Importance:The relationship between air pollution and cardiac remodeling in patients with cancer treated with cardiotoxic therapy is undefined. Objective:To assess the associations between air pollutants and changes in cardiac function, structure, and remodeling in patients with breast cancer treated with anthracyclines and/or trastuzumab therapy. Design, Setting, and Participants:This longitudinal prospective cohort study included patients with breast cancer enrolled at multiple sites of a quaternary health care system from July 1, 2010, to November 1, 2018. All participants were initiating anthracyclines and/or trastuzumab. Data were analyzed from December 1, 2024, to April 30, 2025. Exposures:Three-year average census tract-level concentrations of fine particulate matter with diameter of 2.5 µm or less (PM2.5), particulate matter with diameter of 10 µm or less (PM10), nitrogen dioxide (NO2), and ozone (O3). Main Outcomes and Measures:Core laboratory-quantified, echocardiography-derived measures of cardiac remodeling and function and incidence of cardiac dysfunction, defined as a left ventricular ejection fraction (LVEF) decline of 10% or more from baseline to less than 50%. Multivariable linear regression and generalized estimating equations defined the cross-sectional and longitudinal associations between air pollution and measures of cardiac remodeling and function. Cause-specific hazard models defined the adjusted associations between air pollution and cardiac dysfunction. Results:Across 580 female patients (median age, 50 years [IQR, 42-58 years]), 3642 echocardiograms were obtained at standardized time intervals over a median of 3.1 years (IQR, 2.3-3.6 years) and centrally quantified. Cardiac dysfunction was observed in 98 of 574 participants (17.1%). Concentrations of PM2.5 (median, 9.26 μg/m3 [IQR, 8.49-10.17 μg/m3]) and O3 (median, 47.00 parts per billion [ppb] [IQR, 45.50-48.19 ppb]) were each associated with cardiac dysfunction and adverse remodeling, cross-sectionally and longitudinally. Over time, each IQR-increment increase in PM2.5 (1.68 μg/m3) and O3 (2.69 ppb) was associated with a mean LVEF change of -1.3% (95% CI, -1.8% to -0.8%) and -1.4% (95% CI, -1.8% to -1.0%), respectively; worse longitudinal strain (-1.0% [95% CI, -1.3% to -0.7%] and -1.1% [95% CI, -1.3% to -0.8%], respectively); and left ventricular mass increase of 4.8 g/m2 (95% CI, 3.1-6.5 g/m2) and 3.2 g/m2 (95% CI, 2.1-4.3 g/m2), respectively. Patients in the highest tertiles of PM2.5 (adjusted hazard ratio [AHR], 2.03; 95% CI, 1.17-3.52) and O3 (AHR, 2.15; 95% CI, 1.23-3.78) exposure were at a significantly higher risk of cardiac dysfunction compared with those in the lowest tertile. Neither PM10 (AHR, 0.84; 95% CI, 0.49-1.44) nor NO2 (AHR, 0.92; 95% CI, 0.50-1.70) showed significant associations with cardiac dysfunction. Conclusions and Relevance:In this cohort study, PM2.5 and O3 exposure was independently associated with worse cardiac remodeling and function in patients with breast cancer treated with cardiotoxic therapy. These findings highlight the importance of modifying environmental exposures to mitigate cardiovascular disease risk.

In certain settings, when conducting a randomized trial would be infeasible, electronic health records (EHR) can be used to emulate a target trial and estimate causal effects of an intervention. This process involves specifying the elements of a hypothetical trial protocol and applying these to the design of an observational study conducted with EHR data (or other observational data source). One element of target trial specification includes defining eligibility criteria. However, defining the eligible population with EHR can be complicated by missingness in eligibility-defining variables. Multiple imputation (MI) is one common approach to missingness in EHR data, but it is unclear whether imputation of eligibility criteria should occur before or after excluding ineligible individuals. Motivated by a target trial emulation of two treatments for advanced breast cancer, we explore this question when estimating the average causal effect under a target trial framework with survival outcomes. We illustrate how alternative MI strategies perform using simulated data and in a real-world analysis of oncology EHR data. We found that in most settings with high proportions of missingness in eligibility-defining variables, imputing missing data using a flexible imputation model, such as a random forest, prior to excluding ineligible individuals resulted in lower bias than complete case analysis or imputation after excluding ineligible individuals. Choices about how to handle practical challenges such as this in the application of target trial emulation to messy, real-world data sources can have substantial effects on causal parameter estimation and should be carefully considered to ensure that the results of observational studies are as rigorous as possible.

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Background:Circulating tumor DNA (ctDNA) is an emerging biomarker of treatment response and recurrence risk, while residual cancer burden (RCB) after neoadjuvant treatment (NAT) is a well-established risk factor for distant recurrence. Here, we examined the association between high ctDNA concentration at diagnosis and risk of distant recurrence after neoadjuvant treatment (NAT), in the context of RCB. Methods:The study included 712 patients with high-risk breast cancer in the neoadjuvant I-SPY2 trial. Tumor- informed ctDNA test results at diagnosis were used to stratify patients into ctDNA-negative and ctDNA-positive groups. For this analysis, the ctDNA-positive group was divided into tertiles (low, intermediate, high) based on ctDNA concentration reported as mean tumor molecules per mL [MTM/mL] of plasma. Correlations between MTM/mL at diagnosis and ctDNA dynamics during NAT, residual cancer burden (RCB), and distant recurrence-free survival (DRFS) were examined across all subtypes. Results:In all subtypes, high ctDNA concentration at diagnosis was associated with worse DRFS, whereas low ctDNA concentration or ctDNA-negative status was associated with improved DRFS, even with high tumor burden after NAT (RCB-II/RCB-III). We also found that patients with high ctDNA concentration, regardless of subtype, were less likely to experience early ctDNA clearance; however, those who did had a significantly higher likelihood of achieving a favorable response (RCB-0/RCB-I) than those with late or no ctDNA clearance. Furthermore, across all subtypes, patients with early ctDNA clearance, including those with substantial residual cancer (RCB-II/RCB-III) after NAT, had improved DRFS, irrespective of the ctDNA concentration at diagnosis. Conclusions:Across all subtypes, pathologic response and ctDNA clearance reduce the risk of distant recurrence associated with high ctDNA concentration at diagnosis. ctDNA concentration at diagnosis and ctDNA clearance dynamics during NAT may facilitate the prediction of treatment response and further stratify the risk of metastatic recurrence in non-responders. Trial Registration: NCT01042379.

Importance:Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective:To evaluate the combination of anti-programmed cell death 1 protein (PD-1) cemiplimab and anti-lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2-negative early-stage, high-risk breast cancer. Design, Setting, and Participants:The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2-negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions:Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures:Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results:A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2, 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2-negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance:In this randomized clinical trial, the combination of PD-1 and anti-LAG-3 inhibition with standard NAC was effective in early-stage ERBB2-negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration:ClinicalTrials.gov Identifier: NCT01042379.

TPS615 Background: The TAILORx and RxPONDER trials demonstrated that RS identifies many postmenopausal pts with node-neg and node-pos BC and RS ≤25, who do not benefit from addition of ACT to endocrine therapy (ET). Both trials also showed that certain subsets of premenopausal pts (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25) benefited from adding ACT to ET. Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, we developed OFSET, a phase III, multicenter clinical trial comparing OFS+ET v ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET v ET is an aromatase inhibitor (AI). Choice is per investigator discretion; tamoxifen is allowed if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per investigator discretion per protocol guidelines. The HRQOL sub-study will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score between arms, as well as increased pain severity (PROMIS). Blood and tumor specimens will be collected for future research. Accrual of 3,960 pts is anticipated to be completed in 7 yrs, 7 mos. Per NSABP B-28 and RxPONDER data, 5yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with one-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur~11 yrs after study initiation. OFSETwas activated Aug 2023. As of 1-6-25, accrual is: 188/3,960. NCT #: NCT05879926. Support: U10CA180868, -80822, UG1CA189867, U24CA196067. Clinical trial information: NCT05879926 .

Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for Breast Cancer gene (BRCA)-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluate a radiolabeled PARPi, [18F]FluorThanatrace ([18F]FTT), as a functional biomarker of PARPi response in breast cancer. A single-arm prospective observational trial was conducted at the University of Pennsylvania. [18F]FTT-PET uptake was measured in 24 women with untreated primary breast cancer and correlated with tumor HRD score. In a separate cohort of ten subjects with metastatic HER- breast cancer, [18F]FTT-PET uptake was measured at baseline and after a short interval on a PARPi (a measure of drug-target engagement) and correlated to progression free survival (PFS). Here we show that baseline [18F]FTT-PET uptake does not correlate to HRD tissue score, supporting that [18F]FTT provides distinct information from genetic features. Baseline [18F]FTT-PET uptake and the change in uptake from baseline to after PARPi initiation significantly correlates to PFS in woman with breast cancer who received a PARPi (ρ = 0.74, P = 0.023 and ρ = −0.86, P = 0.012, respectively). These early results suggest the potential of [18F]FTT-PET to select patients for PARPi treatment and monitor in vivo pharmacodynamics after therapy start. Absence of association with HRD scores supports [18F]FTT uptake as a novel measure that may be leveraged as a biomarker. Further studies are warranted. PARP inhibitors are an effective treatment for breast cancer; however, do not work in all patients. Our goal is to identify individuals with breast cancer who are likely to respond to this treatment, so we do not administer the drug to those who will not benefit and could experience side effects. We gave people a probe that is visible by imaging and that binds to the PARP protein in the body. We found that the amount of probe taken up by a person’s tumor was an indicator of whether they would respond well to PARP inhibitor treatment. Using such a probe could help doctors make decisions about whether to treat breast cancer patients with PARP inhibitors. Gitto, Pantel et al. evaluate a PARP-targeted PET imaging ligand, [18 F]FlourThanatrace, as a biomarker of response to PARP inhibitors in patients with breast cancer. There is [18 F]FlourThanatrace uptake in the tumor before treatment, and a decline in uptake after PARP inhibitor therapy initiation, correlating with patient progression free survival.

Representativeness of Study Participants

Early-stage breast cancers resistant to neoadjuvant therapy (NAT), characterized by high residual cancer burden (RCB) after treatment, have an increased risk of metastatic recurrence. Here, we show that circulating tumor DNA (ctDNA) detected using a tumor-informed test (1) can improve risk stratification of patients with NAT-resistant tumors (RCB-II/RCB-III) and (2) predict response to NAT. Stratification using ctDNA status at pretreatment or post-NAT and ctDNA dynamics identified NAT-resistant tumors with a significantly decreased risk of metastatic recurrence. ctDNA clearance as early as week 3 across receptor subtypes predicted favorable responses to NAT, including immunotherapies. Interestingly, less than a fifth of patients with NAT-resistant tumors were ctDNA-positive post-NAT. Serial mutation profiling of NAT-resistant tumors revealed that patient-specific ctDNA assay variants remained detectable over time, including in tumors of patients ctDNA-negative post-NAT. Refining risk stratification for NAT-resistant tumors using ctDNA and understanding ctDNA shedding in these tumors could guide treatment decisions to prevent or delay metastatic recurrence.

Despite the increasing availability of next-generation sequencing (NGS) gene panel analysis for cancers, published reports suggest underutilization of testing, citing the shortage of credentialed professionals available to assist with the interpretation of test results among the key barriers. Obtaining a multidisciplinary consensus regarding a shared best practice NGS molecular biomarker reporting section template may facilitate introduction and/or increased testing for institutions that adopt similar report structures by improving report effectiveness and efficiency for both health care providers and laboratory professionals, leading to improved patient care. To address this challenge, the Association for Molecular Pathology convened a multidisciplinary collaborative expert working group to identify and utilize best practices from current reporting guidelines and approaches to develop an NGS biomarker report template to optimally present complex molecular profiling information for efficient use by oncologists and other health care providers. Seventeen non-small-cell lung cancer NGS biomarker reports from public, private, and academic laboratories were reviewed, and specific components (eg, report length, color use, formatting, presentation order of information, specific information included or omitted, tables, and figures) were assessed for their ability to be considered provider friendly. Based on this review, public and stakeholder input, available literature, and cumulative professional experience of the working group members, a guideline-concordant reporting template was developed based on expert opinion consensus and made freely available online with planned implementation assessment.

Background: Understanding the impact of Social Drivers of Health on shoulder arthroplasty is pivotal for the development of equitable value-based payment models that enhance the quality of patient care. This investigation aims to understand the influence of Area Deprivation Index (ADI) on hospital admissions, readmissions, and associated costs postshoulder arthroplasty. Methods: We conducted an analysis using US Medicare claims data from 2019 to 2021, identifying patients who received shoulder arthroplasty in either an inpatient or outpatient setting using Current Procedural Terminology codes. Our primary outcomes were 90-day unplanned readmissions and postprocedure 90-day care costs. The ADI was our primary exposure variable, calculated at the census block level. Our analysis adjusted for multiple factors using a stepwise modeling approach including patient demographics, 29 Elixhauser comorbid conditions, Medicaid-dual eligibility, and end-stage renal disease status using logistic regression models. Results: A total of 145,435 patients were included in our study. The average age of patients in our cohort was 74.5 year old, with 59.5% being female. Patients in the high ADI group had a higher readmission rate than the lowest ADI group (8.5% vs 6.0%, P < .001).When controlling for confounding factors, there was an independent association between high ADI and readmission (odds ratio {OR}: 1.28 [95% confidence interval {CI} 1.12, 1.46]). Overall, we saw a dose-dependent relationship between ADI and readmission, with the association growing stronger as ADI increased. Conversely, we found a negative association with ADI and high-costs. (High ADI group OR: 0.80 [95% CI 0.70, 0.91]). Patients in the high socioeconomic status (SES) group had higher health care contact days during the 90-day follow-up period, with a median of 16 visits (interquartile range [IQR] 8, 23), compared to 13 visits (IQR 6, 22) in the middle SES group and 10 visits (IQR 5, 20) in the low SES group (P < .001). Conclusion: Socioeconomic disparities significantly influence the outcomes of primary shoulder arthroplasty, as indicated by higher readmission rates for low SES patients. Notably, our analysis shows a strong, independent association between ADI and readmission. Moreover, patients with higher SES incurred greater costs within a 90-day period potentially due to increased resource utilization. (c) 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights are reserved, including those for text and data mining, AItraining, and similar technologies.

Estimating the incidence and prevalence of dementia is challenging. Cohort and brain banking studies can provide very precise estimates of incidence and prevalence in specific populations, but it is not clear how generalizable those estimates are to other populations. Furthermore, diagnoses of dementia made in clinical practice may differ from gold-standard neuropathological diagnoses. Understanding trends in the incidence and prevalence of dementia as determined by routinely collected administrative claims data can provide critical context for clinicians and policymakers. Furthermore, understanding disparities in incidence and prevalence in the population at large can help to ameliorate biases from inequitable representation in survey and cohort designs. We performed a retrospective study of 100% of Medicare claims from 2013-2021 (2013 being reserved as a look-back year). We defined incident dementia diagnoses in each year among patients without a known history of dementia based on validated international classification of diseases (ICD) algorithms. We defined prevalent dementia as patients with any prior history of dementia in each year. We stratified incidence and prevalence by race (classified as Black, non-Hispanic, Other race/ethnicity, and White, non-Hispanic), sex, and neighborhood socioeconomic status, measured by the well-established Area Deprivation Index, which summarizes socioeconomic conditions at the census block group level (roughly 600-1000 people). From 2014-2021, there were 5,721,711 incident cases of dementia in the United States. The average age at diagnosis was 80.5 years. Patients were 57.7% female, 86.6% White and 7.8% Black, 15.8% dually eligible for Medicare and Medicaid, and 41.5% from the South region. Table 1 shows incidence rates and prevalence of dementia from 2014-2021. Table 2 shows incidence rates and prevalence stratified by legal sex and race/ethnicity. Figure 1 shows incidence rates of dementia stratified by neighborhood socioeconomic status. We found declining dementia incidence but increasing dementia prevalence in a sample that includes the vast majority of older adults in the United States. Differences in dementia incidence by sex, race/ethnicity, and neighborhood socioeconomic status remained notable in 2021. Our results have implications for health system performance in providing high-quality and equitable clinical care for a growing population of patients with dementia.

Medical comorbidity burden has a substantial impact on care for patients with dementia and has major impacts on quality of life. No nationwide study has evaluated trends in medical comorbidity burden of patients with a new diagnosis of dementia. We therefore performed a nationwide study of medical claims data to understand the prevalence of comorbid medical conditions at time of dementia diagnosis in real-world clinical practice. We studied 100% of nationwide Medicare claims from 2014-2021 and evaluated the prevalence of medical comorbidities among patients with new diagnoses of dementia. Medical comorbidities were ascertained through searching inpatient and outpatient claims for 1 year prior to dementia diagnosis. We used validated international classification of diseases (ICD) code algorithms to identify both dementia diagnoses and medical comorbidities. We report the number and percentage of patients with each comorbid medical condition. A total of 5,721,711 patients with incident dementia were included in the study. Anxiety disorders were much more common among patients diagnosed in 2021 (29.8%) compared to patients diagnosed in 2015 (23.8%). Depression was also more common among patients diagnosed in 2021 (33.8%) versus 2015 (31.8%). Hypertension remained very common (85.7% in 2021 vs 86.6% in 2015). There was a major decrease in patients with prior history of psychosis (17.8% in 2015 vs 8.1% in 2021). There were modest increases in the rates of comorbid cardiovascular disease (Table 1). Figure 1 shows the percentage of patients with new diagnosis of dementia with various conditions in 2015 and 2021 respectively. In a national database of Medicare claims, there were substantial changes from 2015-2021 in comorbidity burden among patients newly diagnosed with dementia. There was a dramatic decrease in comorbid psychosis which could be attributable to Medicare initiatives to reduce the inappropriate use of antipsychotic medications among patients with dementia. Our results have implications for health system performance and risk adjustment, given an overall increase in comorbidity burden across many disease states from 2015-2021. Strategies to address rising multimorbidity may be increasingly important for patients with dementia.

Importance:There are gaps in the understanding of the clinical actionability of cardiovascular biomarkers for risk stratification during cardiotoxic chemotherapy. Objectives:To gain insights into an N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided approach for cardioprotection in patients with breast cancer or lymphoma treated with anthracyclines and quantify the feasibility, tolerability, and exploratory efficacy of an NT-proBNP-guided strategy compared with usual care. Design, Setting, and Participants:The NT-proBNP guide, a multicenter, randomized (stratified 1:1 by cancer type) clinical trial, included 100 participants with breast cancer or lymphoma initiating anthracyclines from March 18, 2021, to October 20, 2023, who were followed up for 12 months. Interventions:Study participants in the NT-proBNP-guided arm had biomarker concentrations measured prior to anthracycline initiation (baseline), at each cycle, and at 3, 6, 9, and 12 months. An elevated NT-proBNP concentration triggered the initiation or titration of neurohormonal therapy. Participants in the usual care arm received routine care without prospective monitoring of NT-proBNP concentrations. Main Outcomes and Measures:The primary outcomes were feasibility and safety of the NT-proBNP-guided approach. Feasibility was defined by recruitment, retention, and medication compliance rates. Safety outcomes were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0, at each visit. Exploratory outcomes included differences in blinded, centrally quantified echocardiographic measures and NT-proBNP concentrations between the 2 arms. Analysis was performed on an intention-to-treat approach. Results:Across 100 participants (mean [SD] age, 52.2 [14.4] years; 86 women [86.0%]), 74 (74.0%) had breast cancer and 26 (26.0%) had lymphoma. At 12 months, the retention rate was 92.7% (89 of 96). In the NT-proBNP-guided arm, 27 participants had NT-proBNP elevations, with a median time from baseline to first elevation of 14 days (IQR, 0-76 days), and a median time between the first NT-proBNP elevation and neurohormonal therapy prescription of 1 day (IQR, 0.5-9 days). There were no significant differences in targeted adverse events between the NT-proBNP-guided (23 events) and usual care (16 events) arms (P = .13). At 3 months, left ventricular ejection fraction (LVEF) was modestly higher in the NT-proBNP-guided arm compared with usual care (mean difference, 2.0% [95% CI, 0.5%-3.5%]; P = .007). NT-proBNP concentrations increased in both arms over the study duration, but elevations were slightly attenuated in the NT-proBNP-guided arm. Conclusions and Relevance:This randomized clinical trial of an NT-proBNP-guided approach to neurohormonal therapy in patients with cancer treated with anthracyclines demonstrates the feasibility, safety, and potential modest, early improvement in LVEF of a biomarker-guided approach. These findings provide support for further study of an NT-proBNP-guided approach to cardioprotection for patients undergoing cancer treatment. Trial Registration:ClinicalTrials.gov Identifier: NCT04737265.

BACKGROUND:Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) differ in their effects on body weight and risk for reoperation. However, it is unclear whether long-term health expenditures differ by procedure type in patients with diabetes. OBJECTIVE:To compare health expenditures 3 years before and 5.5 years after bariatric surgery between patients with diabetes undergoing RYGB versus SG. DESIGN:Retrospective cohort study using target trial emulation principles. SETTING:Integrated health system. PATIENTS:Patients with diabetes undergoing RYGB (n = 3147) or SG (n = 3510) from 2012 to 2019. MEASUREMENTS:Total, inpatient, outpatient, and medication expenditures. RESULTS:Characteristics of patients undergoing RYGB and SG were well balanced after weighting; 73% were female, average body mass index was 43.8 kg/m2, and average age was 50 years. Expenditures per 6-month period decreased by about 30% for both groups, from $4039.06 (95% CI, $3770.88 to $4326.31) 3 years before to $2441.13 (CI, $2151.07 to $2770.30) 5.5 years after RYGB and from $3918.37 (CI, $3658.75 to $4196.40) 3 years before to $2658.15 (CI, $2279.17 to $3100.16) 5.5 years after SG. Total expenditures after surgery did not differ between groups through 5.5 years (difference at 5.5 years, -$217.02 [CI, -$671.29 to $201.96]) except for the first 6 months, when expenditures were transiently higher in the RYGB group (difference, $564.32 [CI, $232.60 to $895.20]), driven by a higher inpatient admission rate. Otherwise, postsurgical outpatient and medication expenditures did not appear to differ between RYGB and SG. LIMITATION:Unobserved confounding. CONCLUSION:Overall expenditures decreased substantially in the postsurgical period, primarily due to reductions in pharmacy expenditures, with no differences between RYGB and SG except in the first 6 months after surgery. PRIMARY FUNDING SOURCE:National Institute of Diabetes and Digestive and Kidney Diseases.

Background: Sacituzumab govitecan (SG) is a TROP2-directed antibody drug conjugate (ADC) approved for previously treated triple negative and hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) based on improvements in progression-free (PFS) and overall survival (OS) compared to chemotherapy (CT). Benefit with SG was observed regardless of TROP2 expression by immunohistochemistry (IHC), although the increase in response and survival rates with SG was greater in patients (pts) with higher TROP2 levels. SACI-IO HR+ is a randomized, open-label phase II study that compared SG with or without pembrolizumab in HR+/HER2- MBC (NCT04448886). Here we report the correlation of TROP2 expression by quantitative immunofluorescence (QIF) with clinical outcomes. Methods: Pts with unresectable locally advanced or metastatic HR+ (ER≥1% and/or PR≥1%), HER2- breast cancer treated with ≥1 prior endocrine therapy and 0-1 chemotherapy for MBC were randomized 1:1 to Arm A (SG plus Pembrolizumab) or Arm B (SG). TROP2 expression was measured centrally by QIF. FFPE tissue (baseline research biopsy or most recent archival sample prior to study therapy) was stained using a Leica BOND Autostainer and imaged on a RareCyte CyteFinder II HT instrument. TROP2 protein was quantified in amol/mm2 with Qymia extension (v0.0.6) in Qupath (0.4.3) using a cell line standard curve calibrated by mass spectrometry. Association of TROP2 (as a continuous variable, median, and by quartiles) with PFS, OS, and G3 or higher treatment-emergent adverse events (TEAE) was evaluated using the Cox proportional hazards model, and the p-value from the log rank test was reported. Results: Tumor samples from 82 pts (38 Arm A; 44 Arm B) who started study therapy were analyzed, of which 34 (41.5%) had PD-L1+ (defined as CPS ≥1) tumors. 72 (87.8%) pts had received prior CDK4/6 inhibitor therapy; 43 (52.4%) had no prior CT for MBC. Median follow-up was 11.2 months (mo). Median TROP2 protein concentration was 4312.5 amol/mm2. Among all pts, TROP2 was not significantly associated with PFS as a continuous variable (hazard ratio [HR] per 1-unit increase in log amol/mm2: 0.96, p=0.55) or by quartiles (≤25% [ref], median PFS 8.7 mo; >25%-50%, 4.5 mo, HR 1.86, p=0.09; >50%-75%, 6.7 mo, HR 1.14, p=0.74; >75%, 6.2 mo, HR 0.91, p=0.81). Median PFS was not significantly higher in pts with TROP2 levels ≥ vs < median (6.7 vs 5.9 mo; HR 0.77, p=0.31). TROP2 was not associated with PFS in either treatment arm (Arm A: HR 0.90, p=0.34; Arm B: HR 1.01, p=0.91) or by PD-L1 status (PD-L1+: HR 0.92, p=0.44; PD-L1-: HR 0.97, p=0.79). Similarly, no significant associations between TROP2 and OS were observed among all pts (HR per 1-unit increment: 1.05, p=0.66), by treatment arm (Arm A: HR 1.05, p=0.79; Arm B: HR 1.03, p=0.85) or PD-L1 status (PD-L1+: HR 1.08, p=0.70; PD-L1-: HR 1.00, p=0.99). Median OS did not significantly differ by TROP2 levels ≥ vs < median (17.3 vs 18.0 mo; HR 0.93, p=0.86). TROP2 by QIF was not associated with G3 or higher TEAE in all pts (HR per 1-unit increment: 1.00, p=0.99) or by treatment arm (Arm A: HR 0.81, p=0.42; Arm B: HR 1.16, p=0.41). Conclusion: In this prespecified exploratory analysis of the SACI-IO HR+ trial, TROP2 expression by QIF was not associated with survival outcomes across all pts, by treatment arm or by PD-L1 status. Exploratory outcome analyses by TROP2 IHC expression and association with QIF will be reported. Citation Format: Ana Garrido-Castro, Se Eun Kim, Mengni He, Jennifer Desrosiers, Rita Nanda, Yara Abdou, Amy S. Clark, Ruth L. Sacks, Thomas O’Connor, Natalie Sinclair, Steve Lo, Amy Thomas, Eileen Wrabel, Molly DiLullo, Tasnim Rahman, Katherine Junkins, Hajer Rahee, Ashka Patel, Paulina B. Lange, Tess O’Meara, Tanya E. Keenan, Deborah A. Dillon, Nancy U. Lin, Harold J. Burstein, Elizabeth A. Mittendorf, Nabihah Tayob, David L. Rimm, Sara M. Tolaney. Correlation of TROP2 expression with outcomes of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer: an exploratory analysis from the phase II SACI-IO HR+ trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-09-24.

Background: The TAILORx and RxPONDER trials demonstrated that RS identifies many postmenopausal pts with node-neg and node-pos BC and RS ≤25, who do not benefit from addition of ACT to endocrine therapy (ET). Both trials also showed that certain subsets of premenopausal pts (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25) benefited from adding ACT to ET. Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, we developed OFSET, a phase III, multicenter clinical trial comparing OFS+ET v ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI). Choice is per investigator discretion; tamoxifen is allowed if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per investigator discretion per protocol guidelines. The HRQOL substudy will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score between arms, as well as increased pain severity (PROMIS). Blood and tumor specimens will be collected for future research. Accrual of 3,960 pts is anticipated to be completed in 7 yrs, 7 mos. Per NSABP B-28 and RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ∼95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with one-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ∼11 yrs after study initiation. OFSET was activated August 2023. Accrual is 69/3,960 (as of July 3, 2024). NCT #: NCT05879926. Support: U10CA180868, -80822, UG1CA189867, U24CA196067. Citation Format: Shannon L. Puhalla, Gong Tang, Sandra M. Swain, Patricia A. Ganz, N. Lynn Henry, Reena S. Cecchini, Sonya A. Reid, Priya Rastogi, Charles E. Geyer, Jr., Julia R. White, Amy S. Clark, Tufia C. Haddad, Gregory A. Vidal, Norman Wolmark, Eleftherios P. Mamounas. NRG-BR009: A phase III trial evaluating addition of adjuvant chemotherapy to Ovarian Function Suppression + Endocrine Therapy in premenopausal women with pN0-1, HR+/HER2- breast cancer (BC) and Oncotype Recurrence Score (RS) ≤25 (OFSET) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-12-20.

Background: Recurrence after early-stage breast cancer (BC) is a challenge, occurring in ∼30% of patients (pts). Recurrences may arise from reactivation of disseminated tumor cells (DTCs) persisting in a dormant state after primary treatment. The presence of minimal residual disease (MRD) as bone marrow DTCs and/or circulating tumor DNA (ctDNA) in the blood increases the risk of BC recurrence/death. It remains unclear which pts with DTCs will have these reactivate or develop detectable ctDNA before clinical relapse. We evaluated the association and temporal relationship of ctDNA with DTCs in a population of high-risk BC survivors, and the relationship of these markers with subsequent metastatic recurrence. Methods: “PENN SURMOUNT” is a single center, prospective, longitudinal cohort study examining MRD biomarkers among pts within 5 years (y) of BC diagnosis who completed all curative treatment except endocrine therapy. Eligible pts must have had: 1) TNBC, or 2) HER2+ or HR+ BC with positive LN and/or residual disease after neoadjuvant therapy, or 3) HR+ BC with a 21-gene Recurrence score >25 and/or high risk Mammaprint. Pts had annual bone marrow aspirate (BMA) for DTCs by immunohistochemistry (using methods of Naume et al.). DTC+ pts went on therapeutic trial; DTC- pts had up to 5y of annual BMA and blood testing. ctDNA was retrospectively assessed using the RaDaR assay, which targets pt-specific somatic mutations identified by whole-exome sequencing (WES) of primary tumor tissue. Results: Of 184 pts enrolled from 2016 – 2021, 121 had tissue available; 114/121 (94%) had successful WES. A total of 338 plasma samples from 96 pts (median 2 timepoints each, range 1-12) have been successfully tested by RaDaR to date. Overall, ctDNA was detected in 11 samples from 9/96 pts (9.3%) with a median eVAF of 0.009% (range 0.002-0.084%). Two pts were ctDNA+ at baseline (BL), and 7 became positive on surveillance. 87/96 (90.6%) were ctDNA- across all timepoints. 34/96 pts (35%) were DTC+, either at BL (n=24, 25%) or after (n=10, 10%). Considering all timepoints, concordance was 64%. Of 34 ever-DTC+ pts, 4 (12%) were ctDNA+ (of whom 3/4 recurred) and 30 remained ctDNA- (with 1/30 who recurred). Among the 62 pts who remained DTC-, 5 (8%) were ctDNA+ (with 5/5 who recurred), and 57 remained ctDNA- (of whom 5/57 recurred). All ctDNA positivity in DTC+ pts occurred at the time of or after DTC positivity. Over median follow-up (f/u) of 65 months (m), BC recurrence occurred in 14/96 pts (15%), with 2 locoregional-only and 12 distant +/- locoregional recurrences (involving the bone, liver, lung/pleura, and brain); 8/14 pts (57%) were ctDNA+ prior to relapse. 7/12 (58%) with distant recurrences were ctDNA+ prior to metastatic diagnosis, at a median lead time of 15 m (range 0 – 25). Overall, ctDNA+ pts experienced a median lead time from ctDNA positivity to recurrence of 13 m (range 0 – 25). Only 1 of 9 ctDNA+ pts has not recurred; this pt was DTC+ and went on therapeutic trial, without evidence of recurrence over 20 m f/u. 30/34 DTC+ pts (89%) who went on therapeutic trial have not had ctDNA detected during f/u and have not recurred. Overall, ctDNA status was significantly associated with relapse (p<0.01), with a PPV of 89% and NPV of 93%. Of the 24 BL DTC+ pts, 2 became ctDNA+ at subsequent timepoints, an average of 18 m after DTC assessment, and both relapsed (3 and 5 m from ctDNA detection, respectively). Conclusions: In this surveillance study of high-risk BC pts, DTC+ pts were identified who subsequently developed detectable ctDNA and clinical relapse. Where there were discordant results, the timing of DTC and ctDNA positivity revealed a window of opportunity for intervention. A strategy combining both markers for surveillance and intervention to prevent metastatic disease may be of value. Citation Format: Eleanor Taranto, Nicholas J. Seewald, Lauren J. Bayne, Emma Walinsky, Shannon Deluca, Natalie NC. Shih, Pauleen Sanchez, Isoris Nivar, Bana Ambasager, Clodagh Murray, Amber Chevalier, Christopher G. Smith, Igor Makhlin, Killian Rohn, Brooke L. Goodspeed, Jessica Savage, Paul Wileyto, Jianping Wang, George Belka, Elizabeth Chislock, Lindsay R Berry, Don Berry, Anupma Nayak, Michael Feldman, Amy S. Clark, Lewis A. Chodosh, Angela DeMichele. Circulating tumor DNA (ctDNA), dormant disseminated tumor cells (DTCs) and recurrence outcomes in breast cancer survivors on the SURMOUNT Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS9-03.