Citations

Abstract Background: Women with a pathogenic variant in the BRCA1 or BRCA2 gene (carriers) are at a high risk of developing ovarian cancer and recommended to undergo bilateral salpingo-oophorectomy at an early age resulting in surgical menopause. Menopausal hormone therapy (MHT) is the most effective way to mitigate the adverse outcomes of early menopause; however, the safety of MHT on breast cancer risk in this population has not been established. Methods: We conducted a prospective matched analysis of MHT use following menopause (predominantly surgical) and breast cancer risk in BRCA carriers using a matched prospective analysis to emulate a randomized clinical trial. Women without a history of any cancer or bilateral mastectomy and who were enrolled in a longitudinal study with detailed data collection were eligible for inclusion. Women who initiated MHT (exposed) after menopause were matched one-to-one to women who had not initiated MHT (unexposed) by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Cox proportional hazards regression to estimate the hazard ratios (HR) and 95%CIs (CI) of incident breast cancer associated with MHT use. Results: After a mean follow-up of 5.6 years from the date of first MHT use in the exposed woman, there were 87 incident breast cancer cases in the exposed group (12·9%) and 128 cases in the unexposed group (18·9%) (P = 0·002). Compared to their unexposed match, women who used estrogen (E) experienced a significant decrease in the risk of breast cancer (HR = 0·37; 95%: CI 0·24-0·57). There was no protective (or adverse) effect associated with the use of E plus progestogen (E+P) (HR = 0·94; 95%CI 0·54-1·63), with progestogen alone (P) (HR = 1·14; 95%CI: 0·21-6·22) or with tibolone (HR = 0·57; 95%CI: 0·19-1·69). There were no diagnoses of breast cancer in the 43 women who used a CEE + bazedoxifene. Findings were similar for carriers of either gene mutation. Conclusion: To our knowledge, this represents the largest prospective report of MHT use and breast cancer risk in BRCA1 and BRCA2 carriers. Our findings showed no increase in the risk of breast cancer with the use of MHT, irrespective of gene mutation or formulation. These findings provide an evidence-based approach for the management of women at high-risk of breast cancer who are facing the acute and chronic effects of early surgical menopause. The safe use of MHT by BRCA carriers will continue to be an important research topic as formulations continue to evolve. Citation Format: J. Kotsopoulos, M. Seca, G. Jacek, T. Huzarski, P. Møller, R. H. Kim, C. Singer, B. Karlan, A. Aeilts, T. Ramon y Cajal, T. Pal, A. Eisen, L. Bordeleau, W. Foulkes, N. Tung, F. Couch, S. Neuhausen, D. Zakalik, C. Cybulski, O. Olopade, K. Metcalfe, R. Fruscio, P. Sun, J. Lubinski, S. Narod, Hereditary Breast Cancer Clinical Study Group. Menopausal Hormone Therapy and the Risk of Breast Cancer in Women with a Pathogenic Variant in BRCA1 or BRCA2 [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 GS3-01.

Abstract Background: The association of TILs with pathologic complete response (pCR) and survival in HER2+ breast cancer is not well established with several prior studies showing inconsistent results. In this secondary analysis of EA1181, we evaluated the association between stromal TILs (sTILs) and pCR rates. Methods: EA1181 (NCT04266249) enrolled patients (pts) with anatomic clinical stage II/III HER2+ breast cancer who preoperatively received 4 cycles of trastuzumab and pertuzumab with 12 weeks of paclitaxel or docetaxel q3w x 4 (THP), followed by surgery. sTILs density was assessed on full-face hematoxylin and eosin (H&E)-stained tumor biopsy sections. sTILs scores were analyzed per protocol as a continuous variable (every 10% increment) and as a categorical variable (<10% vs 10-60% vs >60% as per Denkert et al, 2018), and also with an exploratory 30% cutoff commonly used in TNBC. Cox proportional hazards models were used to examine the association between sTILs and pCR, adjusting for available baseline factors. The associations between sTILs (by category) and clinicopathologic characteristics were examined using Fishers’ exact test. Results: Among 2141 pts with HER2+ BC treated on EA1181, H&E slides were available for 1328 (62%). The study population evaluated for sTILs was comparable to the overall population. pCR rates were 44.5% overall, 64% for HER2+/ER- and 33% for HER2+/ER+ disease. sTILs distribution was: 623 (47%) <10%, 698 (52%) 10-60%, and 7 (0.5%) >60%, which led us to merge the latter two groups (705 [53%] had ≥10% sTILs). In univariable and multivariable analyses, increasing sTILs (as a continuous variable) were associated with increasing pCR rates in both HER2+/ER+ and HER2+/ER- disease (p<0.001; Table). sTILs analyzed as a categorical variable (<10% vs ≥10%) were significantly associated with pCR for all patients (combined) and for those with HER2+/ER+ disease. In exploratory analysis using a cutoff of <30% vs ≥30% sTILs, an association with pCR was also seen in univariable analysis for both HER2+/ER+ disease (p<0.001) and HER2+/ER- disease (p=0.045), though in multivariable analysis with clinical factors, sTILs >30% remained a significant predictor for pCR only in HER2+/ER+ disease. Additional exploratory analysis with other molecular biomarkers, intrinsic subtypes, and immune signatures will be presented. Conclusion: sTILs were associated with pCR after THP, further supporting the important role of immune mechanisms in HER2+ breast cancer, and highlighting a potentially robust predictive tool to assess pathologic response. Baseline sTILs could potentially inform the preoperative design of future trials of therapy optimalization. Association of baseline sTILs with recurrence free survival in EA1181 will be reported in the future. Citation Format: S. S. Badve, F. Zhao, N. Tung, Y. Gokmen-Polar, C. C. O'Sullivan, A. Prat, E. P. Winer, J. L. Wright, A. Recht, A. C. Weiss, J. A. Tjoe, S. M. Feldman, G. B. Rocque, M. Smith, N. Unni, S. Sardesai, S. Tang, S. Modi, W. J. Irvin, P. Villagrassa, C. Battelli, A. K. Krie, N. Bagegni, M. A. George, M. L. Telli, V. F. Borges, N. D’Abreo, P. Shah, K. D. Miller, A. H. Partridge, L. A. Carey, A. M. DeMichele, A. C. Wolff, ECOG-ACRIN.Tumor infiltrating lymphocytes (TILs) and pathologic complete response (pCR) in stage II/III HER2+ breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): secondary results from the ECOG-ACRIN EA1181/CompassHER2 pCR trial [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 GS1-04.

Abstract Background Intravesical Mycobacterium bovis bacillus Calmette-Guérin (BCG) is standard therapy for high-risk nonmuscle-invasive bladder cancer. However, M bovis infections can occur and are not well understood. We aimed to characterize clinical phenotypes, diagnosis, management, and outcomes of culture-confirmed M bovis BCG infections following intravesical therapy for urothelial carcinoma. Methods A retrospective single-center review of adults with culture-confirmed M bovis infection after intravesical BCG (May 2009–July 2024) was conducted, abstracting clinical, microbiologic, treatment, and outcome data. Results Twenty-two White male patients (median age, 77 years) were included; 8 (36.4%) had localized genitourinary infection, 6 (27.3%) had dissemination limited to blood, and 8 (36.4%) had dissemination to other organs. Patients with bloodstream-only infection presented acutely (median 1.5 days after last BCG), whereas those with localized or organ-disseminated disease presented months to years after BCG, with the longest diagnostic delays in organ-disseminated infection. Despite all cases had culture-proven M bovis BCG infection, acid-fast smear, Mycobacterium tuberculosis complex polymerase chain reaction, and histopathology had limited sensitivity. All isolates were susceptible to rifampin, isoniazid, and ethambutol; all were resistant to pyrazinamide. Median treatment duration exceeded 9 months, 94.7% achieved cure, and attributable mortality was 5.0% (1 vascular graft infection). Conclusions M bovis BCG infections following intravesical therapy have favorable outcomes but are often associated with diagnostic delays and prolonged treatment. Early suspicion, comprehensive diagnostic evaluation, and timely surgical source control when indicated are critical. Management strategies should be tailored based on the extent of disease dissemination and individual host factors.

Background: Aggressive non-Hodgkin lymphoma (aNHL) commonly occurs in older adults. However, geriatric assessments (GAs), which are associated with both survival and treatment-related toxicity, are infrequently performed due to logistical constraints. In this study, we examined how the brief, self-reported Vulnerable Elders Survey-13 (VES-13) screening tool and a comprehensive GA relate to clinical outcomes in this population. Methods: We conducted a longitudinal study of 105 adults aged ≥65 years who were initiating upfront chemoimmunotherapy for aNHL at 2 academic medical centers and their community affiliates between September 2020 and January 2023. Baseline frailty was evaluated using the Fondazione Italiana Linfomi (FIL) GA, which classifies patients as fit, unfit, or frail. The VES-13 was assessed both continuously and by categorizing patients as vulnerable (score ≥3). Using logistic regression controlling for covariates, we examined the association of VES-13 with grade ≥3 nonhematologic toxicity (toxicity), unplanned hospitalization within 6 months of treatment initiation, decline in quality of life (QoL) 1 year after therapy initiation, and death within 1 year of treatment initiation. In addition, we calculated the sensitivity and specificity of both the VES-13 and the FIL GA in identifying patients at risk for these outcomes. Results: The median patient age was 73 years (range, 64–99 years), with 42% aged ≥75 years. GA classified 40% of patients as fit, 10% as unfit, and 51% as frail, while 46% of patients had a VES-13 score ≥3, indicating vulnerability. VES-13 score was significantly associated with toxicity (odds ratio [OR], 1.18; P =.026), unplanned hospitalization (OR, 1.16; P =.043), QoL decline at 1 year (OR, 1.22; P =.027), and death within 1 year (OR, 1.49; P =.010). Using the VES-13 to define vulnerability (score ≥3), sensitivity and specificity were 59% and 61% for predicting toxicity, and 100% and 59% for predicting death within 1 year, respectively. FIL GA frailty had a sensitivity of 63% and specificity of 56% for predicting toxicity, and 100% sensitivity and 54% specificity for predicting death within 1 year. Conclusions: We found that VES-13 score was associated with survival, toxicity, health care utilization, and QoL decline, demonstrating similar sensitivity and specificity to the FIL GA. These findings underscore the potential utility of VES-13 as a screening instrument to identify older patients with aNHL at risk for adverse clinical outcomes.

BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Abstract Background Mitral regurgitation (MR) and tricuspid regurgitation (TR) are prevalent valvular heart diseases associated with significant morbidity and mortality. Traditional echocardiography faces limitations in availability, cost, consistency, and reliability, leading to misdiagnosis and undertreatment. The application of artificial intelligence (AI) to echocardiographic scans has the potential to address these challenges. Methods This study evaluates the performance of an AI algorithm on an external population. The algorithm utilizes deep learning networks to analyze echocardiographic exams for diagnosing atrioventricular valve disorders. We tested the algorithm on transthoracic echocardiography data collected from a single center between 2013 and 2023. The model's performance was compared to ground truth values using two classification schemes: distinguishing between normal-mild and moderate-severe regurgitation, and categorizing results into four groups: normal, mild, moderate, and severe. Results The MR cohort included 280 patients, while the TR cohort comprised 298 patients. The model demonstrated a robust ability to identify clinically significant (moderate and above) atrioventricular valve regurgitation. The MR model achieved an area under the curve (AUC) of 0.98 (95% CI: 0.97–0.99), with 91% accuracy, 95% sensitivity, and 89% specificity. In comparison, the TR model exhibited an AUC of 0.96 (95% CI: 0.94–0.98), with 84% accuracy, 91% sensitivity, and 80% specificity. Conclusion The model demonstrated high diagnostic accuracy and reliability in assessing atrioventricular valve regurgitation severity, highlighting its potential as a valuable clinical tool. The findings underscore the role of AI in complementing expert evaluations and improving access to effective diagnostics, with future applications potentially including point-of-care diagnosis and monitoring of disease progression.

Limited information on the business practices of liver transplant (LT) centers worldwide has been published. Characterizing this data could help identify best practices as well as opportunities for improvement. As such, the International Liver Transplant Society (ILTS) Business Practice Committee conducted a global online survey of LT centers, which was sent to the ILTS membership. Questions focused on 5 main domains: transplant practice and volumes, workforce, finances, quality assessment and performance improvement, and overall program function. Data was compared across program geographic regions and transplant volume. A total of 89 discrete centers were represented, of which 76.4% were academic/university-affiliated, and about one-third each were from Europe (36.0%) and North America (31.5%). The top 3 problems programs reported were finances/funding (60.7%), adequate program support/guidance (48.3%), and transplant volumes (43.8%). In all, 59.6% of respondents felt their salary was undercompensated, consistent across geographic regions. In addition, 69.7% felt their center was not adequately funded to meet program goals, with programs in Europe (N=28/32, 87.5%) and Oceania (N=2/3, 66.7%) most impacted. Transplant surgeon retainment was noted as more difficult for lower volume programs (<50 liver transplants/year, N=13/31). Nearly half (42.7%) of all programs felt under-resourced to provide high-quality care, and the majority (80.9%) felt there was room for growth and improvement under their current model. While international concerns varied widely among LT centers, inadequate salary and center funding, low transplant and referral volumes, and staff retainment were persistent themes. Focusing on adopting region-specific best practices and developing transplant systems of care that focus on these elements is critical to provide optimal care to LT patients worldwide.

Abstract Aims Acute myocardial infarction (AMI) patients face a substantial risk of cardiovascular events and rehospitalization. The impact of the SmartHeart 12-lead electrocardiogram (ECG) telemedicine device on healthcare utilization has not been tested in a US randomized trial. Methods and results Patients with AMI were randomized at discharge to standard of care without (control group) or with the SmartHeart 12-lead ECG device (intervention group). The primary endpoint was the rate of emergency department (ED) visits, hospital readmissions, and any cardiovascular testing from discharge to 90 days of follow-up. The primary endpoint was reached in 57 (59%) patients in the control group and 53 (63%) patients in the intervention group (P = 0.61). However, in the intervention group, only 30% of patients complied with two follow-up training SmartHeart 12-lead ECG transmissions after discharge, and only 24% used the device thereafter. Among device users, ED presentations were lower in the intervention group than in the control group (8.0% vs. 29%, P = 0.04). In all patients advised to present to the ED upon device use (38%), a clinically relevant cardiovascular diagnosis was made. One patient survived a ventricular fibrillation cardiac arrest as advised to present to ED urgently after device use. Conclusion In this US-based RCT, there were no significant differences in the primary outcome in the intention-to-treat analysis. However, according to per-protocol analysis, proper use of the SmartHeart ECG device with 24/7 telemedicine support reduced inappropriate and increased appropriate ED presentations after hospitalization for AMI.