Citations

Abstract Background: Women younger than 40 generally fall outside the routine screening population for breast cancer (BC). We aimed to understand factors influencing diagnosis and treatment delays in these patients, and the impact of delays on disease-free survival (DFS). Methods: We included women aged ≤ 40 years at diagnosis of stage 0-IV BC enrolled in the Young Women’s BC Study from 2006-2016. Sociodemographics, initial BC symptoms, and disease status were collected via annual surveys. Medical record review was used to capture tumor characteristics and recurrence status. We used logistic regression to estimate associations between patient and tumor factors and three delay types: (1) self-delay (≥ 90 days from first symptom to presentation to a provider), (2) diagnosis delay (≥ 90 days from healthcare visit to diagnosis), and (3) treatment delay (≥ 60 days from diagnosis to first treatment). Odds ratios (OR) and 95 % confidence intervals (CI) were estimated in multivariable models after choosing factors via backwards selection (p≤0.05 retained). Hazard ratios (HR) and 95% CIs for the association between delays and DFS, overall and by stage, were estimated via Cox proportional hazard models, adjusted for tumor and treatment factors. Time to event was measured from diagnosis or treatment to recurrence, death, or last follow-up, whichever occurred first. Results: Of 1,297 patients, 1,071 who completed the long-form baseline survey were included. Median time from first symptom to presentation was 14 days (interquartile range (IQR)=2-45), presentation to diagnosis was 14 days (IQR=7-30), and diagnosis to treatment was 41 days (IQR=25-57). Overall, 14% (n=153) had a self-delay and 11% (n=120) had a diagnosis delay. Of 839 patients with self-detected tumors, 18% had a self-delay and 13% had a diagnosis delay. Among those with Stage 1-3 BC (N=928), 22% (n=205) had a treatment delay. In univariable models, income <50K (p=0.01), lower financial comfort (p=0.01), and not living with a partner (p=0.03) were associated with higher odds of self-delay, while pregnancy within 1 year pre-diagnosis (p=0.05) and first-degree family history of any cancer (p=0.04) or BC (p=0.03) were associated with lower odds. Self-delays were more likely for women diagnosed with stage 4 BC (p=0.004) or with HER2+ tumors (p=0.03) and less likely for those with triple negative (TN) BC (p<0.001). In the multivariable model, family history of BC (OR=0.40, 95% CI=0.17-0.80), income <50K (OR=1.97, 95% CI=1.22-3.13) and TN subtype (OR v. luminal A=0.30, 95% CI=0.13-0.60) remained associated. Odds of diagnosis delay were higher among women who were younger (p=0.01) or with Stage 4 BC (p=0.004), and lower for those with luminal B (p=0.04), TN (p=0.01), or high grade tumors (p=0.03). In the multivariable model, younger age (OR per 1-year=0.94, 95% CI=0.89-0.99), and subtype (luminal B v. A OR=0.60, 95% CI=0.38-0.95; TN v. luminal A OR=0.35, 95% CI=0.16-0.70) remained associated. Multivariable models for self-and diagnosis delays remained similar when restricted to self-detected patients.Treatment delays were less likely among unemployed individuals (p=0.001), and women with a positive germline BC risk variant (p=0.002), luminal B (p=0.005) or TN (p<0.001) subtypes, and high-grade tumors (p=0.03). Only tumor factors remained significant in the multivariable model, including subtype (luminal B v. A OR=0.59, 95% CI=0.41-0.86, TN v. luminal A OR=0.25, 95% CI=0.13-0.43), and stage (stage 3 v. 1 OR=0.37, 95% CI=0.20-0.65). Overall and by stage at diagnosis, delays were not statistically significantly associated with DFS before or after adjusting for tumor and treatment factors. Conclusions: Delays in breast cancer care are influenced by multiple psychosocial and clinical factors, and disparities exist by socioeconomic status. It is critical to decrease self- and diagnosis delays to prevent stage 4 breast cancer. Citation Format: B. X. Zhang, T. Sella, Y. Zheng, G. J. Kirkner, K. J. Ruddy, S. M. Rosenberg, V. F. Borges, L. Schapira, S. E. Come, J. Peppercorn, A. H. Partridge, K. D. Brantley. Delays in breast cancer diagnosis and treatment in young women [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 PS3-02-16.

Importance Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown. Objective To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance. Design, Setting, and Participants Phase 3, open-label, randomized clinical trial conducted at 4 United States–based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025). Intervention Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance. Main Outcomes and Measures Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory–Brain Tumor instrument (scale, 0-10; score change range, −10 to 10; −10 = best). A clinically meaningful Δ was defined as 0.98. Results Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory–Brain Tumor score from 2.69 to 2.37 (mean change, −0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, −1.06 [95% CI, −1.54 to −0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively). Conclusions and Relevance In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life. Trial Registration ClinicalTrials.gov Identifier: NCT03075072

Abstract Background Young age is a known risk factor for breast cancer recurrence and mortality, particularly in hormone receptor-positive disease. However, no specific evidence exists on whether age at diagnosis influences clinical behavior and outcomes among carriers of germline BRCA pathogenic or likely pathogenic variants (PVs). Methods The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study including women with germline BRCA1 and/or BRCA2 PVs and diagnosed with stage I-III breast cancer at the age of 40 years or younger between January 2000 and December 2020. The present analysis aimed to evaluate clinical features and outcomes of breast cancer in young BRCA carriers according to age at diagnosis, by comparing patients aged ≤30 years with those aged 31-35 and 36-40 years at breast cancer diagnosis. The primary endpoint was disease-free survival (DFS). Overall survival (OS) was a secondary endpoint. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs), adjusting for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) (time-dependent), and stratifying by country, year of diagnosis, tumor size, nodal involvement, tumor grade and hormone receptor status. Results From 109 centers in 5 continents, 5350 young BRCA carriers were included, of whom 1106 (20.7%) were ≤30 years of age, 1945 (36.4%) were 31-35 years and 2299 (43.0%) were 36-40 years at the time of breast cancer diagnosis. Compared to patients aged 31-35 and 36-40 years, those aged ≤30 years were more likely to harbor BRCA1 PVs (71.3%, 62.4%, 61.1%, respectively), to present with high-grade (G3 in 71.3%, 66.6%, 65.0%, respectively), triple-negative breast cancer (56.3%, 48.1%, 46.6%, respectively), and less frequently smaller tumor size (T1: 31.7%, 36.6% and 39.5%, respectively). Consequently, chemotherapy was administered more frequently among patients aged ≤30 years (94.4%, 92.6%, 89.7%, respectively). At a median follow-up of 8.2 years (IQR, 4.7-12.8), 8-year DFS rate was 65.0% among patients aged ≤30 years, 64.7% in the 31-35 years group, and 65.8% in the 36-40 years group. No significant association between age at diagnosis and DFS outcome was observed (31-35 vs. ≤30 years: aHR 1.03, 95% CI 0.89-1.19; 36-40 vs. ≤30 years aHR 1.00, 95% CI 0.87-1.16). Similarly, no significant association between age at diagnosis and OS was observed (31-35 vs. ≤30 years: aHR 1.10, 95% CI 0.86-1.41; 36-40 vs. ≤30 years: aHR 1.11, 95% CI 0.87-1.43). Subgroup analyses by specific BRCA gene, tumor subtype, tumor size, nodal status, and chemotherapy use revealed no statistically significant interaction with age at diagnosis in terms of DFS or OS (all p for interaction > 0.05). Specifically, no significant differences between age groups were observed among patients with luminal-like tumors for both DFS and OS. Conclusions In this unique international cohort of BRCA carriers diagnosed with breast cancer at a young age (≤40 years), we found no significant differences in DFS nor OS across different age groups. Notably, very young age (≤30 years) at diagnosis was not associated with worse outcomes compared to 31-35 years or 36-40 years. Age per se should not be considered a negative prognostic factor in BRCA carriers when appropriate treatment is provided. Citation Format: E. Blondeaux, A. Meacci, M. Fragío Gil, E. Klocker, F. Coussy, H. Kim, R. Bernstein Molho, F. Hilbers, A. Di Meglio, A. Kwong, K. Pogoda, J. Bajpai, H. Wildiers, E. Agostinetto, J. Balmana, H. C. Moore, K. Phillips, A. H. Partridge, C. Rousset-Jablonski, F. A. Peccatori, A. Toss, T. Renaud, C. Anghelone, A. Benitez Cruz, S. Paluch-Shimon, J. Lee, R. Fruscio, W. Cui, S. M. Wong, M. Lee, M. Rozenblit, C. Vernieri, C. Villarreal-Garza, A. Matikas, M. Dieci, L. De Marchis, J. K. Plichta, K. J. Ruddy, D. Can Guven, F. Puglisi, Z. Kemp, P. A. Meireles, L. Del Mastro, V. Delucchi, M. Lambertini. Association between age at diagnosis and survival among young BRCA carriers with breast cancer: results from an international multicenter hospital-based cohort study [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 PD4-07.

Abstract Background: BRCA2 variants with partially aberrant RNA splicing have been associated with a relatively lower breast cancer risk (reduced penetrance) relative to canonical pathogenic variants. However, the existence of partial loss of function (hypomorphic) missense variants, conferring reduced penetrance, is less certain. Identification and assessment of the clinical relevance of such reduced penetrance pathogenic variants (RPPVs) is needed to provide accurate risk estimates. Methods: Comprehensive functional characterization of hypomorphic missense variants (n=70) in the BRCA2 DNA-binding domain, initially identified through homology-directed DNA repair (HDR) assays, was conducted through multiple independent functional assays, including HDR, CRISPR/Cas9-based endogenous targeting, RAD51 foci formation assay, and Poly(ADP-ribose) polymerase (PARP) inhibitor response assay. Risk estimates were obtained using two large datasets from patients referred for hereditary cancer testing. A ClinGen/ACMG/AMP model was used for clinical classification. Results: The variants consistently demonstrated hypomorphic HDR activity and endogenous survival in HAP1 targeted cells, decreased RAD51 foci formation, and increased sensitivity to PARP inhibitors. These variants were associated with a moderate increase in breast cancer risk, as shown in two independent studies: one using multivariable logistic analysis adjusted for age, ancestry and family history (OR=2.41, 95%CI=1.51-3.85) and another comparing frequencies of variants in breast cancer cases to public reference controls adjusted for ancestry (OR=2.09, 95% CI=1.16-4.08). The mean age of breast cancer diagnosis for carriers of hypomorphic variants was 57 years, which was significantly older than the mean age of diagnosis of 51 years for carriers of protein truncating variants. Functional data were combined with other evidence sources in a ClinGen/ACMG/AMP model to classify 14 variants as “likely pathogenic”. Conclusions: We identified partially functional, hypomorphic missense variants associated with reduced penetrance for breast cancer. Cancer risk management guidelines for this new category of variants should be revisited given that the associated breast cancer risks warrant high risk screening but do not meet the threshold at which risk reducing mastectomy is offered. This study supports a shift in paradigm to considering variant-based risks on a continuum, with implications for risk-appropriate cancer risk management. Citation Format: H. Huang, C. Hu, J. Na, M. Kucera, T. Simmons, E. Mundt, C. C. Young, Z. Heidari, P. C. Lyra, Y. Y. Tan, K. L. Nathanson, T. Pal, R. Karam, T. Pesaran, S. Yadav, S. M. Domchek, A. N. Monteiro, E. Hughes, N. Boddicker, W. Chen, M. E. Richardson, F. J. Couch. Partially functional (hypomorphic) missense variants in BRCA2 are reduced penetrance pathogenic variants [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 PD4-05.

Abstract Background: Young BRCA carriers may undergo breast conserving surgery (BCS) or mastectomy with or without contralateral risk reducing mastectomy at the time of an index breast cancer diagnosis. A variety of factors may influence surgical decision making. Methods: The BRCA BCY Collaboration (NCT03673306) is an international, hospital-based, retrospective cohort study conducted at 109 centres across 5 continents including women with germline pathogenic or likely pathogenic variants (PV) in BRCA1/2 diagnosed between 2000 and 2020 with invasive stage I-III breast cancer prior to or at age 40 years. The primary objective of the present analysis was to evaluate surgical management in these patients. Breast surgery was defined as BCS, unilateral mastectomy, or bilateral mastectomy administered as part of primary treatment for a first diagnosis of invasive breast cancer. Multivariable logistic regression was used to determine factors associated with receipt of bilateral mastectomy. Results: Of 5660 eligible BRCA1/2 carriers, 4715 had unilateral stage I-III breast cancer with surgical treatment details available. The median age of the cohort was 35 years (IQR, 31-38 years). Overall, 1805 (38.3%) patients underwent BCS, 1752 (37.2%) underwent unilateral mastectomy, and 1158 (24.6%) underwent bilateral mastectomy. The proportion of young BRCA1/2 carriers undergoing BCS decreased over the study period (55.7% in 2000 vs. 27.0% in 2020), whereas the use of bilateral mastectomy significantly increased (8.0% in 2000 vs. 44.4% in 2020). Bilateral mastectomy was more common in women who had genetic testing performed before (57.0%) or within 6 months of a breast cancer diagnosis (38.5%), compared to those tested after diagnosis (5.1%, p<0.001). On multivariable analysis, compared to those tested after diagnosis, earlier genetic testing remained the strongest predictor of bilateral mastectomy receipt (testing prior to diagnosis: OR 20.7 [95% CI 15.3-28.1]; testing at diagnosis: OR 6.8 [95% CI 5.4-8.7]). Other predictors of bilateral mastectomy receipt included geographic region, later year of diagnosis, smaller tumor size, node negative disease, and neoadjuvant treatment. In subgroup analysis including 2327 patients who had genetic testing performed before or within 6 months of diagnosis, 42.0% underwent bilateral mastectomy, with the lowest rates reported in Asia/Africa (26.1%) and the highest rates reported in North America (66.4%, p<0.001). In adjusted subgroup analyses, BRCA1 PV, later year of diagnosis, smaller tumor size, node negative disease, neoadjuvant treatment, and geographic region remained independently associated with bilateral mastectomy. Conclusions: In this large, international study of young affected BRCA carriers, geographic region and timing of genetic testing strongly impacted surgical management. These data support early genetic testing for young women with breast cancer to help optimize local therapy decisions. Citation Format: S. M. Wong, E. Blondeaux, V. Delucchi, F. Coussy, R. Bernstein Molho, S. Linn, A. Di Meglio, A. Kwong, K. Pogoda, E. Agostinetto, I. Nevelsteen, J. Balmana, H. C. Moore, A. Toss, A. Ferrari, C. Rousset-Jablonski, T. Renaud, K. Phillips, F. A. PeccatorI, M. Agustina Ipina, S. Paluch-Shimon, J. Ryu, W. Kui, M. Lee, R. Fruscio, M. Rozenblit, C. Vernieri, A. Matikas, M. Dieci, F. J. Couch, L. De Marchis, S. E. Hwang, D. Aguilar-y Mendez, D. Can Guven, M. Swain, C. Gianni, S. Spinaci, G. Montagna, M. Lambertini, H. Kim. Surgical management of young BRCA1/2 carriers with early onset breast cancer [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 PD12-01.

Abstract Aim This study aimed to identify what young adults with type 1 diabetes (T1D) do to make diabetes care fit in their lives and the impact of diabetes and diabetes care on living. Methods Dutch young adults with T1D (18–30 years old) submitted photographed real‐life situations of efforts to make care fit and of the impact of care on their lives. Participants organised their photos in themes, which guided the focus group discussions. We added a reflective questionnaire, semi‐structured interview and iterative validation to identify participant‐defined themes and summarise the data. Results Participants ( N = 18) submitted 240 photographs in total, showing a broad range of situations and emotions. Participants identified 16 themes, grouped into four overarching categories describing their experiences with diabetes: (1) My diabetes: glucose levels, workload, 24/7 present; (2) My life: flow of (daily) life, special and irregular circumstances, life changes, body and health; (3) Support: devices and technology, social network, clinical (diabetes) care; (4) Mental aspects: emotional processes, perspective, being a patient. In the overlap of My diabetes and My life, they identified eating and counting carbohydrates, activity and exercise, recreational substances. Conclusion Young adults with T1D face the complex challenge of fitting their care into their ever‐changing lives. While support systems, such as devices, healthcare professionals and social networks can help, they can also create burdens. Participants emphasised the importance of mental health in their lives with T1D. This study highlights the need for diabetes care that acknowledges the emotional, social and practical realities of young adults' lives.

Abstract Background: Exercise capacity (VO 2peak ) predicts mortality in adult patients with CHD. There is a lack of paediatric exercise capacity data based on specific CHD lesions, limiting the ability to contextualise interpretation based on expected performance during testing. The primary aim of this study was to establish VO 2peak percentiles for paediatric patients with repaired CHD undergoing treadmill-based cardiopulmonary exercise testing (CPET). Methods: Retrospective analysis of CPET data from 2004 to 2022. CPETs were analysed for patients with CHD aged 6–18 years. Patients with repaired CHD were categorised based on their most haemodynamically significant CHD lesion. Percentiles and age-based trends were plotted for each group. Results: A total of 887 patients were included. CHD patients were divided into ten diagnostic subgroups. The mean percent expected VO 2peak for each of the subgroups were as follows: Atrial and ventricular septal defect (94.5 ± 25.1%), pulmonary valve repair (88.1 ± 18.4%), aortic valve repair (92.7 ± 16.4%), tricuspid and mitral valve repair (81.3 ± 20.4%), coarctation of the aorta (93.6 ± 18.8%), transposition of the great arteries (90.5 ± 19.4%), double outlet right ventricle and truncus arteriosus (80.5 ± 16.2%), tetralogy of Fallot (85.6 ± 20.9%), left ventricle dominant Fontan (74.7 ± 18.3%), and right ventricle dominant Fontan (75.7 ± 16.7%). Conclusion: There is a varying degree of reduced exercise capacity in paediatric patients with repaired CHD. Univentricular hearts and tricuspid and mitral valve repair have the lowest VO 2peak . These CHD-specific percentiles may help providers risk-stratify and counsel patients with CHD.

Abstract Objective Dravet syndrome (DS) is the prototypic developmental and epileptic encephalopathy, characterized by drug‐resistant seizures, developmental slowing, and many other morbidities. Detailed characterization of behavioral phenotypes and social–emotional skill development are limited. Methods We prospectively assessed behavioral and social–emotional problems in the ENVISION natural history study (NCT04537832) of children with DS associated with SCN1A pathogenic variants ( SCN1A + DS) enrolled at <5 years of age. Assessments every 3 months for up to 2 years included the Child Behavior Checklist (CBCL), Strengths and Difficulties Questionnaire (SDQ), Brief Infant‐Toddler Social and Emotional Assessment (BITSEA), and Vineland Adaptive Behavior Scales, 3rd Edition (VABS‐3). Results Fifty‐eight children with DS enrolled at 16 sites worldwide. Problematic behaviors—inattention, aggressive or oppositional behaviors, and withdrawn and autistic behaviors—began before age 3 years, became more evident with age, and were clinically significant in many children by age 3–4 years. CBCL Total, Externalizing, and Internalizing Problems T‐scores rose by approximately 3 points per year, and BITSEA Problem scale scores increased by 2.3 points annually ( p = .002). SDQ Hyperactivity scores worsened over time ( p = .013), whereas emotional difficulties remained stable. VABS‐3 Socialization domain scores, which were already more than 1 SD below the normative mean at baseline, decreased further, particularly in younger participants. Correlation analyses showed that poorer communication abilities were associated with increased problematic behaviors ( R = −.55 for CBCL Total Problems and VABS‐3 Communication scores). Mixed‐effects modeling identified age as the strongest predictor of worsening behavioral outcomes. Significance We found that behavioral and social–emotional problems are inherent components of DS that present in toddlerhood and worsen throughout early childhood. This highlights the need to diagnose and manage these issues early. Targeted therapy may alleviate the wide‐ranging morbidities that are intrinsic to DS, including the social–emotional and behavior problems that frequently emerge.

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.