RISE UP (Revolutionizing Investigations to StEp Up Prevention) for breast cancer brought together leading cancer specialists, women’s health providers, basic and population scientists, regulators, politicians, industry leaders, patient advocates, and more from around the world to discuss and chart a radical rethinking of breast cancer prevention and risk reduction through a lens of hormonal management across a woman’s life course. The presentations at RISE UP were organized to outline a path forward by leveraging what we know about breast cancer biology, early detection, treatment, and endocrine therapy toward a better and sustainable approach for breast cancer prevention. Important conference considerations were to expand our thinking about prevention by broadly considering how the hormonal environment during different life phases or common benign conditions could be better managed to minimize breast cancer risk. This set the stage for transitioning to advances in risk prediction, promising risk-reducing agents, and biomarker-driven trials to test them. Biomarker-based trials discussed focused on 1) lower or intermittent doses of standard prevention agents, 2) drugs already approved for other health purposes, and 3) maximizing benefits from lifestyle interventions alone or in combination. Throughout RISE UP, there was a strong focus on promoting health equity, including comprehensive reproductive health access, equitable representation in clinical trials, and strategies to educate women, providers, and advocates about disparities in care and how to successfully reduce them. The meeting concluded with a competition for innovative approaches to breast cancer prevention that could be integrated into hormonal and women’s health interventions. RISE UP was an innovative conference that provided a forum for cross-cutting topics in women’s health that do not currently exist. The insights shared at RISE UP will be paradigm shifting in breast cancer prevention and women’s health space in the years to come.

Abstract Introduction: The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation linked to poor outcomes in several solid tumor malignancies, including breast cancer. Prior studies have shown that its prognostic significance in breast cancer differs by molecular subtype; however, these studies have rarely accounted for racial variation in baseline NLR values, which may affect the interpretation of threshold-based analyses. This study evaluates the prognostic value of pretreatment NLR in breast cancer and whether associations between NLR and survival outcomes differ by race and tumor subtype. Methods: We conducted a retrospective analysis of 754 patients from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort. Eligible patients had an NLR measurement ≤1 year prior to treatment initiation. NLR was analyzed as both continuous and binary variables, using a cohort-wide median cutoff (2.07) and race-specific cutoffs (3.11 for White and 2.56 for Black patients). Outcomes included recurrence-free survival (RFS), overall survival (OS), breast cancer-specific survival (BCSS), and other-cause (OC) mortality. Cox and competing risk regression models were used to estimate the associations between NLR and survival outcomes, adjusting for demographic and clinical covariates. Results: Among 754 patients (mean age at diagnosis 55.9 years), 383 were Black, 308 were White, and 63 were categorized as Other. The median pretreatment NLR was lower in Black patients (1.78, IQR 1.30-2.61) compared to White (2.38, IQR 1.69-3.11) and Other racial patients (2.06, IQR 1.41-2.89). In adjusted analyses, each doubling of NLR was associated with worse RFS (adjusted hazard ratio [aHR] 1.24, 95% CI 1.02-1.52), OS (aHR 1.20, 95% CI 0.98-1.48), and OC mortality (aSHR 1.42, 95% CI 1.07-1.89). When modeled as a binary variable, high NLR (≥2.07) was associated only with higher OC mortality (adjusted sub-distribution hazard ratio [aSHR] 2.11, 95% CI 1.11-4.02). Stratified analyses showed that the association between NLR and survival outcomes was most pronounced in HER2-negative and hormone receptor-positive tumors, whereas no significant associations were observed in hormone receptor-negative tumors. When using race-specific thresholds, high NLR (≥2.56) was significantly associated with worse RFS (aHR 2.02, 95% CI 1.27-3.21), OS (aHR 1.93, 95% CI 1.15-3.21), and BCSS (aSHR 2.31, 95% CI 1.12-4.78) in Black patients, but not in White patients. Conclusion: Our study demonstrates that pretreatment NLR may be used as a prognostic marker for breast cancer outcomes, but its predictive value varies by race and tumor subtype. Baseline racial differences in NLR underscore the need for race-specific thresholds. Larger, diverse studies are needed to validate these findings and clarify underlying biological mechanisms. Citation Format: Armaan Jamal, Lendy Chu, Jincong Q. Freeman, Rita Nanda, Olufunmilayo I. Olopade, Wenji Guo, Dezheng Huo.. The prognostic role of pretreatment neutrophil-to-lymphocyte ratio in a multiethnic cohort of breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5368.

Background and Methods: Point of care genetic testing has grown but cascade testing of At-Risk Relatives (ARR) remains underutilized. Between July and September 2023, we surveyed 912 individuals enrolled in the Cancer Prone Study, a registry of diverse high-risk families who received genetic counseling from cancer genetic experts. We analyzed correlates of familial disclosure and cascade testing among carriers of pathogenic/likely pathogenic variants (PV). Data on carrier status of PV in cancer-predisposing genes, penetrance level of variants, receipt of a family letter, familial disclosure, and follow up cascade testing of ARRs were collected. Results: Of 912 respondents, 39.4% were carriers of PV. Among these carriers, 78% had highly penetrant PVs (most common genes were BRCA1 : 39% and BRCA2 : 18%) and 17.5% had moderate penetrance PVs; Rate of disclosure of PV to at least one family member; receipt of family letter explaining genetic test results; and sharing of information with ARRs were 98%, 69% and 82% respectively. Cascade testing was more likely among carriers with highly penetrance PV (91.1%) compared to those with moderate penetrance PV (58.3%) (adjusted odds ratio [AOR], 5.70; 95% CI, 2.03-16.02), and among carriers who received a family letter than among those who did not receive (87.2% vs. 73.0%; AOR, 3.70; 95% CI, 1.42-9.61). These data suggest that access to family-based counseling facilitated by cancer genetic experts improves understanding of familial risks and improves cascade testing following results disclosure. Our data support family based clinical interventions to optimize precision prevention and cancer control in high-risk individuals.

Importance:The prevalence of pathogenic or likely pathogenic variants (PVs) in breast cancer susceptibility genes in the US population-regardless of family history risk factors-remains largely unknown because population-based genetic screening is not routinely performed. Objective:To identify the prevalence of PVs in a large cohort of women offered criteria-independent genetic testing and to evaluate the relationship of test positivity to family history and other patient characteristics. Design, Setting, and Participants:The Women Informed to Screen Depending on Measures of Risk (WISDOM) randomized clinical trial enrolled women without breast cancer aged 40 to 74 years between August 2016 and February 2023 in a pragmatic randomized screening trial comparing annual screening mammography with personalized risk-based screening. Data were analyzed from August 2023 to November 2025. Exposures:All women in the personalized screening arm were offered germline testing for 9 breast cancer susceptibility genes: BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, and TP53. Main Outcomes and Measures:The prevalence of PVs in the trial and the distribution of self-reported demographic and family history data in this subpopulation of carriers. Results:Among 23 098 women who completed germline genetic testing (mean [SD] age, 54.3 [9.6] years), 714 (3.1%) carried a PV. Excluding 109 who were previously aware of their PV, the detection rate was 2.6%. PVs were most common in CHEK2 (337 [1.5%]) and ATM (101 [0.4%]) but less common in higher-penetrance genes (BRCA1, 33 [0.1%]; BRCA2, 82 [0.4%]; PALB2, 44 [0.2%]). PVs in the CDH1, PTEN, STK11, and TP53 genes were rare (less than 0.1%). Notably, 180 of 605 women with PVs (29.8%) did not report a first-degree or second-degree female relative with breast or ovarian cancer, male relative with breast cancer, or Jewish ancestry. Conclusions and Relevance:In this secondary analysis of the WISDOM trial, criteria-independent genetic testing in a pragmatic trial identified a substantial number of women with clinically actionable results, many of whom would not have qualified for genetic testing under current guidelines. These findings support broader access to genetic testing as part of personalized breast cancer risk assessment. Trial Registration:ClinicalTrials.gov Identifier: NCT02620852.

Breast cancer (BC) is the leading cause of cancer in women worldwide with rising incidence in low- and middle-income countries (LMIC). We examined trends in reproductive and lifestyle factors for breast cancer across birth cohorts of Nigerian women. We conducted a cross-sectional analysis of 2,309 female control participants (mean age, 42.5 ± 13.0 years) recruited between 1998 and 2017 as part of the Nigerian Breast Cancer Study (NBCS), an ongoing case-control study. Birth cohort was modeled as an ordinal predictor to evaluate temporal trends. Reproductive and lifestyle factors were analyzed across six birth cohorts (< 1940, 1940–1949, 1950–1959, 1960–1969, 1970–1979, and ≥ 1980). Analyses of reproductive variables were repeated among women aged ≥ 40 years, and hormonal contraceptive use was additionally evaluated among women aged ≥ 30 years. Among all women, mean age at menarche declined from 16.0 years among women born before 1940 to 15.1 years among those born in or after 1980 (P for trend = 0.001), whereas age at thelarche remained stable across birth cohorts. Among women aged ≥ 40 years, mean parity declined from 6.1 to 4.1 live births, and cumulative lifetime breastfeeding duration decreased from 114 to 75 months (both P for trend < 0.001). Mean breastfeeding duration per live birth showed only a modest decline. Among women aged ≥ 30 years, the prevalence of ever hormonal contraceptive use increased from 7.2

Abstract Background: There are profound global inequities cancer genomics research, with publications focusing on cancer genetics from Africa representing only 0.016% of the global total. This genomic underrepresentation creates significant barriers to equitable cancer care and precision medicine for African populations. BRCA1/2 mutations remain critically understudied in these communities, limiting our understanding of hereditary breast cancer patterns. This pioneering study characterizes BRCA1/2 mutations among Cameroonian patients to lay the foundation for future genomic research and address critical knowledge gaps. Methods: This hospital-based study recruited 82 breast cancer patients from 2 major treatment centers in Cameroon, an underserved population with limited access to genetic services. Following pre-test genetic counseling, saliva samples were collected and analyzed using next-generation sequencing for 29 cancer-associated genes. AI was used to improve the clarity of the language of this abstract. Results: Pathogenic mutations were identified in 23 patients (28%), with BRCA1 (15) and BRCA2 (2) accounting for 73.9% of all mutations (18.3% and 2.4% of the total population, respectively). The most frequent BRCA1 mutation was c.4484G>T(p.Arg1495Met), present in 7 patients (46.7% of BRCA1 mutations, 8.5% of total population), followed by c.5155dup(p.Val1719Glyfs6) in 3 (including 1 with bilateral breast cancer) patients (20% of BRCA1 mutations). BRCA2 mutations included c.1813dup(p.Ile605Asnfs11) and c.5572del(p.Thr1858Glnfs*5). Family history of cancer was reported in 73.9% of mutation carriers compared to 62.2% overall. Variants of uncertain significance were detected in 25.6% of patients. Two of those with the c.4484G>T BRCA1 mutation had an associated VUS in the PALB2 gene (c.365A>G(p.Asp122Gly)). They were both under 30 and had at least 4 first- and second-degree relatives with breast and ovarian cancer. Two other patients had the same VUS in APC (c.3760A>G(p.Ile1254Val)), all with at least 2 relatives with cancer and 1 had the BRCA1 c.4484G>T mutation and the other had no pathologic mutation identified. Conclusions: This pioneering study reveals striking cancer health disparities, with BRCA1/BRCA2 mutation frequencies exceeding rates in well-studied populations. The predominance of specific mutations and VUSs suggests population-specific genetic architecture requiring tailored approaches. Our work provides a foundation for developing culturally-appropriate cancer prevention strategies, reducing genetic testing disparities, and advancing precision medicine accessibility in vulnerable populations, ultimately contributing to the global effort to eliminate cancer health disparities. Citation Format: Kenn Chi Ndi, Berthe Sabine Esson Mapoko, Vanessa Mouaye, Carmen Vanvolkenburgh, Bonaventure Dzekem, Paul Ndom, Dezheng Huo, Olufunmilayo I. Olopade. Characterizing BRCA1 and BRCA2 mutations in Cameroonian breast cancer patients: Efforts towards bridging the genomic gap in Africa [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3596.

BACKGROUND:Breast cancer survivors face many health challenges, including tinnitus, hearing loss, and vertigo which will grow with an aging population and improved treatment outcomes. However, the prevalence of hearing/vestibular problems, racial differences, and relationships to physical function are poorly characterized in breast cancer survivors. METHODS:Between July and September 2023, we surveyed the Chicago Multiethnic Epidemiologic Breast Cancer Cohort. Tinnitus, hearing loss, and vertigo were self-reported and verified through electronic health records. Physical function impairment was measured using the SF-36 10-item instrument. We fit logistic regression models for hearing/vestibular problems and linear regression models for physical function score, controlling for sociodemographic and clinical factors. RESULTS:Of 1466 breast cancer survivors (mean [SD] age, 63.5 [11.8] years), 16.6%, 17.3%, and 8.6% reported experiencing tinnitus, hearing loss, and vertigo, respectively. Black survivors had lower odds of hearing loss (adjusted odds ratio [AOR] = 0.51; 95% confidence interval [CI] = 0.31 to 0.86) but greater odds of vertigo (AOR = 2.29; 95% CI = 1.34 to 3.89) than White survivors. Survivors with hearing/vestibular problems had higher average impairment scores (worse physical function) than those without. In the adjusted regression models, survivors who reported experiencing tinnitus (β = 0.76; 95% CI = 0.10 to 1.43), hearing loss (β = 0.73; 95% CI = 0.06 to 1.40), or vertigo (β = 1.70; 95% CI = 0.81 to 2.58) had a higher level of physical function impairment. CONCLUSIONS:This study demonstrates racial differences in hearing/vestibular problems and associations between these problems and physical function impairment. Survivorship programs should consider routine screening and interventions to improve hearing health and physical function among breast cancer survivors.

Abstract Breast cancer genomic studies have been conducted primarily in European-ancestry populations, limiting both diversity and statistical power. In this study, we substantially increased the representation of African- and Asian-ancestry women and markedly expanded the sample size of European descendants, creating the largest multi-ancestry dataset for breast cancer genome-wide association studies (GWAS) to date. With 237,817 cases and 1,679,059 controls, we conducted GWAS and transcriptome-wide association studies (TWAS) across ancestries and identified 326 risk loci and 113 genes associated with overall breast cancer risk at a P < 5 × 10⁻⁸ (for GWAS) and Bonferroni-corrected P of 1.54 × 10⁻⁴ (for TWAS), respectively. Of them, 153 risk loci and 69 genes were not reported previously. Subtype-specific analyses for estrogen receptor (ER) positive, ER-negative and triple-negative breast cancer (TNBC) revealed an additional 89 loci and 64 genes associated with breast cancer risk, including 61 loci and 12 genes not previously reported. Moreover, associations for 25 loci and 11 genes differed significantly by ER status, and 22 loci and eight genes were exclusively associated with risk of triple-negative breast cancer. Risk genes identified in this study were significantly enriched in pathways related to transcriptional regulation, estrogen response, mitotic spindle processes, and DNA damage repair. Together, these findings substantially expand the landscape of breast cancer susceptibility, subtype-specific genetic architecture, and provide added insights into breast cancer biology and genetics. Citation Format: Zheng Guo, Guochong Jia, Jie Ping, Xingyi Guo, Shuai Xu, Yulu Zheng, Thomas U. Ahearn, Christine Ambrosone, Montserrat Garcia-Closas, Jian Gu, Christopher A. Haiman, Dezheng Hu, Motoki Iwasaki, Sun-Young Kong, Sun-Seog Kweon, Koichi Matsuda, Keitaro Matsuo, Katherine L. Nathanson, Barbara Nemesure, Katie M. O'Brien, Olufunmilayo Olopade, Tuya Pal, Julie Palmer, Sue K. Park, Michael F. Press, Melissa Troester, Song Yao, Bingshan Li, Ran Tao, Xiao-Ou Shu, Jirong Long, Wei Zheng. Multi-ancestry genome- and transcriptome-wide association studies expand the susceptibility landscape for breast cancer overall and across subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB207.

10572 Background: Breast cancer outcomes in sub-Saharan Africa are marked by early onset, advanced stage at diagnosis, and high mortality. Although prior studies demonstrate a high burden of inherited cancer susceptibility variants in African populations, access to ancestry-informed genetic counseling and testing remains limited due to infrastructure constraints and poor integration into routine oncology care. The GenCAF program was developed to translate prior genomic evidence from Nigeria into a scalable, clinically embedded cancer genomics implementation model in African settings. Methods: Consecutive breast cancer patients were prospectively enrolled and offered genetic counseling and testing regardless of age or family history. Germline testing was performed using the Color Hereditary Cancer Test (Color Health Inc). Counseling and result disclosure were delivered by locally trained oncology nurses or breast health specialists using a structured protocol. Clinical and tumor characteristics were correlated with genetic findings. The program was designed for scalability across English- and French-speaking sites. Results: Among 263 participants, 235 unrelated index breast cancer cases underwent germline testing. Overall, 43.0% (101/235) had a reportable germline finding, including 21.7% (51/235) with pathogenic or likely pathogenic (P/LP) variants and 21.3% (50/235) with variants of uncertain significance (VUS). Among genes present in ≥5% of cases with variant calls, VUS were most frequent in APC, ATM, PALB2, PMS2 , and BRCA2 , with several moderate-penetrance DNA repair genes exhibiting disproportionately high VUS burden, representing key candidates for future reclassification as African-ancestry reference data and gene–environment context expand. P/LP variants were most common in BRCA1 (n = 22), BRCA2 (n = 13), ATM (n = 4), and PALB2 (n = 4). P/LP carriers tended to be diagnosed before age 30 (13.7% vs 7.6%) and were more frequently diagnosed with advanced-stage disease (stage III–IV, 30.6%). Mean age did not differ overall; however, BRCA1 P/LP carriers had an earlier onset (mean age 40.1 years). Conclusions: These findings support integrating germline cancer genetics into routine breast cancer care in Africa through a scalable, nurse-led counseling model. The substantial VUS burden underscores the need for ancestry-informed interpretation and future reclassification efforts incorporating population-specific and environmental data. Planned implementation of point-of-care next-generation and long-read sequencing will further strengthen local diagnostic capacity and enable sustainable, locally driven precision prevention and oncology through risk-informed care. Age Group (yrs) P/LP (%) VUS (%) <30 13.7 7.6 30–39 15.7 23.9 40–49 23.5 23.4 50–59 27.5 26.6 ≥60 15.6 19.0

Importance:Risk-based breast cancer screening has emerged as a viable alternative to annual mammography. To guide implementation, knowledge is needed on the contribution of testing for pathogenic variants (PVs) beyond clinical risk factors and common genetic variants for population-based risk stratification. Objective:To evaluate how many PV carriers in a risk-based breast cancer screening trial would have been recommended for high-risk screening based on clinical risk or clinical plus polygenic risk. Design, Setting, and Participants:This cohort study used retrospective data from the WISDOM Study, a national clinical trial of risk-based vs annual breast cancer screening, to compare screening assignments informed by PV status vs those based on a clinical risk model alone or a clinical risk model combined with a polygenic risk score. WISDOM participants aged 40 to 74 years who tested positive for a PV as part of risk-based screening were included. Data were collected from September 2016 to February 2023, with follow-up to September 2025. Data were analyzed from January to May 2026. Main Outcomes and Measures:Concordance between actual (considering participants' PV status) and hypothetical screening assignments based on a clinical (Breast Cancer Surveillance Consortium) risk model or a clinical model plus polygenic risk score. Results:Of 712 included women with a PV, the median (IQR) age was 53 (46-62) years. A total of 232 PVs (33%) were high penetrance, 278 (39%) were moderate penetrance, and 202 (28%) were CHEK2 low penetrance. There was little overlap between actual screening assignments based on PV status and hypothetical assignments based on a clinical model plus polygenic risk score. Among high-penetrance PV carriers (a group recommended high-risk screening with magnetic resonance imaging alternating with mammography every 6 months), 2 of 232 (0.9%) would have received the same screening assignment based on clinical plus polygenic risk. Overall, 178 of 279 PV carriers aged 40 to 49 years (63.8%) would have otherwise been recommended to defer screening until age 50 years based on clinical plus polygenic risk, whereas 385 of 433 carriers aged 50 to 74 years (88.9%) would have been recommended biennial mammography. Results were similar when comparing assignments based on a clinical model alone. Conclusions and Relevance:In this cohort study, most participants with PVs in breast cancer genes would not have been recommended for high-risk screening based on their clinical or clinical plus polygenic risk. PV testing therefore may identify different subsets of high-risk women than clinical risk factors and polygenic risk scores. These findings highlight the importance of population-based PV testing in risk-based screening. Trial Registration:ClinicalTrials.gov Identifier: NCT02620852.

Background: β-thalassaemia is considered rare in Africa; however, recent screening-based studies suggest a β-thalassaemia trait prevalence of 6% – 10% among individuals with sickle cell disease (SCD) and up to 25% in those without SCD. Co-inheritance with SCD may modify disease severity, highlighting the need for molecular confirmation. Objective: To ascertain the prevalence and genetic basis of β-thalassaemia trait in Nigerians with and without SCD. Methods: We recruited 260 participants (130 per group; aged 3 years – 69 years, median [interquartile range] = 16 [9–29]). Haemoglobin fractions were analysed using high-performance liquid chromatography, and full blood counts were obtained. A 1.6 kb region of the β-globin gene was amplified and sequenced by Sanger sequencing. Variants were annotated and haplotypes constructed. An additional 26 samples from a separate SCD cohort were also genotyped. Results: Molecular analysis revealed a β-thalassaemia trait prevalence of 1% in both groups, contrasting with recent screening-based reports. In addition to sickle cell, haemoglobin C, and β-thalassaemia mutations, eight other variants were identified, three of which were unique to SCD patients and in linkage disequilibrium. Sickle cell and haemoglobin C mutations occurred on the major ancestral haplotype, whereas the only β-thalassaemia mutation detected (rs33915217CA) was associated with a minor ancestral haplotype atypical of Africa. Two rare variants (rs537944366TC and rs33915217CA) are reported for the first time in the Yoruba population. Conclusion: These findings indicate a low prevalence of β-thalassaemia trait in Nigeria and underscore the need to re-evaluate diagnostic approaches in African populations for optimal clinical management of SCD and other anaemias. What this study adds: This study provides the first molecular confirmation of the low prevalence of β-thalassaemia trait in the Yoruba population. It identifies two rare variants, including a β-thalassaemia mutation on a minor, atypical haplotype, and highlights the limitations of high-performance liquid chromatography, underscoring the importance of genetic testing for accurate diagnosis.

Purpose:To develop and validate a multimodal recurrence-risk model integrating histology, genomic testing, and clinical variables. Methods:We developed AI-Path, a whole-slide image biomarker for recurrence prediction trained in CALGB 9344, and validated it in three independent cohorts: TAILORx, a multi-site Chicago cohort, and the MDX-BRCA cohort. We then integrated AI-Path with Oncotype DX Recurrence Score (RS), tumor size, and nodal status into a Cox model, PathClinRS, fit using 60% of cases from TAILORx, with the remaining 40% held out for validation. The primary end point was distant recurrence-free interval. Performance was assessed using Harrell's concordance index (C-index) and Kaplan-Meier analyses. Results:A total of 12,418 patients were included. In TAILORx, AI-Path outperformed RS for distant recurrence (C-index, 0.682 vs 0.647; P = .038), driven by superior prediction of late recurrence (0.656 vs 0.567; P < .001). In node-negative disease, PathClinRS outperformed RSClin in the TAILORx fitting (0.72 vs 0.70; P = .016) and validation sets (0.74 vs 0.70; P = .004). In node-positive disease, PathClinRS outperformed RSClinN+ in Chicago (0.94 vs 0.74; P < .001) and MDX-BRCA (0.71 vs 0.66; P = .004) cohorts. Compared with NATALEE eligibility, PathClinRS identified nearly twice as many high-risk node-negative patients while maintaining a comparable 10-year distant recurrence risk (16.7% vs 16.6% per NATALEE eligibility in TAILORx fitting; 21.0% vs 19.4% in TAILORx validation). PathClinRS identified 68% of intermediate risk premenopausal patients as low-risk with no evidence of chemotherapy benefit, compared to only 36% identified as low risk by standard clinicopathologic criteria. Conclusion:Digital histopathology provides prognostic information complementary to genomic assays and has the potential to personalize therapy beyond existing clinicogenomic tools.

Importance:Active surveillance has emerged as a deescalation strategy for low-risk ductal carcinoma in situ (DCIS) to reduce overtreatment while maintaining favorable outcomes. Emerging data in low-risk DCIS, eg, the COMET trial, have highlighted growing interest in surveillance-based management for carefully selected patients. However, recent clinical adoption and national trends in managing low-risk, hormone receptor (HR)-positive DCIS have not been evaluated in the US. Objective:To examine trends and sociodemographic variations in nonsurgical management and other treatment modalities for low-risk, HR-positive DCIS. Design, Setting, and Participants:This cross-sectional study analyzed data from the National Cancer Database from January 1, 2004, to December 31, 2022, and included patients aged 18 years or older with grade 1 to 2, HR-positive DCIS and at least 12 months of follow-up since initial diagnosis. Analyses were performed between January 10 and August 31, 2025. Exposures:Year of diagnosis and sociodemographic characteristics. Main Outcomes and Measures:Nonsurgical management, lumpectomy alone, lumpectomy plus adjuvant radiotherapy, unilateral mastectomy, bilateral mastectomy, and endocrine therapy were measured using descriptive statistics. Results:A total of 316 590 female patients were included (mean [SD] age, 60.8 [12.0] years; 5.8% Asian or Pacific Islander, 13.9% Black, 6.1% Hispanic, 73.3% White, and 0.9% other race and ethnicity). From 2004 to 2022, nonsurgical management increased from 2.1% to 3.5%, bilateral mastectomy increased from 4.1% to 8.7%, and lumpectomy increased from 22.0% to 25.1%, while lumpectomy plus adjuvant radiotherapy decreased from 50.9% to 45.6% and unilateral mastectomy decreased from 20.9% to 17.1%. Nonsurgical management was more common among Black patients and patients with no insurance. Bilateral mastectomy was common in younger, White, and privately insured patients and those who lived in higher-income areas. Endocrine therapy use increased from 2004 to 2020 but declined thereafter. Endocrine therapy was highest after lumpectomy plus adjuvant radiotherapy (69.6%), followed by lumpectomy alone (43.9%), unilateral mastectomy (35.3%), and nonsurgical management (29.2%), with the lowest use in patients younger than 50 years in the no surgery (15.2%) and lumpectomy alone (38.6%) groups. Since 2018, radiotherapy use has increased and become progressively more risk adapted, with increasing use with higher Oncotype DX DCIS scores (low risk, 34.5%; intermediate risk, 63.9%; high risk, 73.1%). Conclusions and Relevance:This cross-sectional study highlights increasing trends and socioeconomic disparities in the nonsurgical management of and the need for precision-based, patient-centered care for low-risk DCIS. Precision prevention may enhance the identification of patients who could benefit most from preventive surgery, prolonged endocrine therapy, or treatment deescalation, paving the way for individualized strategies.

523 Background: Chemotherapy and endocrine therapy have known neurobiological effects, yet evidence on their associations with long-term cognitive impairment remains limited. This study examined the relationship between prior chemotherapy, endocrine therapy, and cognitive impairment among long-term breast cancer survivors. Methods: Between July and September 2025, 1,338 participants from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort were surveyed and completed the Functional Assessment of Cancer Therapy-Cognition (FACT-Cog), a validated self-report instrument assessing 4 specific domains: perceived cognitive impairment (PCI; scores 0–72), cognitive-related quality of life (QoL; scores 0–16), perceived cognitive abilities (PCA; scores 0–27), and comments-from-others (scores 0–16). Lower scores reflect worse cognitive function. Cognitive impairment was defined as a PCI score <54. Multivariable logistic regression was used to evaluate associations between chemotherapy and endocrine therapy with cognitive impairment. Multiple linear regression was used to assess associations with continuous FACT-Cog domain scores. All models were adjusted for age, race/ethnicity, radiotherapy, surgery history, and educational attainment. Results: The mean age at survey of the 1,338 study participants was 64.3 years (SD 11.7), and the median time from diagnosis to survey was 9.4 years (IQR 6.1–14.1). Overall, 299 (22.3%) met criteria for cognitive impairment. Additionally, 594 (44.4%) and 851 (63.6%) of the participants had prior chemotherapy and endocrine therapy, respectively. In adjusted analyses, chemotherapy (adjusted odds ratio [aOR] 1.39; 95% CI 1.03 to 1.89; p =0.033) and endocrine therapy (aOR 1.86; 95% CI 1.35 to 2.57; p <0.001) were significantly associated with cognitive impairment. Chemotherapy was associated with lower PCI ( β −2.11; 95% CI −3.61 to −0.61; p =0.006), and lower QoL ( β −0.60; 95% CI −1.01 to −0.19; p =0.04). Endocrine therapy was associated with lower scores in PCI ( β −2.52; 95% CI −4.02 to −1.02; p =0.001), QoL ( β −0.55; 95% CI −0.96 to −0.14; p =0.009), PCA ( β −1.54; 95% CI −2.29 to −0.79; p <0.001), and comments-from-others ( β −0.28; 95% CI −0.49 to −0.07; p =0.008). In joint models, those who received both chemotherapy and endocrine therapy (aOR 2.46; 95% CI 1.46 to 4.18; p =0.001) and those who received endocrine therapy alone (aOR 1.71; 95% CI 1.04 to 2.81; p =0.035) had significantly higher odds of cognitive impairment than participants who received neither therapy. Conclusions: In this multiethnic cohort of long-term breast cancer survivors, prior chemotherapy and endocrine therapy were independently associated with worse perceived cognitive functioning across multiple domains. These findings underscore the need for future studies to identify neuroprotective strategies and interventions to mitigate treatment-related cognitive sequelae.

PURPOSE:BRCA carriers face high risks of developing both breast and ovarian/fallopian tube cancers (hereafter referred to as ovarian). Among BRCA carriers with ovarian cancer, it is not clear whether the risk of breast cancer is sufficiently high that risk-reducing mastectomy should be offered. This study aimed to assess the risk of breast cancer BRCA carriers after a diagnosis of ovarian cancer. METHODS:We included women with a pathogenic/likely pathogenic variant in BRCA1 or BRCA2, a diagnosis of ovarian cancer, and no other cancer history and no risk-reducing bilateral mastectomy. Women were followed for incident breast cancer from the date of ovarian cancer diagnosis or the date of baseline questionnaire, whichever came last. The 5-, 10-, and 15-year cumulative risks of breast cancer were compared for women with ovarian cancer and an age-matched set of control women without ovarian cancer. RESULTS:A total of 960 participants with ovarian cancer were identified (814 BRCA1 and 146 BRCA2 carriers). After a mean follow-up of 4.9 years, 41 women (4.3%) developed breast cancer, at a mean age at diagnosis of 57.5 years (range, 39-74). Actuarial cumulative breast cancer risks after ovarian cancer were 4.4%, 8.9%, and 11.5% at 5, 10, and 15 years, respectively. Only three breast cancer-related deaths occurred. Among 741 age-matched BRCA carriers without ovarian cancer, actuarial cumulative risks of breast cancer were 20.9%, 38.6%, and 47.2% at 5, 10, and 15 years, respectively. The hazard ratio for breast cancer, after an ovarian cancer diagnosis, compared with no ovarian cancer, was 0.18 ([95% CI, 0.12 to 0.27]; P < .0001). CONCLUSION:After ovarian cancer, BRCA carriers have a relatively low risk of breast cancer. Risk-reducing mastectomy should not be recommended routinely, but might be considered for long-term survivors. Magnetic resonance imaging surveillance and/or mammography is a realistic alternative.

Abstract Background: Triple negative breast cancer (TNBC) is among the most aggressive and lethal breast cancer subtypes, disproportionately affecting young women and women of African ancestry. Most patients do not respond to current immunotherapy and chemotherapy regimens. Resistance is driven not only by tumor genetics but also by environmental pressures within the tumor microenvironment, including hypoxia, chronic inflammation, and suppressive stromal signals, which collectively reshape tumor-immune interactions and foster immune evasion. These factors promote metastasis and therapy failure, yet the molecular mechanisms connecting hypoxia to immunosuppression remain unclear. Patients with hypoxic TNBC have limited treatment options, highlighting an urgent need for strategies that can reprogram the tumor microenvironment and restore immune function. Here, we identify BACH1 as a key non-HIF hypoxia-responsive regulator that links cellular stress adaptation with immune escape in TNBC. Methods: We leveraged an integrated multi-omics approach to investigate hypoxia-induced plasticity and immune evasion in TNBC. Single-cell RNA sequencing and spatial transcriptomics mapped hypoxia-driven transcriptional changes in murine TNBC models and human xenografts. ATAC-seq and motif analysis identified accessible chromatin regions and key regulatory networks. Functional roles of BACH1 were assessed using CRISPR-mediated knockout and overexpression under hypoxic conditions. In vivo experiments with immune-competent and immune-deficient models distinguished tumor-intrinsic from host-dependent effects. Immune profiling by single-cell RNAseq, proteomics, and flow cytometry characterized immune activation in tumors and draining lymph nodes. We tested therapeutic reprogramming by treating tumors with hemin, an FDA-approved drug that promoted BACH1 degradation. Finally, artificial intelligence classifiers based on BACH1 activity signatures were developed and validated in independent breast cancer cohorts from Yale, the University of Chicago, and I-SPY 2. Results: BACH1 was robustly stabilized and induced by hypoxia in multiple TNBC cell lines and patient-derived organoids, independent of canonical HIF signaling. Unlike HIF1A, which supports cell survival during acute hypoxia, BACH1 drives stem-like transition states, enabling rapid shifts into pre-metastatic states and providing an alternative adaptation to hypoxic stress. This mechanism significantly impacts immune regulation, with critical consequences for tumor-immune interactions and therapy resistance. Notably, these BACH1-high stem-like states negatively correlate with T-cell infiltration in patient tumors across breast cancer cohorts, predicting immune exclusion and therapy resistance. Consistent with this observation, loss of BACH1 in cancer cells promoted an immune-inflamed tumor phenotype characterized by enhanced T-cell recruitment and activation, an increased CD8⁺/Treg ratio, decreased early stage tumor growth and significantly reduced lung metastasis in a syngeneic model. Conversely, re-expression of BACH1 restored T-cell exclusion in knockout tumors. Flow cytometry profiling revealed that BACH1-deficient tumors triggered early and sustained T-cell activation, while limiting T-cell PD-1 expression in tumor-draining lymph nodes. Mechanistically, BACH1 acts in part by repressing the Type I interferon alpha locus, suppressing immunostimulatory macrophages and promoting T cell exhaustion in tumor-draining lymph nodes. Genetic BACH1 knockout combined with immune checkpoint blockade potentiated therapeutic efficacy. Short-course hemin treatment reproduced the effects of genetic BACH1 deletion, enhancing T-cell priming and synergizing with immunotherapy. In contrast, continuous hemin dosing was immunosuppressive, highlighting the importance of precise therapeutic timing. Together, genetic loss and optimized pharmacologic inhibition of BACH1 sensitized TNBC tumors to checkpoint blockade. To identify patients likely to benefit from BACH1-targeted therapy, AI models trained on xenograft-derived BACH1 signatures were developed. These models predicted immune exclusion and resistance more effectively than bulk BACH1 mRNA levels, which is confounded by expression in immune cells. Elevated BACH1 activity correlated with poor T-cell infiltration and immunotherapy resistance across breast cancer cohorts. Stratifying patients by BACH1 activity provided high associative value for checkpoint inhibitor response and identified individuals with hypoxic TNBC who may benefit from BACH1-targeted treatment. Significance: This study identifies BACH1 as a central regulator of hypoxia-driven transcriptional plasticity and immune evasion in TNBC. By coordinating hypoxia, chromatin remodeling, and interferon suppression, BACH1 promotes metastatic and immunotherapy-resistant tumor states. Inhibition of BACH1 restores interferon signaling, enhances immune cell infiltration, and increases sensitivity to checkpoint blockade, suggesting BACH1 as a promising therapeutic target. We also present an AI-based biomarker strategy that stratifies patients by BACH1 activity, supporting clinical translation. Overall, these findings establish non-HIF hypoxia sensors as key drivers of tumor adaptation and position BACH1 as an actionable target to reprogram the tumor microenvironment and improve immunotherapy outcomes in aggressive cancers. Citation Format: Long Chi Nguyen, Madeline Henn Bungert, Emily Shi, Christopher Dann, Buu Truong, Kent Schechter, Dongbo Yang, Thomas Jiyoung Li, Eva Suarez, Wenchao Liu, Geetha P. Yerradoddi, Margarite D. Matossian, Joana Pinheiro, Jinjun Gao, Yoo Jane Han, Anran Li, Andrea Ziblat, Jing Zhang, Mitsuyo Matsumoto, Yan Li, Yingming Zhao, Scott Andre Oakes, Jingshu Wang, Thomas F. Gajewski, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Frederick Matthew Howard, Jonathan A. Trujillo, Marsha Rich Rosner. BACH1 drives hypoxia-induced stem-like transition states and immune evasion in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr NG01.

12084 Background: Breast cancer treatment, in some cases, can cause hearing/vestibular dysfunction and negatively affect patients’ quality of life. The breast cancer survivor population is both growing and aging. Despite evidence that other cancer survivors have higher rates of hearing/vestibular problems than the general population, little is unknown about the impact of hearing/vestibular dysfunction on long-term changes in psychosocial well-being (PSWB) among breast cancer survivors. Methods: We surveyed the Chicago Multiethnic Epidemiologic Breast Cancer Cohort regarding whether patients had ever been told by a doctor that they had tinnitus, hearing loss, and/or vertigo between July and September 2023. PSWB was assessed repeatedly using the 10-item PROMIS on psychological distress/social isolation in 2020, 2021, 2022, and 2025. Total scores range from 0 to 40, with higher scores reflecting better PSWB. We fit separate linear mixed-effects models for hearing/vestibular dysfunction, controlling for age, race/ethnicity, marital status, income, insurance, comorbidity, AJCC stage, and treatment modality. Adjusted coefficients ( β ) and 95% CIs were calculated. Results: 1,466 breast cancer survivors were included: the mean age at survey was 63.5 years (SD 11.7); 69.6% identified as White, 22.6% as Black, 3.7% as Asian or Pacific Islander, and 3.6% as Hispanic. Overall, 16.5%, 17.4%, and 8.6% had tinnitus, hearing loss, and vertigo, respectively. The distribution of PSWB scores and trend over time are presented in the table. Survivors with hearing/vestibular dysfunction had lower mean scores than those without. After covariate adjustment, tinnitus ( β –1.12; 95% CI –1.93, –0.30), hearing loss ( β –1.12; 95% CI –1.93, –0.30), and vertigo ( β –1.34; 95% CI –2.44, –0.24) were associated with significantly lower PSWB scores. In all subgroups, the PSWB score increased significantly over the years. Furthermore, Hispanic ethnicity, Medicaid, and being single were correlated with lower scores; whereas higher income levels were associated with higher scores. Conclusions: In this diverse cohort, breast cancer survivors with hearing/vestibular dysfunction experienced suboptimal PSWB over the study period. PSWB also varied by socioeconomic status. Oncology programs should consider screening for hearing/vestibular dysfunction and unmet sensory healthcare needs to improve PSWB and quality of life among breast cancer survivors. PSWB score, mean (SD) Tinnitus Hearing loss Vertigo Survey year No Yes No Yes No Yes 2020 28.7 (6.0) 28.4 (6.0) 28.8 (6.0) 28.2 (5.9) 28.7 (6.0) 28.3 (6.1) 2021 29.4 (5.6) 28.9 (5.9) 29.4 (5.6) 29.0 (5.5) 29.5 (5.6) 27.8 (6.0) 2022 30.1 (5.6) 29.2 (6.1) 30.0 (5.7) 29.7 (6.0) 30.1 (5.6) 28.5 (6.5) 2025 33.3 (5.6) 32.1 (6.4) 33.3 (5.6) 32.4 (6.2) 33.2 (5.6) 31.8 (6.3) Trend per year ( p -value) 0.89 (<0.001) 0.75 (<0.001) 0.87 (<0.001) 0.86 (<0.001) 0.89 (<0.001) 0.66 (<0.001)

QuestionWhat proportion of women with pathogenic variants (PVs) in breast cancer genes would receive high-risk screening using models based on clinical risk alone or clinical plus polygenic risk?FindingsIn this cohort study including 712 women with a PV, most would have received less intensive screening based on their clinical and polygenic risk. For instance, less than 1% with a high-penetrance PV would have been recommended magnetic resonance imaging alternating with mammography every 6 months based on their clinical and polygenic risk.MeaningIn this study, most participants with PVs in breast cancer genes would not have been recommended for high-risk screening based on their clinical risk alone or clinical plus polygenic risk. This cohort study evaluates how many pathogenic variant carriers in a risk-based breast cancer screening trial would have been recommended for high-risk screening based on clinical risk or clinical plus polygenic risk. ImportanceRisk-based breast cancer screening has emerged as a viable alternative to annual mammography. To guide implementation, knowledge is needed on the contribution of testing for pathogenic variants (PVs) beyond clinical risk factors and common genetic variants for population-based risk stratification.ObjectiveTo evaluate how many PV carriers in a risk-based breast cancer screening trial would have been recommended for high-risk screening based on clinical risk or clinical plus polygenic risk.Design, Setting, and ParticipantsThis cohort study used retrospective data from the WISDOM Study, a national clinical trial of risk-based vs annual breast cancer screening, to compare screening assignments informed by PV status vs those based on a clinical risk model alone or a clinical risk model combined with a polygenic risk score. WISDOM participants aged 40 to 74 years who tested positive for a PV as part of risk-based screening were included. Data were collected from September 2016 to February 2023, with follow-up to September 2025. Data were analyzed from January to May 2026.Main Outcomes and MeasuresConcordance between actual (considering participants' PV status) and hypothetical screening assignments based on a clinical (Breast Cancer Surveillance Consortium) risk model or a clinical model plus polygenic risk score.ResultsOf 712 included women with a PV, the median (IQR) age was 53 (46-62) years. A total of 232 PVs (33%) were high penetrance, 278 (39%) were moderate penetrance, and 202 (28%) were CHEK2 low penetrance. There was little overlap between actual screening assignments based on PV status and hypothetical assignments based on a clinical model plus polygenic risk score. Among high-penetrance PV carriers (a group recommended high-risk screening with magnetic resonance imaging alternating with mammography every 6 months), 2 of 232 (0.9%) would have received the same screening assignment based on clinical plus polygenic risk. Overall, 178 of 279 PV carriers aged 40 to 49 years (63.8%) would have otherwise been recommended to defer screening until age 50 years based on clinical plus polygenic risk, whereas 385 of 433 carriers aged 50 to 74 years (88.9%) would have been recommended biennial mammography. Results were similar when comparing assignments based on a clinical model alone.Conclusions and RelevanceIn this cohort study, most participants with PVs in breast cancer genes would not have been recommended for high-risk screening based on their clinical or clinical plus polygenic risk. PV testing therefore may identify different subsets of high-risk women than clinical risk factors and polygenic risk scores. These findings highlight the importance of population-based PV testing in risk-based screening.Trial RegistrationClinicalTrials.gov Identifier: NCT02620852