Pruthi, Sandhya

Abstract Background Breast cancer chemoprevention is underutilized among high-risk women. We examined whether decision support could increase informed decision making. Methods We conducted a cluster randomized controlled trial to evaluate the effect of a patient-facing decision aid (RealRisks) and provider tool (BNAV) compared with standard education on the number of women with high-risk breast lesions making informed choices. Questionnaires were administered at baseline and 6 and 12 months. The primary outcome was chemoprevention informed choice (defined as adequate knowledge and attitudes congruent with decision) at 6 months. Secondary endpoints included breast cancer risk perceptions, worry, chemoprevention knowledge, decision conflict, and chemoprevention decision. Results Across 31 randomized sites, we enrolled 210 providers, who were primarily breast health specialists. Of these, 24 sites (14 intervention, 10 control) enrolled 412 patients. Among 287 patients evaluable for the primary outcome, there were no statistically significant differences in informed choice between the intervention and control arms at 6 months (35% vs 27%, respectively; P = .20) and 12 months (37% vs 25%, respectively; P = .05). At 6 months, women in the intervention compared with control arm were more likely to have accurate breast cancer risk perceptions (31% vs 21%, respectively; P = .03) and adequate chemoprevention knowledge (33% vs 23%, respectively; P = .04). At 12 months, 52% of women in the control and 50% in the intervention arm self-reported initiating chemoprevention. Conclusion Decision support led to modest improvements in accurate risk perceptions and chemoprevention knowledge but not informed choice. Relatively high chemoprevention uptake was achieved among women with high-risk breast lesions managed mainly by breast health specialists. Trial Registration NCT04496739, https://clinicaltrials.gov/study/NCT04496739?cond=NCT04496739&viewType=Card&rank=1

10513 Background: Prior reports of high frequency of BRCA1 and BRCA2 ( BRCA1/2 ) PVs among South Asian women from Bangladesh, India, Nepal, and Pakistan with breast or ovarian cancer require validation in large prospective unselected cohorts. Methods: Individual-level anonymized patient data from two prospective cohorts were pooled to evaluate the prevalence of germline PVs among South Asian women: the South Asian Regional Alliance for Hereditary Cancers (SARAH Consortium) in Bangladesh, Nepal, and Pakistan, and the previously reported Nurse-led Genetic Counseling and Awareness (NuGenA) expansion cohort in India. Both studies enrolled consecutive cases of histologically confirmed newly diagnosed breast or epithelial ovarian cancer irrespective of age at diagnosis or family history. In both studies, participants completed questionnaires on personal and family history (first-, second- or third-degree) and provided blood for germline genetic testing after written consent. PVs in cancer predisposition genes including ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, PALB2, RAD51C, RAD51D, and TP53 were identified as part of the studies utilizing a multigene panel and the results were returned to ordering clinicians. The data cutoff date for this analysis was November 30, 2025. Results: The analysis included 1,711 South Asian women with breast (n=1,210) or ovarian (n=501) cancer. A family history of breast or ovarian cancer was noted in 177 (10.3%). Among breast cancers, 94% were invasive, 84% were ductal, 35% were triple-negative and over two-thirds presented with nodal involvement. Germline PVs across 13 predisposition genes were observed in 17.7% of breast and 35.9% of ovarian cancers. Notably, BRCA1/2 PVs accounted for most of these PV (13.6% of breast and 28.3% of ovarian cancer cases) with PVs in all genes except BRCA1/2 under 1%. The frequency of BRCA1/2 PVs was 24.4% in triple-negative breast cancer and 8.0% in ER+/HER2-. BRCA1/2 PV carriers were diagnosed with breast cancer at a younger age than non-carriers (Median age: 42 vs 46 years, P<0.001), with no age difference observed in ovarian cancer (50 vs. 51 years, P=0.79). Notably, among the 306 BRCA1/2 PV carriers identified, 229 (74.2%) did not report a family history of breast or ovarian cancer. Conclusions: We confirm a high prevalence of BRCA1/2 PVs among unselected South Asian women with either breast or ovarian cancer. The observations of younger age at cancer diagnosis, and low rates of family history support the need for population-specific germline genetic testing and risk management strategies in South Asia.

Abstract Background Artificial intelligence (AI)–based, mammography breast cancer risk prediction models show improved discriminatory accuracy relative to clinical risk models. However, data on their calibration are limited. This study compared model performance of 3 clinical breast cancer risk models: Gail, Tyrer–Cuzick v8, and Breast Cancer Surveillance Consortium v3 with the MIRAI AI-risk model. Methods Digital mammograms were ascertained from a screening mammography cohort of 12 308 women within the Mayo Clinic Biobank with 250 incident breast cancers (176 invasive) within 5 years. We predicted 5-year breast cancer risk, estimated discriminatory accuracy (C-index), and calibration (observed-to-expected ratio) of both overall and invasive breast cancer and compared estimates using bootstrapping approaches. Results MIRAI demonstrated similar or improved discriminatory accuracy of overall breast cancer (C-index = 0.71, 95% confidence interval [CI] = 0.68 to 0.74) and invasive breast cancer (C-index = 0.71, 95% CI = 0.67 to 0.75) compared with clinical models (overall breast cancer: C-index = 0.59-0.68; invasive breast cancer: C-index = 0.60-0.68). MIRAI’s calibration for risk of overall breast cancer (observed-to-expected ratio = 0.96, 95% CI = 0.85 to 1.08) was improved compared with Gail (observed-to-expected ratio = 1.22, 95% CI = 1.07 to 1.38) and Breast Cancer Surveillance Consortium (observed-to-expected ratio = 1.38, 95% CI = 1.22 to 1.56) but similar to TC with volumetric percent density and polygenic risk score (observed-to-expected ratio = 0.99, 95% CI = 0.87 to 1.13). However, for low-risk women (approximately 50%), MIRAI overestimated risk of overall breast cancer. MIRAI also overestimated risk of invasive breast cancer across the risk spectrum (observed-to-expected ratio = 0.68, 95% CI = 0.58 to 0.78), whereas clinical models had good calibration (observed-to-expected ratio = 0.86–0.99). Conclusion MIRAI demonstrated stronger discriminatory accuracy than clinical models for 5-year overall and invasive breast cancer risk prediction but overestimated risk for both breast cancer endpoints. AI-based risk models should consider discriminatory accuracy and calibration for invasive cancer before implementation.

10512 Background: Polygenic risk scores (PRSs) combine information from single-nucleotide polymorphisms (SNPs) across the genome to explain substantial genetic breast cancer (BC) susceptibility. Previous studies have demonstrated that a multiple-ancestry PRS (MA-385) based on 56 ancestry-informative and 329 BC-associated SNPs is accurate for diverse populations and ranks among the most important known factors affecting the risk of BC development. However, medical guidelines call for more evidence before endorsing the clinical use of PRS, including studies to evaluate possible interactions of SNPs with environmental and hormonal risk factors. Here, we use longitudinal outcomes from the UK Biobank (UKB) to explore interactions of MA-385 and the five most informative individual BC-associated SNPs with the widely used Tyrer-Cuzick (TC) risk model and individual TC risk factors. Methods: The study cohort included 197,509 female UKB participants with no history of cancer at the time of study enrollment. We used Cox proportional hazards models to test associations of MA-385, individual BC SNPs, TC, and individual TC risk factors with BC outcomes. Effect modification of MA-385 and individual SNPs by clinical risk factors was evaluated by including interaction terms in the models. All models were adjusted for age at UKB enrollment and 10 principal components. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported per standard deviation, and significance tests were performed using two-sided p-values based on likelihood-ratio test statistics. Results: After a median follow-up of 11.8 years, 7,419 (3.8%) participants were diagnosed with BC.In a model including both MA-385 and TC, MA-385 was a significantly better predictor of BC development (HR = 1.56; 95% CI 1.53-1.60, p = 3.2 x 10 -329 ) over the TC model (HR = 1.21; 95% CI 1.18-1.23; p = 5.4 x 10 -69 ). We found no evidence of interaction between MA-385 and TC ( p = 0.31) , nor between individual SNPs and TC. After Bonferroni adjustment for multiple testing (102 tests), we found no evidence of interaction between MA-385 or individual SNPs with clinical TC factors. The strongest evidence for interaction was found between a BC SNP on chromosome 2 (rs13387042) and age at UKB enrollment (unadjusted p = 0.002; Bonferroni adjusted p = 0.23). Conclusions: In a longitudinal analysis of UKB, MA-385 was a highly significant predictor of BC risk and substantially improved prediction over TC. In contrast, interactions of MA-385, and individual BC SNPs, with TC and individual clinical factors in the TC model were not statistically significant. Clinical TC factors have minimal, if any, impact on the strength of the association between MA-385 and BC. These results may help to alleviate concerns expressed in guidelines that SNPs interact with environmental or hormonal risk factors.

10544 Background: Incorporation of Polygenic Risk Scores (PRS) can refine traditional breast cancer risk assessment models to provide precise estimates of breast cancer risk. However, the impact of such an integrated model on clinical decision-making related to breast cancer surveillance and preventive strategies is not fully understood. Methods: The GENRE-2 is a prospective single-arm multisite clinical trial (NCT04474834) incorporating PRS into standard breast cancer risk assessment models to determine the impact of PRS on clinical decisions on breast cancer prevention and surveillance. Women at high risk of breast cancer due to NCI-BCRAT 5-year risk of ≥ 3%, or IBIS (Tyrer-Cuzik) 10-year breast cancer risk of ≥5%, biopsy-proven high-risk breast lesion, or a pathogenic variant (PV) in ATM , BRCA1, BRCA2, CHEK2 or PALB2 , were enrolled from five sites in the United States. All women were invited to complete surveys on their breast surveillance and cancer prevention decisions based on pre-PRS standard risk models and post-PRS risk estimation, and further annual surveys are planned for 10 years. Results: Among 902 women enrolled in the study, 605 (median age: 52 years) received PRS results and completed a survey to date. Of those who received PRS results,195 (32.2%) were PV carriers. Among non-carriers, the median 10-year and lifetime pre-PRS IBIS-based risk was 10.0% and 28.7%, respectively. Among PV carriers, the CanRisk-based 10-year and lifetime pre-PRS risk estimates were 6.3% and 25.2% for ATM , 22.3% and 77.6% for BRCA1 , 18.5% and 77.7% for BRCA2 , 7.1% and 25.7% for CHEK2 , and 16.8% and 38.0% for PALB2 PV carriers, respectively. After the incorporation of PRS, the lifetime risk of breast cancer increased by at least 10% in 31% of non-carriers and 7.7% of PV carriers and decreased by at least 10% in 10.7% of non-carriers and 7.7% of PV carriers. The proportion of non-carriers with lifetime risk < 20% or > 40% changed from 17.3% and 22.0%, respectively, in the pre-PRS evaluation to 24.4% and 32.9%, in the post-PRS evaluation. A higher lifetime post-PRS score was associated with intent to take preventive action (surgery or endocrine agents). In non-carriers, the proportion of women with a lifetime risk < 20% with intent to take preventive action was 11%, compared to 36.8% of those with a lifetime risk > 40% (p < 0.001). Similarly, in PV carriers, the proportion of women with lifetime risk < 20% with intent to take preventive action was 20.8% compared to 41.1% of those with lifetime risk > 40% (p = 0.015). Conclusions: The GENRE-2 trial demonstrates that the incorporation of PRS into breast cancer risk assessment models in high-risk women is feasible and leads to clinically meaningful changes in breast cancer risk estimates and decision-making regarding preventive strategies. Evaluation of the implementation of breast cancer risk management strategies in study participants is ongoing and will be reported. Clinical trial information: NCT04474834 .

Abstract Background: Ovarian cancer is the sixth leading cause of cancer deaths among women in the United States. South Asians in the USA, including Asian Indians and Pakistani Americans (AIPA), are a rapidly growing yet under-researched group. This study aims to analyze the clinical features, survival rates, treatment, and outcomes of ovarian cancer among AIPA women in the United States. Methods: Adult women diagnosed with ovarian cancer between 2000 and 2023 within the Surveillance, Epidemiology, and End Results (SEER) registry were identified utilizing ICD codes. The analysis focused on comparing clinical characteristics and outcomes between AIPA and Non-Hispanic White (NHW)women and excluded all women of other races/ethnicities or unknown race/ethnicity. Baseline characteristics, including age at diagnosis, disease stage, and treatment, were compared between AIPA and NHW women utilizing a chi-squared test for categorical variables and a t-test for continuous variables. The 5-year overall survival (OS) was estimated for each race/ethnicity by the Kaplan-Meier method, and the OS was further compared between AIPA and NHW in a cox-proportional hazard regression analysis adjusting for age at diagnosis, grade, histology, TNM stage, surgical debulking, completeness of debulking surgery, and receipt of chemotherapy. Similar comparisons of baseline characteristics and OS were also performed in the subset of women with high-grade serous ovarian cancer (HGSOC). Result: A total of 86, 485 women met the inclusion criteria, of which 1, 179 were AIPA and 85, 306 were NHW. AIPA had a significantly younger median age at diagnosis compared to NHW women in the overall population (57 vs. 65 years, p&lt;0.001) and among 448 AIPA and 29, 677 NHW women with HGSOC (58 vs. 65 years, p&lt;0.001). Approximately two-thirds of women in both groups presented with Stage III or IV ovarian cancer at diagnosis and had a serous subtype of ovarian cancer. Similarly, after the exclusion of unknown grade, high-grade tumors accounted for more than two-thirds (75 vs. 72%) of the ovarian cancer cases in both groups. AIPA were more likely to undergo debulking surgery (85 vs. 80%, p&lt;0.001) and receive chemotherapy (77 vs. 72%, p&lt;0.001) compared to NHW women. The unadjusted 5-year OS for AIPA and NHW women were 56% vs. 43% in the overall population, and 53% vs. 41% among women with HGSOC, respectively. In multivariate analysis of the entire study population, AIPA women had a significantly better OS than NHW women (HR: 0.86, 95%CI: 0.79 - 0.94, p&lt;0.001). Among women with HGSOC, a similar trend of better OS was noted in multivariate analysis among AIPA women compared to NHW (HR: 0.88, 95%CI: 0.77 - 1.01, p=0.07), although this did not reach statistical significance. Conclusion: The younger age at diagnosis, along with a generally better prognosis, among AIPA women compared to NHW women, suggests a possible enrichment of DNA-repair gene alterations among AIPA women. Citation Format: Aditi Karki, Sumeet Kumar Yadav, Muhammad Rafiqul Islam, Raja Pramanik, Ramila Shilpakar Dangol, Zeba Aziz, Sandhya Pruthi, Maryam Shahi, Jamie N. Bakkum-Gamez, Scott H. Kaufmann, Fergus J. Couch, Siddhartha Yadav. Clinical characteristics and survival outcomes of ovarian cancer among South Asian women in United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7118.

Objective: This study evaluated the feasibility and satisfaction of using a wearable brain activity sensing device for stress reduction among patients experiencing Long COVID (LC). Patients and Methods: Patients with LC (N = 45) were invited to participate in an open-label pilot study. Participants were asked to use a brain-sensing electroencephalogram (S-EEG) wearable device (Muse-S™) daily for 90 days and followed for an additional 90 days (180 days total participation). Study enrollment began June 28, 2022, and ended July 28, 2023. Results: Patients were predominantly female (82%), white (96%), and with an average age of 47.6 (±12.5) years. At the end of treatment (90 days), cognition, sleep, self-efficacy, and quality-of-life quality of life improved ( P < .001 to P = .04). In addition, stress and anxiety were significantly reduced ( P < .001). These significant changes persisted by end-of-study (180 days). For stress ( P = .023) and anxiety ( P = .033), a change from the baseline during follow-up was significantly associated with the amount of S-EEG usage. The end-of-study satisfaction survey indicated that patients were very satisfied with the S-EEG device, and 97% planned to continue using it. Conclusion: Results suggest that the S-EEG device improved cognition in LC, which is one of the main severe symptoms we see in our LC clinic. In addition, it helped reduce stress and anxiety. These findings have important clinical implications for LC patients using S-EEG as an adjunct to concurrent LC clinical care which includes pharmacotherapies.

Abstract Background Most breast biopsies are diagnosed as benign breast disease, with 1.5- to 4-fold increased breast cancer risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in breast cancer risk assessment of these patients. We assessed whether a 313–single nucleotide variation (formerly single-nucleotide polymorphism) polygenic risk score stratifies risk of benign breast disease patients. Methods We pooled data from 5 Breast Cancer Association Consortium case-control studies (mean age = 59.9 years), including 6706 participants with breast cancer and 8488 participants without breast cancer. Using logistic regression, we estimated breast cancer risk associations by self-reported benign breast disease history and strata of polygenic risk score, with median polygenic risk score category among women without benign breast disease as the referent. We assessed interactions and mediation of benign breast disease and polygenic risk score with breast cancer risk. Results Benign breast disease history was associated with increased breast cancer risk (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.37 to 1.60; P &lt; .001). Polygenic risk score increased breast cancer risk, irrespective of benign breast disease history (Pinteraction = .48), with minimal evidence of mediation of either factor by the other. Women with benign breast disease and polygenic risk score in the highest tertile had more than twofold increased odds of breast cancer (OR = 2.73, 95% CI = 2.41 to 3.09), and those with benign breast disease and polygenic risk score in the lowest tertile experienced reduced breast cancer risk (OR = 0.79, 95% CI = 0.70 to 0.91) compared with the referent group. Women with benign breast disease and polygenic risk score in the highest decile had a 3.7-fold increase (95% CI = 3.00 to 4.61) compared with those with median polygenic risk score without benign breast disease. Conclusion Breast cancer risks are elevated among women with benign breast disease and increase progressively with polygenic risk score, suggesting that optimal combinations of these factors may improve risk stratification.

Abstract Purpose Many women are employed at the time of breast cancer (BC) diagnosis. Pre-diagnosis psychological distress is prevalent among early-stage BC patients. We prospectively evaluated return to work (RTW) in BC patients with and without reported pre-diagnosis psychological distress over a 15-month period to determine if such distress affects workforce participation and mental health status after curative treatment. Methods 188 patients with newly diagnosed stage 0-III BC and working 35-plus hours/week participated at Mayo Clinic in Minnesota and Florida. Patients received an email survey at diagnosis and 3 and 15 months later. Incidence of severe psychological distress (SPD) per the Kessler Psychological Distress Scale (K6, score ≥ 13) was assessed at each timepoint. Results 77/188 survey respondents (41%) reported pre-diagnosis psychological distress, with 23.5% noting job-related stress. 59/188 patients (31%) had SPD at diagnosis, with similar incidence in the group that had pre-diagnosis distress (+ stress) and the non-stressed group (no-stress). The sample was highly educated and well salaried. The + stress group worked more hours on average at diagnosis (41.3 vs. 39.3 hours, p = 0.034). At 3 months, 83/141 respondents (60.1%) reported taking time off work after diagnosis, with 46.6% returning within 2 weeks and 42.5% requiring > 4 weeks’ break. More + stress patients reported RTW to maintain health insurance (13/56 vs. 6/85, p = 0.006), although this difference resolved by 15 months. SPD rates decreased over time but affected 17/104 respondents (16.3%) at 15 months. Conclusion Job-related stress is a primary driver of pre-diagnosis psychological distress. Three months after BC diagnosis, many women with pre-diagnosis psychological distress were motivated to RTW to keep employer-linked health insurance. SPD is prominent in BC patients; while SPD declined over time, it did not resolve completely.

Abstract Women at increased risk for breast cancer may benefit from taking risk-reducing medication (RRM) with tamoxifen (tam). Historical uptake of tam in women who qualify has been low. Recent studies have shown low-dose tam to have similar efficacy to standard dosing, with lower risk for adverse events. In this study, we aimed to evaluate uptake, adherence, and tolerability of low-dose tam in women at increased risk for breast cancer and those with ductal carcinoma in situ (DCIS). In this two-site prospective study, women who qualified for breast cancer RRM were offered participation and received consultation with a breast specialist for discussion of RRM rationale, benefits, side effects, and risks. Patients received baseline and 1-year follow-up surveys. A total of 41 patients consented for participation, and 31 completed 1-year follow-up. After initial consultation, 90% (n = 37) reported good/complete understanding of breast cancer risk. Of patients included in 1-year follow-up, 5 had DCIS, 13 had high-risk intraepithelial lesion, and 13 qualified based on Breast Cancer Risk Assessment Tool/International Breast Intervention Study calculation. Furthermore, 74% (n = 23) of patients reported that they took low-dose tam after consultation, with 78.2% (n = 18) of those still taking medication at 1 year. Patients who continued medication had higher estimated breast cancer risk compared with those who discontinued (International Breast Intervention Study 10-year risk, 12.7% vs. 7.6%; P = 0.027). All patients with DCIS initiated low-dose tam, and only one patient with DCIS had discontinued at 1 year. Uptake of low-dose tam after informed discussion is high. Adherence and tolerability at 1-year follow-up improved compared with those with traditional dosing of tam. Prevention Relevance: tam has been used extensively for breast cancer prevention in high-risk women. Historical uptake has been low because of concern for side effects and poor tolerability. Herein, we demonstrate that in the clinical setting, effective patient education and offering of a low-dose option can improve uptake in this high-risk population. See related Spotlight, p. 545