Validation Study on Risk-Reduction Activities after Exposure to a Personalized Breast Cancer Risk-Assessment Education Tool in High-Risk Women in the WISDOM Study

We performed a 318-participant validation study of an individualized risk assessment tool in women identified as having high- or highest-risk of breast cancer in the personalized arm of the Women Informed to Screen Depending on Measures of risk (WISDOM) trial. Per protocol, these women were educated about their risk and risk reducing options using the Breast Health Decisions (BHD) tool, which uses patient-friendly visuals and 8th grade reading level language to convey risk and prevention options. Prior to exposure to the educational tool, 4.7% of women were already taking endocrine risk reduction, 38.7% were reducing alcohol intake, and 62.6% were exercising. Three months after initial use of BHD, 8.4% of women who considered endocrine risk reduction, 33% of women who considered alcohol reduction, and 46% of women who considered exercise pursued the risk-reducing activities. Unlike lifestyle interventions which are under the control of the patient, additional barriers at the level of the healthcare provider may be impeding the targeted use of endocrine risk reduction medications in women with elevated breast cancer risk.

which are under the control of the patient, additional barriers at the level of the healthcare 58 provider may be impeding the targeted use of endocrine risk reduction medications in women 59 with elevated breast cancer risk .  60   61  62  63  64  65  66  67  68  69  70  71  72  73  74  75  76  77  78  INTRODUCTION  79  80 Breast cancer is the second leading cause of cancer death in the United States and the most 81 common cancer in women, with one in eight (12.3%) women developing breast cancer in their 82 lifetime. 1 While there are effective strategies for breast cancer prevention with level 1 evidence, 83 there is little evidence that the women who would stand to benefit most are being counseled. 84 Current strategies to identify women at higher risk include genetic testing of women with strong 85 family histories, and recommendations for more intensive surveillance or prophylactic surgery in 86 women found to be mutation carriers. The vast majority of women are not mutation carriers, but 87 many still have risk and are not routinely screened. For women found to be at elevated risk, 88 there are several strategies to reduce risk, including lifestyle interventions (reduction of alcohol 89 intake, increasing exercise, weight loss), the use of endocrine risk reduction medications 90 (selective estrogen receptor modulators and aromatase inhibitors), and avoidance of combined 91 hormone replacement after menopause. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] While lifestyle modifications are recommended for 92 all women, randomized controlled clinical trials support the addition of endocrine risk reduction 93 in women at high risk of developing breast cancer. 2,17-20 The United States Preventative Task 94 Force guidelines encourage primary care providers to identify high risk women and offer 95 endocrine risk reduction. 18 Risk models including Gail used  educates high-and highest-risk women on their personal breast cancer risk and risk-reducing 112 strategies using personalized genetic testing results, patient-friendly visuals, and 8th grade 113 reading level language. 33,34 The purpose of developing the tool was to deploy a risk assessment 114 tool to aid women in considering and pursuing risk-reducing activities, and to learn if high risk 115 women would be particularly compelled to pursue endocrine risk reduction. The broader aim was 116 to assess whether the risk-assessment tool would ease anxiety about breast cancer risk by 117 providing actionable risk reduction steps and to determine if understanding risk would reduce 118 breast cancer anxiety in the high and highest-risk groups. While the pilot study evaluated high-119 and highest-risk women's"immediate desires to pursue risk-reducing activities after using the 120 tool, it did not determine whether they truly implemented the strategies. 121 122 Here, we describe results of the validation study of the WISDOM Study risk assessment tool in 123 women of high and highest breast cancer risk. The study builds upon our previous pilot study by 124 not only comparing efficacy of a new educational risk assessment tool between high and highest 125 5 breast cancer risk groups but also temporally evaluating uptake of risk reducing strategies 126 through an immediate feedback and three-month follow up survey. Through this unique lens, we 127 hope to further our understanding of the following questions: 128 1. Is the use of the WISDOM Study risk assessment tool in high-and highest-risk women 129 associated with changes in health-related behavior and uptake of endocrine risk 130 reduction? 131 2. What are barriers to health-related behavior change and endocrine risk reduction uptake 132 among high-and highest-risk women following use of an educational risk assessment 133 tool? 134 3. To what extent does an educational risk-assessment tool affect breast cancer anxiety in 135 high and highest breast cancer risk women? 136

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Risk Assessment Tool Validation Study Participants 140 141 The validation study included 318 WISDOM study participants who were classified as elevated 142 risk in the top 2.5% of BCSC score by age group, which corresponds to high-risk women 143 recommended annual screening or highest-risk women recommended every six-month screening 144 ( reported risk-reducing activity (endocrine risk reduction, alcohol reduction, and exercise) across 154 three time points: before using tool, considerations immediately after using tool, and activities 155 that were implemented 3 months later. Before using the tool, 4.7% of women were taking 156 endocrine risk reduction, 38.7% were reducing alcohol intake, and 62.6% were exercising (Table  157 2). Immediately after using the tool, 34.6% of women surveyed considered endocrine risk 158 reduction, 14.8% considered decreasing alcohol use and 30.8% considered increasing exercise 159 (Table 2). Next, we examined whether a greater proportion of individuals who considered a risk-160 reducing activity after using the decision tool pursued it three months later compared to those 161 who did not initially consider it (Supplementary Tables 3a -c). For endocrine risk reduction, 4 162 out of 48 women (8.4%) who considered it began taking endocrine risk reduction three months 163 later, while 8 out of 61 (13.1%) who did not consider it began taking endocrine risk reduction 164 three months later (Supplementary Table 3a). For alcohol reduction, 31 out of 93 women 165 (33.3%) who considered reducing began to do so three months later, while 11 out of 16 (68.7%) 166 who did not consider it began three months later (Supplementary Table 3b). Lastly, 39 out of 85 167 women (45.9%) who considered exercising more did so three months later while 14 out of 24 168 women (58.3%) who did not consider it began three months later (Supplementary Table 3c (Table 3). Healthcare providers 186 recommended endocrine risk reduction to 17% of high-and highest-risk women, alcohol 187 reduction to 14%, and increased exercise to 20% (Table 3). These recommendation percentages 188 were not significantly different between high-and highest-risk women (Table 3). 189 190 Barriers to discussing risk with provider and using risk-reducing strategies 191 192 The most common reason for not discussing one#s risk with a provider was the $other" category, 193 with most participants stating that they have not had their appointment or risk reduction was not 194 brought up during their appointment (Supplementary Table 4). The most commonly selected 195 barriers to endocrine risk reduction were $other" and $fear of side effects" (Supplementary Table  196 4). Within the $other" category, most women stated that the provider did not recommend the 197 9 medication. Furthermore, a majority of women who were not reducing alcohol intake or 198 increasing exercise were not doing so because they were already performing the risk-reducing 199 activities (Supplementary Table 4 Table 1). After stratifying for breast cancer risk, no difference 207 between high and highest-risk women were found (Fig. 4). When asked about the frequency women worried about their breast cancer risk three months after 223 first using the decision tool, 5.5% often worried, 48.6% of women sometimes worried, and 45% 224 did not worry at all (Supplementary Table 2). After stratification for breast cancer risk level, no 225 difference between high-and highest-risk women were found (Fig. 5) While our initial results are promising, our data also suggests that factors other than initial risk 254 assessment education continue to influence final risk-reduction decisions. To illustrate, a large 255 proportion of all participants (30-40%) considered endocrine risk reduction after using the tool, 256 however the proportion of women taking endocrine risk reduction three months later remains 257 11 significantly less than those who considered the medication ( Fig. 1-3, Table 2). In fact, only 258 8.4% of women who considered endocrine risk reduction pursued it three months later compared 259 to 30-50% of individuals who considered lifestyle modification (Supplementary Tables 3a-c). 260 Furthermore, the use of endocrine risk reduction was not statistically different between high-and 261 highest-risk women ( Fig. 1-3). 262 263 Lifestyle interventions are under control of the patient while endocrine risk reducing strategies 264 require the support and intervention of a primary care physician or breast cancer prevention 265 specialist. The majority of women who did not pursue endocrine risk reducing medication 266 reported that they either did not have a follow up visit with their primary care physician, or the 267 topic was not brought up. These results suggest that women continue to face barriers to pursue 268 endocrine risk reduction despite becoming more educated and having a desire to take the 269 medication after using the risk assessment tool. There was no active outreach to the participants'" 270 physicians regarding the results of the risk assessment and BHD tool, thus it is also unclear how 271 many of the participants were considered to have elevated risk by their primary care physician. 272 To that end, highest risk women do not have higher uptake of endocrine risk reduction than high 273 risk women after using the educational risk assessment tool. 274

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We did not capture all of the barriers to medication use after the session using the risk 276 assessment tool. Prior papers have suggested that there are barriers to endocrine risk reduction 277 uptake at the provider level in the clinic. 29,30,35 Past literature indicates that when assessing risk, 278 most providers never calculate Gail scores (76%). 35 While many providers discuss increased risk 279 to high risk women (58%) and tailor screening based on risk (53%), fewer providers usually or 280 always discuss endocrine risk reduction (13%). 35 Challenges faced by providers include lack of 281 confidence in risk assessment and knowledge, identifying suitable candidates for preventative 282 strategies, insufficient knowledge of risk-reducing medications, more immediate issues, and lack 283 of time during clinic visits. 29,30,35 Despite our efforts in providing a printout summarizing their 284 risk for women to bring to their appointments, this information does not appear to be routinely 285 shared with the primary care physicians. Even when identified as high risk by our study, women 286 are still not getting counseling at the level of their primary care physician, which further confirm 287 the existing literature that indicates that providers are not consistently assessing risk, discussing 288 it, and recommending endocrine risk reduction to high-and highest-risk women who could 289 benefit. Therefore, despite clinical guidelines, providers may not be targeting high-risk women 290 interested in endocrine risk reduction for discussions. Furthermore, when asked about barriers to 291 taking medication, many women noted that their provider did not recommend doing so and that 292 they listen to what their provider recommends (Supplementary Table 4 No studies to date have assessed educational tools' impact on breast cancer anxiety and worry, 305 which is prevalent especially in women with a family history of breast cancer, baseline anxiety, 306 negative illness perceptions, and genetic testing, and impacts decision-making. [40][41][42][43][44][45] Providing 307 women with breast cancer risk estimates has minimal negative effects on anxiety but it is unclear 308 if actionable risk reduction strategies from educational tools like the risk assessment tool can 309 have a positive effect. 43,46,47 In this preliminary investigation of anxiety and worry about breast 310 cancer risk after use of an educational tool, a majority of women report that the tool alleviated or 311 did not affect their emotional state, with no difference noted between high-and highest-risk 312 women ( Fig. 4-5, Supplementary Table 2). These findings suggest that greater knowledge 313 regarding one#s risk is not associated with negative emotions and may even alleviate anxiety. It is 314 also possible that providing next steps in risk reduction, as done in the educational tool, 315 empowers women and positively contributes to their emotional well-being. Our study has several limitations. First, the COVID-19 pandemic began during our data 327 collection process, so results may be confounded by the public health crisis. In particular, the 328 14 lockdown and closure of gyms and recreational centers during the COVID crisis may have 329 contributed to the difficulties in scheduling healthcare appointments. Second, due to the nature of 330 the study, we cannot draw causal conclusions. Third, our results are limited by the smaller 331 sample size in our follow up survey results, and the response rate was 35% thus raising the 332 possibility of response or attrition bias. Lastly, our study used a pre-post design and did not 333 include a control group. Thus, subsequent attitudes and health behaviors following use of the 334 BHD tool may have been affected by other intervening temporal factors beside the tool itself. 335 336 We also note that several factors limit the generalizability of our study. The WISDOM study 337 participants who used the risk-assessment tool may share characteristics not reflective of the 338 general population. Our participants were predominantly white and highly educated with no 339 African Americans in the highest-risk group. Furthermore, we did not include participants who 340 were high risk by virtue of pathogenic genetic variants. 341 342

Future improvements in our approach 343
There is accumulating evidence that the standard breast cancer risk tools, as well as polygenic 344 risk (PRS), identify women with slower growing hormone positive tumors. This means that our 345 current tools are better at identifying the women most likely to benefit from taking medications 346 to lower their risk. We have increased the diversity of the population of the women in WISDOM 347 so future results should reflect this change. We are working on ways to assess which women are 348 benefiting from endocrine risk reducing therapy. 50 We have modified the tool to educate women 349 about small doses of tamoxifen and exemestane previously described. We are working more 350 directly with primary care groups to determine how to best share risk assessment information 351 15 about their patients. We are also working to determine if a virtual prevention program can be set 352 up to support women in the WISDOM trial, as well as primary care physicians. Studies are also 353 underway testing new medications to reduce risk in women at risk for developing hormone 354 positive breast cancer. Finally, we can explore partnerships with devices that measure physical 355 activity and diet to assist women in quantifying their lifestyle changes. 356

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METHODS AND DATA AVAILABILITY 358 359 360 Modifications of the Risk Assessment Tool 361 362 Previously, our team published results of the risk-assessment tool#s pilot study with 17 363 participants. 33 We modified the risk-assessment tool based on participants"feedback and updated 364 the references before implementing it to a broader WISDOM study population. 365 366 Study sample 367 368 The study sample consisted of 318 WISDOM Study participants in the personalized arm with 369 elevated breast cancer risk in the top 2.5% of BCSC score by age without breast cancer mutation Salesforce is an online platform where study coordinators of the WISDOM study can 382 communicate with and perform coordinator tasks for WISDOM participants. The breast health 383 risk assessment tool was provided through the participants' Salesforce platforms and was 384 accessible after they log into their WISDOM study portal on their own electronic device. The 385 Salesforce platform allowed study coordinators to visualize whether the risk-assessment tool was 386 ever used through a checkbox function. 387

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Procedure 389 390 High-and highest-risk participants were provided the opportunity to go through the risk-391 assessment tool with their breast health specialist through a virtual consultation. Previously in the 392 WISDOM study, breast health specialists contacted high-and highest-risk participants to talk 393 about their risk and answer questions. The risk-assessment tool provided a visual aid for the 394 specialist during the discussion. High-and highest-risk participant who did not respond or 395 declined the consultation had the option to use the risk-assessment tool independently. 396 397 After participants completed the breast health risk assessment tool once, they were provided the 398 immediate feedback survey found in the last page of the tool.   % % calculated is out of total who either considered endocrine risk reduction, or the total 490 who did not consider endocrine risk reduction from feedback survey response 491 % ≠ = statistical significance between high-and highest-risk group 492 % High risk = WISDOM screening assignment recommendation yearly, highest risk = 493 WISDOM screening assignment every 6 months (alternating mammography and MRI). 494 Only high-and highest-risk participants receive a breast health specialist consult with the 495 BHD tool. The low-risk participants however have access to the tool to look through on 496 their own. 497 498 Description: Table including reasons why participant did not discuss risk with provider, and why  501 they did not pursue endocrine risk reduction, alcohol, or exercise. 502 503 Note: Pearson#s Chi-squared test with Yates"#continuity correction was performed. No statistical 504 significance noted between high-and highest-risk groups 505 506 Description: Bar graph of frequency of worry about breast cancer risk after use of tool. 539 Responses obtained through Likert Scale in 3-month follow up survey and subset into high-and 540 highest-risk groups. 541 542 Note: N/A 543 544