Edwards, Kelly K.

Abstract Background: The Breast Cancer Index (BCI) is clinically validated to stratify patients with hormone receptor-positive (HR+), early-stage BC based on the risk of overall (0-10 years [y]) and late (5-10 y) distant recurrence (DR) with N0/N1 lymph node involvement. Validation of BCI in patients with HR+ HER2+ BC has been limited, especially in patients treated with adjuvant trastuzumab-based chemotherapy. The HOXB13 and IL17BR genes constitute the predictive component of BCI and are known to exhibit an ER-dependent correlation pattern with HER2. We evaluated the prognostic performance of BCI in patients with HR+ HER2+ disease enrolled in the NCCTG N9831 (Alliance) trial treated with the combination of chemotherapy and trastuzumab. Methods: All available tumor specimens from patients with HR+ HER2+ N0/N1 BC in arms B (sequential trastuzumab) and C (concurrent trastuzumab) of the trial were included. BCI testing was performed blinded to clinical outcomes. The primary endpoint was distant recurrence-free interval (DRFI). BCI (N0) and BCIN+ (N1) risk groups were calculated based on prespecified cut points. Kaplan-Meier analysis and log-rank testing were used to assess the prognostic significance of BCI/BCIN+ risk groups based on DR. Cox proportional hazard models with and without clinical covariates were used to estimate hazard ratios (HRs), and the associated 95% confidence intervals (CIs). Results: A total of 454 HR+ patients (234 arm B, 220 arm C), including 69 N0 and 385 N1 patients, were analyzed (median age was 47 y, 85% N1, 55% T2, 63% G3). BCIN+ scores were available for 378 of the 385 N1 patients due to missing tumor grade for 7 patients. The median follow-up was 12.7 years. In the overall cohort, BCI/BCIN+ stratified 51 (11%), 24 (5%) and 372 (83%) patients as low-, intermediate- and high-risk with 10-y DRFI rates of 96% (95% CI: 84-99%), 100% (100-100%) and 89% (86-92%), respectively. Since the low and intermediate risk groups had few patients and a similar risk of 10-y DRFI, they are combined into a single low-risk group hereafter. Thus, for overall 10-y DR, 75 (17%) and 372 (83%) of patients were classified by BCI/BCIN+ as low and high risk with 10-y DRFI rates of 97% (95% CI: 89-99%) and 89% (95% CI: 86-92%), respectively (HR=4.50, 95% CI: 1.09-18.61; p = 0.038). BCI/BCIN+ remained statistically significant in the multivariable analysis, adjusting for age, treatment, and nodal status (HR=7.54, 95% CI: 1.34-42.64; p = 0.022). For 69 N0 patients, BCI stratified 54 (78%) and 15 (22%) patients as low and high risk with 10-y DRFI rates of 100% (95% CI, 100-100%) and 77% (95% CI, 44-92%), respectively (p = 0.012). For 378 N1 patients, BCIN+ stratified 21 (6%) and 357 (94%) of patients as low and high risk with 10-y DRFI of 90% (95% CI, 66-97%) and 90% (95% CI, 86-93%), respectively (p = 0.07). Of the 21 patients classified as BCIN+ low-risk, two had BCIN+ scores of 6.75 and 6.73 in close proximity to the cut point (6.93) and experienced DR after 5 years, resulting in the same 10-y DRFI for both BCIN+ low- and high-risk patients. Conclusions: BCI is significantly prognostic for the risk of overall DR (0-10 y) in patients with HR+ HER2+ disease treated with adjuvant trastuzumab-based chemotherapy. Optimization of BCI cut points may further improve prognostic performance in HR+ HER2+. Additional validation in other HR+ HER2+ cohorts treated in the modern setting with anti-HER2-based therapy is warranted, given the small sample size of N0 patients and relatively low DR rate in the late recurrence cohort. In summary, these results provide further evidence of BCI’s utility to support clinical decision-making for adjuvant endocrine therapies for HR+ HER2+ BC. Support: U10CA180821, U10CA180882, U24CA196171, Genentech; Clinicaltrials.gov Id: NCT00005970; https://acknowledgments.alliancefound.org. Citation Format: S. Chumsri, E. Liu, K. Edwards, Y. Wen, Y. Zhang, A. K. Anderson, A. H. Partridge, L. Carey, K. Ballman, E. Perez, K. Treuner, M. Goetz, E. Thompson. Prognostic performance of Breast Cancer Index in patients with early-stage HR+ HER2+ breast cancer (BC) treated with adjuvant trastuzumab: NCCTG N9831 (Alliance) [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 PS3-08-08.

Abstract Introduction: The prevalence of venous thrombosis and pulmonary embolism (VTE) increases with age. Definitive VTE diagnosis or exclusion relies on imaging modalities, which are found to be negative in a high proportion of tested patients. Algorithms based on pretest clinical probability (low and intermediate) in conjunction with negative d-dimer test results have reliably excluded VTE sparing the need for additional imaging studies. Currently, the cutoff for a negative d-dimer is based on reference ranges regardless of age of the donor population. Since baseline d-dimer increases with aging, an age-adjusted d-dimer (AADD) cutoff for patients older than 50 years (age*10 ng/mL FEU) has been shown to improve specificity of diagnosis while still maintaining a high sensitivity (>97%) of detecting VTE/PE (Righini, et al. JAMA, 2014). Due to FDA restrictions, clinical laboratories cannot implement and report such AADD cutoffs. Major hurdles include: AADD cutoffs are assay-dependent, and there is a lack of feasible strategy for laboratories to verify the AADD cutoffs. We hypothesize that an adequate study of age-distribution of baseline d-dimer levels of healthy donors can assist the verification of AADD cutoffs and ultimately ensure patient safety in the VTE patient population. Objective: Establish an age dependent reference range for patients 50 years or older with the HemosIL HS 500 D-dimer reagent on the ACL TOP 700 (Instrumentation Laboratory, Bedford MA, USA); and compare this range with the manufacturer provided and literature recommended AADD cutoffs. Methods: D-dimer assay was performed on plasma samples from normal adult donors per the manufacturers' instructions. D-Dimer age, gender distribution and association were analyzed using non-parametric Wilcoxon rank sum, Kolmogorov-Smirnov tests, and quantile regression methods to estimate the 95th percentile to establish a reference range. Results: We studied 241 healthy donors, ranging from 21-91 years of age. Statistically significant differences between males and females (100 [42%] male) were detected (p-value <0.001; p-value =0.0009). Using CLSI guidelines, these statistical differences (median d-dimer for men = 200, while median d-dimer for women = 300) are not considered clinically significant, since only 6% of women would be outside an overall reference range (CLSI guideline states to partition if over 8% for either group would be outside the overall reference range). Using the quantile regression method, a significant association between d-dimer and age was found at the median (P<0.0001). We then established a reference range (95th percentile) for donors younger than age 50 at 635 ng/mL FEU for both men and women and AADD reference range for patients 50 and older (635 + (age - 50)*10 ng/mL) (Figure 1). This reference range was verified with our sample set, with only 6.2% of donors higher than the established reference limit. If we used the non-AADD cutoff provided by the manufacturer for donors younger than 50 (500 ng/mL FEU) and the literature recommended AADD cutoffs for older donors (age*10 ng/mL FEU), 13.3% of our normal donors were above the limits, resulting in not validating this literature reference range per CLSI guidelines in EP28-A3c. These data imply that if both manufacturer and literature recommended AADD cutoffs were adopted, HemosIL HS 500 D-dimer assay should have sufficient sensitivity and negative predictive value, although with slightly lower specificity than those reported by Righini, et al. for detecting VTE/PE. Conclusion: Our study verifies the association between d-dimer level and age and for the first time, to our knowledge, determined AADD normal range for the HemosIL HS 500 D-dimer assay. The manufacturer and literature recommended AADD cutoffs should provide sufficient sensitivity and negative predictive value for VTE/PE exclusion. Figure 1 Age distribution of D-Dimer values (n=241). Figure 1. Age distribution of D-Dimer values (n=241). Disclosures No relevant conflicts of interest to declare.

ObjectiveTo determine the cross‐sectional and longitudinal associations between diabetes treatment type and cognitive outcomes among type II diabetics.MethodsWe examined the association between metformin use, as compared to other diabetic treatment (ie, insulin, other oral medications, and diet/exercise) and cognitive test performance and mild cognitive impairment (MCI) diagnosis among 508 cognitively unimpaired at baseline type II diabetics enrolled in the Mayo Clinic Study of Aging. We created propensity scores to adjust for treatment effects. We used multivariate linear and logistic regression models to investigate the cross‐sectional association between treatment type and cognitive test z scores, respectively. Mixed effects models and competing risk regression models were used to determine the longitudinal association between treatment type and change in cognitive test z scores and risk of developing incident MCI.ResultsIn linear regression analyses adjusted for age, sex, education, body mass index, APOE ε4, insulin treatment, medical comorbidities, number of medications, duration of diabetes, and propensity score, we did not observe an association between metformin use and cognitive test performance. Additionally, we did not observe an association between metformin use and cognitive test performance over time (median = 3.7‐year follow‐up). Metformin was associated with an increased risk of MCI (subhazard ratio (SHR) = 2.75; 95% CI = 1.64, 4.63, P < .001). Similarly, other oral medications (SHR = 1.96; 95% CI = 1.19, 3.25; P = .009) and insulin (SHR = 3.17; 95% CI = 1.27, 7.92; P = .014) use were also associated with risk of MCI diagnosis.ConclusionsThese findings suggest that metformin use, as compared to management of diabetes with other treatments, is not associated with cognitive test performance. However, metformin was associated with incident MCI diagnosis.

Background: Previous studies reported that slower gait speed might predict cognitive impairment and dementing illnesses, supporting the role of gait speed as a possible subclinical marker of cognitive impairment. However, the predictive value of other gait parameters for cognitive decline is unclear. Objective: To investigate and compare the association with, and prediction of, specific gait parameters for cognition in a population-based sample. Methods: The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging. At baseline and every 15 months (mean follow-up = 1.93 years), participants had a study coordinator evaluation, neurological examination, and a neuropsychological assessment using nine tests that covered four domains. Gait parameters were assessed with the GAITRite ® instrument. General linear mixed effects models were used to compute the annualized rate of change in cognitive domain z-scores, controlling for age, sex, education, depression, comorbidities, body mass index, APOE ɛ 4 allele, and visit number, and excluding individuals with a history of stroke, alcoholism, Parkinson’s disease, subdural hematoma, and normal pressure hydrocephalus. Results: Spatial (stride length), temporal (ambulatory time, gait speed, step count, cadence, double support time), and spatiotemporal (cadence) gait parameters, and greater intraindividual variability in stride length, swing time, and stance time were associated with a significant decline in global cognition and in specific domains including memory, executive function, visuospatial, and language. Conclusions: Spatial, temporal, and spatiotemporal measures of gait and greater variability of gait parameters were associated with and predictive of both global- and domain-specific cognitive decline.

AbstractIntroductionThe feasibility and validity of brief computerized cognitive batteries at the population‐level are unknown.MethodsNondemented participants (n = 1660, age 50–97 years) in the Mayo Clinic Study on Aging completed the computerized CogState battery and standard neuropsychological battery. The correlation between tests was examined and comparisons between CogState performance on the personal computer (PC) and iPad (n = 331), and in the clinic vs. at home (n = 194), were assessed.ResultsWe obtained valid data on greater than 97% of participants on each test. Correlations between the CogState and neuropsychological tests ranged from −0.462 to 0.531. Although absolute differences between the PC and iPad were small and participants preferred the iPad, performance on the PC was faster. Participants performed faster on Detection, One Card Learning, and One Back at home compared with the clinic.DiscussionThe computerized CogState battery, especially the iPad, was feasible, acceptable, and valid in the population.