Seymour, Lisa R.

Abstract Uptake of tamoxifen is limited to 5-15% of all eligible women due to concerns regarding medication side effects combined with the lack of ability to predict which women will benefit from the therapies. We used a unique retrospective sample of n=92 high-risk women with paired benign biopsies obtained before (PreTam) and during tamoxifen (OnTam) to discover tissue gene expression biomarkers of biologic response, defined as change (Δ) in lobular Ki67. Ki67 was digitally quantified in normal lobules from PreTam and OnTam benign tissue samples and samples with PreTam Ki67 = 0 were excluded. Data were analyzed from 51 women with both PreTam and OnTam Ki67 (median age = 49 years and median BMI = 25.5 kg/m2 at PreTam biopsy). OnTam biopsies were collected a median of 11.5 months after PreTam biopsy (median 6.5 months after starting tamoxifen; dose 20 mg/day in 86%). Median Ki67 significantly decreased overall (Δ Ki67 = -0.29%, p=0.003), but the effect was restricted to women with baseline Ki67 ≥ 0.5% (n=38, Δ Ki67 = -0.78%, p=0.0002); no significant change occurred with baseline Ki67 < 0.5 (Δ Ki67 = 0.19%, p=0.23). Δ Ki67 was inversely proportional to baseline Ki67. RNA-seq was successful for 171 benign tissue samples (including 53 PreTam-OnTam pairs). After edgeR normalization (>14,600 genes), PreTam vs OnTam comparison across 33 pairs with baseline Ki67 ≥ 0.5% yielded 66 differentially expressed genes (fold-change > 2 and p<0.01). At p<0.01, ranked gene set enrichment analysis revealed 27 gene sets enriched for reduced expression with Tam (with top-ranked gene set related to steroid hormone biosynthesis) and 59 gene sets enriched for increased expression with Tam (with top-ranking gene sets related to B cell and T cell receptor signaling, regulation of cell cycle, and other immune-related pathways). To identify predictors of response, we correlated baseline PreTam gene expression with Δ Ki67 in 37 women with available baseline PreTam RNAseq and Δ Ki67 data. Partial correlation analysis (via ‘ppcor’ package, adjusted for library qubit) revealed 73 genes with significant positive correlation (rho > 0.50) and 14 genes with significant negative correlation (rho < -0.50) with Δ Ki67 (p<0.01). At p<0.01, ranked gene set enrichment analysis yielded 67 gene sets enriched with negative correlation (i.e. increased expression associated with a reduction in Ki67), including pathways related to ribosome biogenesis, DNA recombination, and nucleic acid metabolic processes; there were 62 gene sets enriched for positive correlation (i.e. decreased expression associated with a reduction in Ki67), including pathways such as VEGF and ERBB signaling. Our data support (i) baseline Ki67 ≥ 0.5 % and (ii) an 87-gene baseline signature as complementary biomarkers of tamoxifen response. Prospective validation of this combined assay could target tamoxifen to the women most likely to benefit, potentially overcoming a major barrier to chemoprevention uptake. Citation Format: S. J. Winham, C. Wang, Y. Liu, B. M. McCauley, D. J. Tabrizi, D. L. Gehling, J. L. Fischer, L. R. Seymour, M. H. Solanki, M. E. Sherman, K. R. Lohani, T. L. Hoskin, D. C. Radisky, A. C. Degnim. Gene expression signatures of beneficial response to tamoxifen for breast cancer prevention [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-18.

Abstract Background: Artificial intelligence (AI) algorithms based on deep learning approaches show promise in improving breast cancer (BC) detection on mammography and may also improve prediction of future BC risk compared with clinical risk prediction models. Historical clinical risk prediction models underperform among women with BBD; however, AI models for BC detection on mammography have not been tested among women at elevated BC risk due to benign breast disease (BBD). We evaluated if an AI cancer detection algorithm can aid BC risk prediction among women with BBD. Methods: We examined women without a prior BC who had an initial BBD biopsy at Mayo Clinic, Rochester, between 2002 and 2013. Incident BC occurring after BBD was identified using the Mayo Tumor Registry and supplemented by follow-up questionnaires. Only women with a full field digital mammogram at least 2 years prior to BC diagnosis were eligible. A breast pathologist evaluated BBD according to increasing severity, as non-proliferative (NP), proliferative disease without atypia (PDWA) or atypical hyperplasia (AH). AI malignancy scores derived from the Transpara detection algorithm (1-10) and volumetric percent density (VPD) from Volpara (per one standard deviation, SD) were assessed from mammograms close to BBD diagnosis. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) with 95% Confidence Intervals (CIs), adjusted for age and BMI. C-statistics were estimated to assess the contribution of each factor to BC risk prediction. Likelihood ratio tests (LRTs) and bootstrapping methods were used to compare model performance with the addition of AI malignancy score. Results: The BBD cohort with mammography consisted of 3,125 women followed for a median 12.9 years, with 250 incident BC. Of these, 221 BC occurred at least two years after the mammogram and were used in analyses. As expected, increased BC risk was associated with BBD severity [for AH HR=3.18 (95%CI: 2.04, 4.95) and for PDWA HR=1.59 (95%CI: 1.17, 2.14) compared to NP] and with higher VPD [HR=1.24 per SD (95% CI: 1.05, 1.45)] (Table ). The AI-malignancy score alone was also associated with BC risk [HR=1.16 per 1 unit score (95%CI: 1.09,1.23)] and showed similar discriminatory accuracy [C-statistic=0.626 (95%CI: 0.586, 0.665)] as the model with BBD severity and VPD combined [C-statistic=0.627, (95%CI: 0.585, 0.669)] (Table ). In models with BBD severity and VPD, the AI-malignancy score was an independent risk factor for BC [HR=1.14 (95%CI: 1.07, 1.21); PLRT<0.001] but only achieved a marginally significant improvement in discriminatory accuracy [C-statistic=0.651 (0.609, 0.693), ΔC-statistic=0.024 (95% CI: 0.000, 0.047)]. Conclusion: In this preliminary study, an AI BC detection algorithm achieved similar performance in predicting future BC risk compared to established risk factors. Citation Format: C. M. Vachon, S. Winham, M. Jensen, D. Hursh, L. Pacheco-Spann, A. Norman, J. Fischer, S. Schrup, L. Seymour, D. Gehling, S. Nyante, M. Troester, N. Karssemeijer, R. Vierkant, D. Radisky, C. Scott, S. I. Maimone, A. Degnim, M. Sherman. An AI algorithm for breast cancer detection improves future BC risk prediction among women with benign breast disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-02.

Abstract Background Benign breast disease (BBD) increases breast cancer (BC) risk progressively for women diagnosed with nonproliferative change, proliferative disease without atypia (PDWA), and atypical hyperplasia (AH). Leveraging data from 18 704 women in the Mayo BBD Cohort (1967-2013), we evaluated temporal trends in BBD diagnoses and how they have influenced associated BC risk over 4 decades. Methods BC risk trends associated with BBD were evaluated using standardized incidence ratios (SIRs) and age–period–cohort modeling across 4 eras—premammogram (1967-1981), precore needle biopsy (CNB) (1982-1992), transition to CNB (1993-2001), and CNB era (2002-2013). Results With a median follow-up of 15.8 years, 9.9% of women were diagnosed with BC (invasive and/or DCIS). From the premammogram era to the CNB era, we observed a significant increase in BC risk, rising from an SIR of 1.61 to 1.99. The proportion of proliferative BBD diagnoses (PDWA or AH) increased markedly over time (28.1%-49.7%), as did the proportion of DCIS events (11%-28%; χ2 P < .001). Within specific BBD categories, the risk of invasive BC increased modestly. Conclusions Absolute risk of BC within BBD categories remained stable, but the relative risk of BC after BBD increased over time due to notable increases in higher risk BBD lesions, specifically PDWA and AH. These findings illustrate how evolving screening practices have changed the risk profile of BBD and should inform management strategies for patients with BBD in modern clinical settings.

Abstract Introduction: Although Hispanic White (HW) females have a lower incidence of breast cancer than non-Hispanic White (NHW) females, breast cancer risk is unclear for HW females after benign breast disease (BBD). Methods: We compared BBD characteristics and subsequent breast cancer risk among HW and NHW females in New Mexico using a population-based collection of benign breast biopsies (1996–2007). BBD was categorized as nonproliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). Breast cancer risk was assessed as absolute risk (AR) using cumulative incidence and RR by comparing the number of breast cancer events in BBDs to non-BBD. Results: This study included 3,684 HW and 6,587 NHW females with BBD. HW females had similar proportions of NPD (58.6% vs. 54.3%), PDWA (21.4% vs. 23.5%), and AH (3.6% vs. 3.3%) as NHW females. Breast cancer risk among all females with BBD was higher than population-based expected rates (RR, 1.87) and was similar for HW and NHW subgroups (RR = 1.99 vs. 1.84). As expected, breast cancer risk increased with increasing BBD severity, both overall [RR, 1.81 (NPD), 1.85 (PDWA), and 3.10 (AH)] and in the HW and NHW subgroups. Adjusted AR of breast cancer at 5 years also increased with the severity of BBD (HW vs. NHW; NPD: 1.4% vs. 2.1%; PDWA: 1.5% vs. 2.7%; AH: 6% vs. 4.8%). Conclusions: We found similar breast cancer RRs and ARs in HW and NHW. Risk counseling should ensure that HW females receive breast cancer clinical management warranted by their similar absolute risks. Impact: The present population-based provides evidence for the clinical management of HW females with BBD for the prevention of breast cancer.

Importance Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD. Objectives To estimate BC risk associated with BBD in the percutaneous biopsy era irrespective of surgical biopsy. Design, Setting, and Participants In this retrospective cohort study, BBD biopsy specimens collected from January 1, 2002, to December 31, 2013, from patients with BBD at Mayo Clinic in Rochester, Minnesota, were reviewed by 2 pathologists masked to outcomes. Women were followed up from 6 months after biopsy until censoring, BC diagnosis, or December 31, 2021. Exposure Benign breast disease classification and multiplicity by pathology panel review. Main Outcomes The main outcome was diagnosis of BC overall and stratified as ductal carcinoma in situ (DCIS) or invasive BC. Risk for presence vs absence of BBD lesions was assessed by Cox proportional hazards regression. Risk in patients with BBD compared with female breast cancer incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) program were estimated. Results Among 4819 female participants, median age was 51 years (IQR, 43-62 years). Median follow-up was 10.9 years (IQR, 7.7-14.2 years) for control individuals without BC vs 6.6 years (IQR, 3.7-10.1 years) for patients with BC. Risk was higher in the cohort with BBD than in SEER data: BC overall (standard incidence ratio [SIR], 1.95; 95% CI, 1.76-2.17), invasive BC (SIR, 1.56; 95% CI, 1.37-1.78), and DCIS (SIR, 3.10; 95% CI, 2.54-3.77). The SIRs increased with increasing BBD severity (1.42 [95% CI, 1.19-1.71] for NP, 2.19 [95% CI, 1.88-2.54] for PDWA, and 3.91 [95% CI, 2.97-5.14] for AH), comparable to surgical cohorts with BBD. Risk also increased with increasing lesion multiplicity (SIR: 2.40 [95% CI, 2.06-2.79] for ≥3 foci of NP, 3.72 [95% CI, 2.31-5.99] for ≥3 foci of PDWA, and 5.29 [95% CI, 3.37-8.29] for ≥3 foci of AH). Ten-year BC cumulative incidence was 4.3% for NP, 6.6% for PDWA, and 14.6% for AH vs an expected population cumulative incidence of 2.9%. Conclusions and Relevance In this contemporary cohort study of women diagnosed with BBD in the percutaneous biopsy era, overall risk of BC was increased vs the general population (DCIS and invasive cancer combined), similar to that in historical BBD cohorts. Development and validation of pathologic classifications including both BBD severity and multiplicity may enable improved BC risk stratification.

Abstract Introduction: We used micro-computed tomography (microCT), a high-resolution imaging option, to detect and characterize microcalcifications (MCs) in three dimensions within pathology blocks of benign and malignant breast tissues. Methods: A set of 44 formalin-fixed, paraffin-embedded breast tissue blocks were assessed from n=22 women at two time points: benign breast biopsy and subsequent DCIS or DCIS with invasive disease breast cancer. Blocks were scanned using the Bruker Skyscan 1276 microCT at a resolution of 10 µm. SkyScan analysis CTAn software was utilized to prepare and analyze morphological parameters and multiple MCs contained within each block were averaged. Paired morphological parameters were compared between the benign and subsequent cancer samples within women using Wilcoxon signed-rank tests. Results: Median age of patients was 53 years (range 37-77 years) at initial benign biopsy and developed breast cancer at median of 5.6 years (range: 2.3-12.8 years) later. The initial benign biopsies were for proliferative disease without atypia in the majority (59%), while 23% had non-proliferative lesions and 18% atypical hyperplasia. The average structural model index was consistent with a near rod-like shape (median 2.99, range: 2.71-3.29). Paired comparisons between benign and cancer blocks showed that the average surface area of MCs was significantly higher in the cancer samples (p=0.0467), as was the average volume of MCs (p=0.0298) (Table 1). Conclusions: Preliminarily, we demonstrate that microCT of routinely prepared pathology blocks of breast tissues may be useful in characterizing the 3-D morphometry of MCs with suggestive differences in benign and cancer tissues. Given that MCs are a sentinel radiologic marker of DCIS but are common in benign breast disease, developing improved approaches for classifying MCs may have value in breast cancer screening and management. Table 1. Comparison of MC parameters in biopsy tissues (IQR = Interquartile Range). Benign sample from women who later developed breast cancer Breast cancer after prior benign sample Paired Differences (Cancer - Benign) Wilcoxon signed-rank p value (N=22) (N=22) (N=22) Number of Objects (Median (IQR)) 43.5 (14, 789) 69.5 (33, 289) -6 (-139, 67) 0.6830 Average Surface Area (mm2)(Median (IQR)) 0.0225 (0.0134, 0.0393) 0.0342 (0.0185, 0.0656) 0.0113 (-0.0027, 0.0322) 0.0467 Average Volume (mm3) (Median (IQR)) 0.0003 (0.0001, 0.0007) 0.0007 (0.0003, 0.0022) 0.0003 (0.000002, 0.0020) 0.0298 Average Surface Area/Volume (mm−1)(Median (IQR)) 214.92 (162.25, 328.39) 199.55 (151.89, 230.52) -20.85 (-86.05, 27.04) 0.1433 Average Structural Thickness (mm)(Median (IQR)) 0.0341(0.0196, 0.0446) 0.0395 (0.0336, 0.0505) 0.0074 (-0.0062, 0.0153) 0.1173 Average Structural Model Index (Median (IQR)) 2.9758 (2.8465, 3.1175) 3.0026 (2.9281, 3.0927) 0.0075 (-0.1073, 0.1381) 0.7656 Citation Format: Sarah E. Schrup, Thomas de Bel, Tanya Hoskin, Teresa Allers, Stacey Winham, Derek Radisky, Laura Pacheco-Spann, Lisa Seymour, Amy Degnim, Mark Sherman. High resolution microCT to analyze the 3D morphology of microcalcifications in benign breast disease and breast cancer biopsy tissues. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3587.

Abstract Introduction: Benign breast disease (BBD) is an important breast cancer (BC) risk factor, which may be classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) for risk stratification. Data related to the frequency of specific types of BBD and their relationship to BC risk in the Hispanic American population are limited. To address this knowledge gap, we compared BBD and associated BC risk among Hispanic white (HW) and non-Hispanic white (NHW) in New Mexico (NM). Methodology: A retrospective IRB-approved study was performed of women 19 years or older residing in six counties in NM (Bernalillo, Sandoval, Sante Fe, Socorro, Torrance, Cibola/Valencia) between 1996 and mid-2007 to compare the frequency of BBD subtypes and BC risk among HW and NHW. We excluded women who had a history of BC prior to BBD diagnosis or who were diagnosed with BC within 6 months after BBD biopsy. Race and ethnicity were self-reported by women at the time of biopsy. BBD was categorized as NPD, PDWA, or AH based on medical records. Incident BC (in-situ or invasive) was ascertained via linkage to the NM Surveillance Epidemiology End Results (SEER) Registry and BC risk was assessed using standardized incidence ratios (SIRs), comparing the observed number of BC events to that expected based on the NM SEER six-county race- and ethnicity-specific incidence rates, accounting for age and calendar period. Results: Our analysis included 3,870 HW and 6,996 NHW women with BBD. The HW were younger (47.1 vs. 51 years) compared to NHW. HW women had slightly more NPD (69.4% vs. 66.6%) but less PDWA (26.2% vs. 29.4%) and similar frequency of AH (4.3% vs. 3.9%) as compared to NHW. Over a median post-BBD follow-up period of 13 years (range 6 months-17 years), 644 BCs were observed (4.81% in HW and 6.55% in NHW). The observed BC risk among women with BBD was higher than population-based expected rates (SIR 1.98, 95% CI 1.82-2.13, p<0.001) and showed expected increases in risk with increasing degrees of BBD abnormality: SIR=1.90 for NPD, 2.00 for PDWA, and 3.01 for AH. Comparing BC risk by ethnic subgroups, HW women had an overall risk of BC after BBD that was statistically indistinguishable from NHW women (SIR=2.17, 95% CI 1.86-2.48 in HW women, and SIR=1.91, 95% CI 1.73-2.08 in NHW women). Within the major subgroups of the BBD findings, there were no significant differences in risk of BC after BBD for HW versus NHW women. Conclusions: In this population-based study, benign breast disease subtypes and their associated breast cancer risk were similar among the Hispanic and non-Hispanic white women. Citation Format: Kush Raj Lohani, Andrea M. Nibbe, Robert A. Vierkant, Laura M. Pacheco-Spann, Lisa R. Seymour, Celine M. Vachon, Mark E. Sherman, Amy C. Degnim, Deirdre Hill. Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4213.

ObjectivesThe aim of the present study was to engage a national advocacy group and local stakeholders for guidance in developing a bipolar disorder biobank through a web‐based survey and a community advisory board.MethodsThe Depression and Bipolar Support Alliance and the Mayo Clinic Bipolar Biobank conducted a national web‐based survey inquiring about interest in participating in a biobank (i.e., giving DNA and clinical information). A community advisory board was convened to guide establishment of the biobank and identify key deliverables from the research project and for the community.ResultsAmong 385 survey respondents, funding source (87%), professional opinion (76%), mental health consumer opinion (79%), and return of research results (91%) were believed to be important for considering study participation. Significantly more patients were willing to participate in a biobank managed by a university or clinic (78.2%) than one managed by government (63.4%) or industry (58.2%; both p < 0.001). The nine‐member community advisory board expressed interest in research to help predict the likelihood of bipolar disorder developing in a child of an affected parent and which medications to avoid. The advisory board endorsed the use of a comprehension questionnaire to evaluate participants' understanding of the study (e.g., longevity of DNA specimens, right to remove samples, accessing medical records) as a means to strengthen the informed consent process.ConclusionsThese national survey and community advisory data support the merit of establishing a biobank to enable studies of disease risk, provided that health records and research results are adequately protected. The goals of earlier diagnosis and individualized treatment of bipolar disorder were endorsed.