind, avoid conflict with the patient, and improve cosmetic outcomes. The surgeons who participated in our study considered similar patient motivation factors, such as patient anxiety level and cosmetic outcome ( Table 4).
When asked about confidence when counseling those with moderate penetrance breast cancer susceptibility genes, the majority of surgeons reported high confidence for certain genes and lower confidence for other genes. The moderate penetrance breast cancer susceptibility genes where the surgeons reported lower confidence were the genes that our participants reported seeing less frequently clinically (Table 3). This information indicates that there is an opportunity for education on these genes, to increase surgeon confidence with managing women with pathogenic variants in these genes. A study conducted by Carroll et al. (2009) aimed to increase primary care providers' knowledge and confidence with genetics through providing a workshop and a series of questionnaires to measure outcomes. After the educational intervention, participants reported increased knowledge and confidence related to adult-onset genetic disorders as well as many core genetics competencies, including risk assessment for genetic disorders and discussing benefits, risks, and limitations of genetic testing (Carroll et al., 2009). A similarly designed workshop with a stronger focus on moderate penetrance breast cancer genes may benefit breast cancer surgeons through increasing their knowledge and thus their confidence.
Our participants identified numerous barriers faced by patients when implementing a treatment plan. These barriers then influence the recommendations that our participants provide to women with pathogenic variants in moderate penetrance breast cancer genes.
Participants reported they may not make the recommendations they would like to because of financial concerns or health literacy. Other studies have found that financial concerns such as insurance, out of pocket expenses, and transportation are major barriers reported by patients with cancer (Barris et al., 2019;Lin et al., 2008). It has also been established that financial barriers can decrease patient adherence to treatment, which was also reported to be a barrier by our participants (Barris et al., 2019). Another study found that uptake of recommended colorectal cancer screening was lower among those with lower health literacy, which indicates health literacy can also impact patient adherence to treatment (Kobayashi et al., 2014).
Ideally, these barriers should be minimized to allow for the surgeons to make recommendations based on the patient and their situation, rather than on external factors.
When inquiring about the content of discussions our participants have with women with pathogenic variants in moderate penetrance breast cancer susceptibility genes, in general the participants mentioned similar topics of discussion. Variation in topics and time for each appointment could be influenced by institution requirements.
The shared decision-making approach that most of our participants described using has been recommended in the literature (Jatoi, 2018;Weiss et al., 2018). It has been demonstrated that the majority of cancer patients desire a collaborative role with their physicians in cancer treatment decision making (Degner & Sloan, 1992;Keating et al., 2002). It has also been recommended that for patients with any hereditary predisposition for breast cancer, surgeons should inform them of all three options to manage their risk, specifically screening, chemoprevention, and risk-reducing surgery (Jatoi, 2018). Other studies have recommended that when discussing management with patients with pathogenic variants in moderate penetrance genes, breast cancer surgeons should convey that there is no definitive data on the risk of contralateral breast cancer and that surgical risk reduction is not recommended (Weiss et al., 2018).
In our study, several participants discussed conveying to this patient population that there is no data supporting the benefit of surgical risk reduction while agreeing to offer prophylactic surgery for a patient strongly motivated to pursue this course of treatment. This demonstrates that our participants are willing to take patient opinions into consideration when deciding on a management course.
Other recommended topics for discussion are benefits and harms of each management option, which the majority of our participants stated they discuss (Jatoi, 2018).
In an area of medicine with so much uncertainty, it was felt that surgeons may often be asked "what would you do in this situation?" The most common response of "I don't know" reflects that same un- with these genes, which shows that there is also not one clear correct course of management for the unknown risk genes.

| Limitations and future research
The results of this study are qualitative and meant to be exploratory rather than generalizable. It would be beneficial to conduct a quantitative survey of a wider and more diverse group of breast surgeons based on these results to see if these findings are consistent, as the participants in this study were relatively homogenous and from the same geographic region. An anonymous survey could also address concerns about social desirability bias. The participants in the current study may have been influenced to give an answer that they believe would be viewed as correct by the researchers or their colleagues, rather than answering with their actual practices. The participants in the current study also all stated that they use a genetic counseling service in some capacity, whether within their practice or referring out to genetic counseling; this indicates that this group may be more familiar with genetics and genetic counseling and therefore may be more familiar with moderate penetrance breast cancer genes. Future studies could hopefully include a more heterogeneous group of surgeons, including participants who do not readily have access to genetic counselors.
While we did ask participants if knowing the specific moderaterisk gene impacted their recommendations, the element of nonsyndromic gene vs syndromic gene could have been further explored and this is an area for future research.
As breast surgeons are not the only professionals who help to manage the screening and treatment of this patient population, future research could investigate how other healthcare professionals who work in high-risk clinics counsel for women with pathogenic variants in moderate penetrance breast cancer susceptibility genes.
Future studies could also work to develop a decision aid tool that could use all of the factors identified in this study to help surgeons and patients make risk management decisions. Breast surgeons may also find benefit from discussions with genetic counselors regarding the best recommendations for their patients with a pathogenic variant in a moderate penetrance breast cancer susceptibility gene. In this study, we found that surgeon opinions were swayed through discussion with other surgeons during focus groups; in practice, joint discussion between breast surgeons and genetic counselors may allow for greater surgeon confidence with providing recommendations to this patient population, as well as the best possible recommendations for patients.

| Genetic counseling practice implications
Armed with the knowledge that breast surgeons highly value patient preference for women with pathogenic variants in these genes, genetic counselors could begin exploring patient preference as well.
This could allow for the patient to have more time to self-reflect, before meeting with a breast surgeon to discuss management. Genetic counselors could use the results of this study to better describe what an appointment with a breast surgeon will look like for their patients with pathogenic variants in moderate penetrance breast cancer susceptibility genes, which could potentially decrease patient anxiety around the unknown. One study determined that providing an educational session to women undergoing mammography for the first time significantly decreased patient anxiety (Lungulescu et al., 2018). This education session involved general information about the screening program, length of the examination, symptoms to expect during the mammography, benefits of early cancer detection, as well as emotional support (Lungulescu et al., 2018). Overall, the results of this study can help educate genetic counselors regarding what factors breast surgeons take into consideration when making recommendations for women with pathogenic variants in moderate penetrance breast cancer susceptibility genes. Genetic counselors can then use this information to educate patients.

| CON CLUS ION
Genetic testing for moderate penetrance breast cancer susceptibility genes is being offered in a clinical setting, so breast surgeons have to manage the screening and treatment of this patient population. The NCCN guidelines provide a framework for what is appropriate for the management of these women; however, the NCCN guidelines are just one factor of many that breast surgeons take into consideration when making management recommendations to women with pathogenic variants in moderate penetrance breast cancer susceptibility genes. Through focus groups and interviews, we have identified many factors breast surgeons take into consideration when making recommendations for this patient population.
Patient motivation/opinion, family history, patient current health status, patient personal preference, and patient anxiety level were among the most common factors mentioned. This information could be used to help patients and their healthcare providers with decision making around treatment for individuals with pathogenic variants in moderate penetrance genes.

AUTH O R CO NTR I B UTI O N S
April Vanderwal confirms that they had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All of the authors made substantial contributions to the conception and design of the work, as well as analysis and interpretation of the data. April Vanderwal and Kimberly Widmeyer were responsible for acquisition of the data.
April Vanderwal drafted the work, and all authors were involved in revising it critically for important intellectual content. All of the authors gave final approval of this version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

ACK N OWLED G M ENTS
This study was conducted when the first author was enrolled in the Genetic Counseling Graduate Program, College of Medicine,

University of Cincinnati and Division of Human Genetics, Cincinnati
Children's Hospital Medical Center, Cincinnati, OH. The authors would like to acknowledge the National Society of Genetic Counselors Cancer SIG grant for providing funding for this research.
The authors would also like to thank the participants and the individuals who helped to organize the focus groups and interviews, as well as the secondary transcript coder Katherine Perry.

CO N FLI C T O F I NTE R E S T
April Vanderwal, Jaime Lewis, Janet Basil, Carrie Atzinger, and Kimberly Widmeyer declare that they have no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

H U M A N S TU D I E S A N D I N FO R M E D CO N S E NT
This study was approved by and conducted according to the ethical standards of the Cincinnati Children's Hospital institutional review board. All applicable international, national, and/or institutional guidelines were followed. This study was approved by the IRB and was granted an informed consent waiver.

A N I M A L S TU D I E S
No non-human animal studies were carried out by the authors for this article.