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TPS1122 Background: Treatment options for patients (pts) with unresectable or metastatic BC have improved with the development of novel targeted therapies including trastuzumab deruxtecan (T-DXd), an ADC directed against HER2 with a cytotoxic topoisomerase I inhibitor as a payload. Currently, there are limited treatment options for pts with HER2+ or HER2-low metastatic BC that has progressed on T-DXd. BB-1701 is an ADC consisting of a monoclonal antibody targeting HER2 with eribulin (microtubule inhibitor) as a payload that is capable of exerting a bystander effect. A first-in-human dose-finding Study 101 of BB-1701 is ongoing. Here we describe Study 205, an open label, multicenter, phase 2 study of BB-1701 in pts with HER2+ or HER2-low unresectable or metastatic BC who have disease progression after treatment with T-DXd. Methods: Study 205 (NCT06188559) includes dose-optimization and dose-expansion parts for BB-1701. Eligible pts must have histologically confirmed HER2+ or HER2-low, unresectable or metastatic BC, with measurable disease per RECIST v1.1. Prior treatment must include 1–3 prior chemotherapy-based regimens for unresectable or metastatic BC, including T-DXd. The primary objectives of the dose-optimization part include determining the recommended dose (RD) and evaluating safety and tolerability of BB-1701. The RD will be assessed by randomly assigning ~50 pts into 1 of 3 dosing cohorts (1.6 mg/kg on day 1 Q3W, 0.8 mg/kg on days 1 and 8 Q3W, and 1.2 mg/kg on day 1 Q3W; IV) in a 2:2:1 ratio. Randomization will be stratified by HER2 status (HER2+ vs. HER2-low) documented prior to T-DXd treatment. The dose-expansion part will enroll ~85 pts at RD; the primary objective includes evaluating the efficacy of BB-1701 at the RD. In both study parts, secondary objectives include assessment of additional efficacy measures (i.e., duration of response [DOR], progression free survival [PFS], overall survival [OS], disease control rate [DCR], clinical benefit rate [CBR], and time to response [TTR]), and pharmacokinetics. Efficacy endpoints will be assessed per RECIST v1.1 by the investigator during the dose-optimization part or by Blinded Independent Central Review during the dose-expansion part. Safety assessments will consist of recording, monitoring, and grading of adverse events (AEs) based on CTCAE v5.0, AEs of special interest, and serious AEs. In both study parts, exploratory objectives will include evaluation of biomarkers of response to BB-1701 and BB-1701 immunogenicity; other efficacy measures (i.e., PFS on the next line of therapy) and population pharmacokinetics will be analyzed in the dose-expansion part only. Pt enrollment is currently open. Clinical trial information: NCT06188559 .

e12641 Background: Many promising agents or combinations regimens relevant to breast cancer lack sufficient clinical information for use in the neoadjuvant setting. To enable acceleration of drug development by reducing time and cost of clinical trial planning and conduct, the Phase I initiative PRE-ISPY Program was created. Methods: The PRE-ISPY Program is built within the I-SPY network, with the overall aim to streamline the regulatory pathway and the processes of trial design, contracting, activation, enrollment, execution, data gathering and analysis, as well as reporting of new therapeutic agents or combinations of relevance to breast cancer. Results: The PRE-ISPY trial is an open-label platform phase IB study designed to evaluate compelling single agent or combination regimens with the overall goal of moving promising drug regimens into I-SPY2 Trial and/or into other oncology-based trials in a timely manner. Graduation of a PRE-ISPY regimen to I-SPY2 is not mandatory. The primary objectives in each study Arm are to determine safety and to obtain preliminary efficacy data of the new regimen in patients with metastatic cancer, including a cohort of breast cancer patients. Each Arm may contain a Part 1 (dose finding) and a Part 2 (dose expansion). The new treatment can be tested also in patients with other solid malignancies than breast cancer, in which the treatment may be applicable, as specified in the design of the Arm. A breast cancer specific cohort is required in Part 2. Candidate treatment regimens are selected with advice from the I-SPY2 Agent Selection Working Group. The PRE-ISPY/Phase IB trial has multiple ongoing drug regimen Arms subsequently added as new protocol appendices through amendments to a Master protocol. There is no randomization; participants are enrolled, and treatment selected according to the relevance of therapy to their disease. Prospective companion biomarkers are evaluated. The current arms under study are PRE1: ALX-148 combined with trastuzumab deruxtecan; PRE2: tucatinib combined with zanidatamab; and PRE3: vidutolimod combined with cemiplimab. Selected agents or therapeutic combinations are tested through this protocol in the I-SPY Network Centers that participate in the PRE-ISPY Program. Toxicities are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Clinical responses are evaluated based on RECIST v1.1 criteria. Conclusions: Once safety is established, promising regimens can be rapidly transitioned to I-SPY 2.2 or other phase 2/3 trials. The first patient was enrolled on 2/1/2023. Clinical trial information: NCT05868226 .

Abstract Background This study aimed to assess the performance of currently available risk calculators in a cohort of patients with malignant peripheral nerve sheath tumors (MPNST) and to create an MPNST-specific prognostic model including type-specific predictors for overall survival (OS). Methods This is a retrospective multicenter cohort study of patients with MPNST from 11 secondary or tertiary centers in The Netherlands, Italy and the United States of America. All patients diagnosed with primary MPNST who underwent macroscopically complete surgical resection from 2000 to 2019 were included in this study. A multivariable Cox proportional hazard model for OS was estimated with prespecified predictors (age, grade, size, NF-1 status, triton status, depth, tumor location, and surgical margin). Model performance was assessed for the Sarculator and PERSARC calculators by examining discrimination (C-index) and calibration (calibration plots and observed-expected statistic; O/E-statistic). Internal–external cross-validation by different regions was performed to evaluate the generalizability of the model. Results A total of 507 patients with primary MPNSTs were included from 11 centers in 7 regions. During follow-up (median 8.7 years), 211 patients died. The C-index was 0.60 (95% CI 0.53–0.67) for both Sarculator and PERSARC. The MPNST-specific model had a pooled C-index of 0.69 (95%CI 0.65–0.73) at validation, with adequate discrimination and calibration across regions. Conclusions The MPNST-specific MONACO model can be used to predict 3-, 5-, and 10-year OS in patients with primary MPNST who underwent macroscopically complete surgical resection. Further validation may refine the model to inform patients and physicians on prognosis and support them in shared decision-making.

e23536 Background: Circulating tumor DNA (ctDNA) has gained prominence as a potential indirect marker for minimal residual disease (MRD) in various cancers, including soft tissue sarcomas (STS). Previous studies have suggested that indirect hematologic ratios – such as Neutrophil-Lymphocyte Ratio (NLR), Monocyte-Lymphocyte Ratio (MLR), Platelet-Lymphocyte Ratio (PLR), and Eosinophil-Lymphocyte Ratio (ELR) may correlate with worse outcomes. We sought to evaluate the correlation of NLR, MLR, PLR and ELR in a real world cohort of Non-Hispanic Whites (NHW) and Hispanics (H) with advanced STS. Methods: We performed a retrospective chart review at Dignity Health Cancer institute using our Electronic Medical Records (EMR) and Signatera™ assay to obtain our data points. Inclusion criteria were STS patients of all ages and stages of disease with complete records. We reviewed 33 patient charts, 14 NHW and 19 H patients. Of the NHW population, 11 were male (M) and 3 females (F). For the H population, 14 were M, and 5 were F. We utilized Spearman's rank correlation coefficient to assess monotonic relationships between ct-DNA levels and the hematologic ratios. ct-DNA was quantified through standardized assays per Protocol, with the resultant values treated as continuous variables in our statistical analyses. Power considerations, based on expected effect sizes and type I error rate adjustments were performed. Results: The Spearman’s correlation coefficients and p-values indicated varied associations across ethnic groups. For NHW, the correlations were generally weak and non-significant (NLR: r = 0.18, p = 0.54; MLR: r = -0.04, p = 0.89; PLR: r = 0.35, p = 0.21; ELR: r = 0.001, p = 1.00). Conversely, in the Hispanic cohort, stronger and statistically significant correlations were observed, particularly with NLR (r = 0.78, p < 0.0001) and MLR (r = 0.70, p < 0.001). Overall, the correlations across the entire study population did not reach statistical significance. Conclusions: This study revealed notable racial variations, particularly in the H population, in the relationship between ctDNA levels and hematologic ratios. The noteworthy associations found with NLR (r = 0.78, p < 0.0001) and MLR (r = 0.70, p < 0.001) highlight the possible usefulness of these ctDNA and these indirect biomarkers in assessing disease status in STS. These findings suggest the possibility of using hematologic ratios, particularly in the Hispanic population, as markers of disease progression similar as ctDNA. Hematologic ratios are more easily accessible to the general population compared to ctDNA in many underserved countries and communities. Future studies with larger cohorts are need to further analyze its validity.

e23535 Background: Our study aims to examine the relationship between the presence of circulating tumor DNA (ctDNA) and lactate dehydrogenase (LDH) in patients diagnosed with soft tissue sarcoma (STS). There is emerging yet limited data on the applicability of ctDNA in STS. LDH is a cheaper readily available test that has been associated with unfavorable overall survival in different malignancies. This research aims to understand the correlation between ctDNA and LDH as a tool to assess its utility as indirect markers of response to treatment in STS. Methods: This was a single-center retrospective chart review on patients diagnosed with STS. Eligibility criteria included a confirmed diagnosis and available measurements of both ctDNA and LDH levels. Correlation was compared between Non-hispanic whites (NHW) and Hispanics (H). Data was sourced from our electronic medical record and Signatera™ assay to obtain the primary endpoints. Specimens were standardized in accordance to Natera’s™ specifications. Study endpoints included the correlation coefficients between ctDNA and LDH levels. A two-stage study design was applied for a robust analysis. Spearman's rank correlation coefficient (denoted as r) was employed for statistical analysis, assessing the strength and direction of the monotonic relationship between ctDNA and LDH levels. Marker values were treated as continuous variables in these analyses. All analyses were executed in GraphPad Prism software. Results: The cohort comprised 33 patients with STS (14 NHW, 19 H). The median LDH in H was 189 (interquartile range (IQR) = 184) vs 184 (IQR = 105) in NHW. Comparatively, the median ctDNA in H was 0 (IQR = 39.3) and also 0 (IQR = 11.1) in NHW. The overall correlation between ctDNA and LDH levels was moderate positive (r = 0.5, p = 0.002), indicating a consistent, though not necessarily linear, relationship. Subgroup analysis showed r = 0.19 (p = 0.52) in NHW and r = 0.43 (p = 0.1) in H groups, suggesting ethnic variability in the ctDNA-LDH correlation. These findings were statistically significant within the predefined confidence limits and probability values. Conclusions: Our study demonstrated a significant correlation between ctDNA levels and LDH in STS patients, implying that higher ctDNA may be associated with higher LDH levels. This association can lead clinicians in monitoring LDH more frequently as an indirect marker of response to treatment in STS. This correlation suggests an increased tumor burden with a higher inflammatory response, with variations across different racial groups. The wider availability of LDH testing compared to ctDNA in many centers highlights LDH's potential as an indirect marker for STS. Further research with larger prospective cohorts is essential to confirm LDH's role paired with ctDNA in guiding treatment decisions in STS, enhancing its utility in clinical practice.

e23534 Background: The use of tumor genomic profile (TGP) has led to improved genomic-directed therapies in many solid cancers. Due to its heterogeneity, soft tissues sarcomas (STS) have not benefited much from these genomic advances. Emerging research indicates that about 30% STS have actionable alterations which can lead to potential treatment options (Gounder et al. Nature 2022). Our study aimed to compare the differences in genomic-directed therapy between Non-Hispanic White (NHW) and Hispanic (H) patients with STS at Dignity Health Cancer Institute. Methods: We performed a retrospective analysis of medical records using the electronic medical record. Our study specifically examined patients diagnosed with STS, with a sample size of 14 NHW and 19 H individuals.The eligibility criteria consisted of known diagnosis of STS with completed TGP. We conducted a descriptive analysis using GraphPad Prism Software, where mutations were evaluated as continuous variables. The statistical significance of differences between groups was assessed using an unpaired t-test, with a significance level of < 0.05. Results: We found 73 tumor alterations, with 11 potentially targetable (15.2%). Most patients had negative to low tumor mutational burden (0-2 mut/Mb) with only 2 patients with high TMB ( > 10 mut/Mb). The most common mutations were TP53 and CDK4 with 9 patients (12%) each. The NHW group had an average of 2.57 mutations (standard deviation = 2.87), whereas the H group had an average of 1.42 mutations (standard deviation = 1.35). The median values were 2 and 1, respectively, with no statistically significant difference (p = 0.21). The average for mutations of unknown significance was 1.54 in NHW individuals, while it was 1.00 in Hispanics. In the NHW group showed 11 males and 3 females, while the H group included 14 males and 5 females. There was no significant difference in gender representation between the two groups (p = 1). 3 patients (9%) received non-FDA approved treatments based on TGP (1 CDKN2A-abemaciclib, 1 CDK4-ribociclib and 1 IDH1-ivosidenib) and 2 patients (6.6%) were enrolled in clinical trials. Conclusions: Our investigation reveals that there is no statistically significant disparity in the frequency of mutations between NHW and H groups in our sample. Nevertheless, there was an evident inclination towards an increased frequency of mutations in NHW. Similarly, the occurrence of mutations with uncertain significance was slightly higher in NHWs, although the difference was not statistically significant. Only a minority of patients had targetable mutations or were enrolled in clinical trials. However, the routine use of genomic profiles may lead to more personalized treatments. Our research emphasizes the need to expand the use of comprehensive genomic profiles to increase directed treatments for patients with STS.

e23533 Background: Circulating tumor DNA (ctDNA) has shown promise as a biomarker for cancer detection and tracking in multiple malignancies like melanoma, colon and lung. Due to the heterogeneity of sarcoma, there has been limited research on ctDNA as a tool for measuring minimal residual disease (MRD). Differences in baseline in ctDNA for STS in racial minorities have been poorly studied. To identify potential racial differences in the efficacy of this tool, this study compares the quantitative values of baseline ctDNA between non-Hispanic white (NHW) and Hispanic (H) patients with soft tissue sarcoma (STS). Methods: The medical records of 33 STS patients who had ctDNA analysis from Natera™ were examined retrospectively at Dignity Health Cancer Institute.There were 19 H patients and 14 NHW patients in the group. All Black (B), Asian (A), and Other (O) racial groups were excluded due to lower numbers. GraphPad Prism software was used to examine the baseline ctDNA levels. Using continuous measures for statistical analysis, we conducted descriptive statistics and determined the mean, standard deviation, and median ctDNA levels for each group. The ctDNA levels were compared between groups using a two-tailed t-test with a significance level of p < 0.05. Results: The average ctDNA levels were 416.675 (standard deviation = 1349.394) in NHW and 300.305 (standard deviation = 1000.543) in H. The median levels were 0 for both groups. The statistical analysis showed that there was no significant differences in the baseline ctDNA levels between the two groups (p = 0.73). Furthermore, the gender distribution among NHW and Hs in the cohort was comparable, with a p-value of 1.00. Conclusions: This study establishes that there is no substantial differences in baseline levels of ctDNA between H and NHW patients with STS. These findings indicate that ctDNA levels in these populations can be equally utilized for diagnostic and monitoring reasons in clinical settings. Nevertheless, to gain a comprehensive understanding of the racial disparities in ctDNA utility and its implications in customized treatment for STS, it is necessary to conduct more extensive research with larger sample sizes and incorporate additional variables.

e23526 Background: Racial, ethnic, and socioeconomic factors have been implicated in the variability of survival rates among soft tissue sarcoma (STS). These disparities are multifactorial and may reflect differences in disease biology, access to care, treatment responses, and others. In situations where different racial groups have equitable access to healthcare, healthcare disparities can decrease, and survival gaps can narrow. Differences in survival in STS in racial minorities have been poorly studied. Recognizing the potential impact of such disparities, our study thereby contributes to the ongoing discourse on healthcare equity in STS outcomes. Methods: We conducted a retrospective analysis of 30 STS patients, stratifying them into Hispanic (H) and non-Hispanic white (NHW) groups at Dignity Health Cancer Institute in Phoenix, Arizona. The Mann-Whitney U test was chosen to compare survival distributions, given the non-normal distribution of our sample. Survival analysis was performed using the Kaplan-Meier method, and the log-rank test was applied to determine statistical significance. All analyses were executed in GraphPad Prism software. Results: Our cohort comprised 13 (43%) NHW and 17 (57%) H patients. The mean ages were 57.2 years for NHW and 48.9 years for H, with a balanced gender distribution across groups. The most common subtypes of STS in NHW were liposarcoma (n = 3, 23.1%), and spindle cell carcinoma (n = 2,15.4%). Comparatively, the most common subtypes of STS in H were liposarcoma (n = 5, 29.4%) and leiomyosarcoma (n = 3, 17.6%). All patients were diagnosed with Stage 4 STS. Treatment modalities differed marginally, with NHW patients undergoing more surgical interventions, while H patients were more frequently administered chemotherapy. Median overall survival from the start of first-line therapy was 412 days for NHW and 500 days for H patients. Despite the longer median overall survival observed in Hispanics, the intergroup difference did not reach statistical significance (P = 0.68). Conclusions: The similar survival times between H and NHW STS patients at our institution may hint at an equitable provision of care across racial demographics in a relatively controlled single-center experience. However, the trend of extended survival in the Hispanic group, while not statistically confirmed, raises questions that merit further inquiry. This study serves as a preliminary exploration into racial disparities in STS, advocating for larger-scale research with more diverse patient populations. Further studies are essential to understand these findings and identify and optimize factors contributing to narrowing the survival gap in minorities, with the goal of enhancing STS prognosis for all racial groups.

Background Coronary microvascular function and hemodynamics may play a role in coronary circulation and myocardial remodeling in patients with aortic stenosis (AS). We aimed to evaluate the relationship between myocardial blood flow and myocardial function in patients with AS, no AS, and aortic valve sclerosis. Methods and Results We included consecutive patients who had resting transthoracic echocardiography and clinically indicated positron emission tomography myocardial perfusion imaging to capture their left ventricular ejection fraction, global longitudinal strain (GLS), and myocardial flow reserve (MFR). The primary outcome was major adverse cardiovascular event (all‐cause mortality, myocardial infarction, or late revascularization). There were 2778 patients (208 with aortic sclerosis, 39 with prosthetic aortic valve, 2406 with no AS, and 54, 49, and 22 with mild, moderate, and severe AS, respectively). Increasing AS severity was associated with impaired MFR ( P <0.001) and GLS ( P <0.001), even when perfusion was normal. Statistically significant associations were noted between MFR and GLS, MFR and left ventricular ejection fraction, and MFR and left ventricular ejection fraction reserve. After a median follow‐up of 349 (interquartile range, 116–662) days, 4 (7.4%), 5 (10.2%), and 6 (27.3%) patients experienced a major adverse cardiovascular event in the mild, moderate, and severe AS groups, respectively. In a matched‐control analysis, patients with mild‐to‐moderate AS had higher rates of impaired MFR (52.9% versus 39.9%; P =0.048) and major adverse cardiovascular event (11.8% versus 3.0%; P =0.002). Conclusions Despite lack of ischemia, as severity of AS increased, MFR decreased and GLS worsened, reflecting worse coronary microvascular health and myocardial remodeling. Positron emission tomography–derived MFR showed a significant independent correlation with left ventricular ejection fraction and GLS. Patients with prosthetic aortic valve showed a high prevalence of impaired MFR.

Aging is a significant risk factor for cardiovascular disease and is known to be associated with an increase in vascular stiffness and decrease in sensitivity to NO mediated vasodilatation. However, the underlying mechanism for these changes in vascular function is unknown. Smooth muscle tone is known to be regulated by the expression and phosphorylation of both nonmuscle (NM) and smooth muscle (SM) myosin. NM and SM phosphorylation is regulated by the activity of myosin light chain kinase (MLCK) and MLC phosphatase. MLC phosphatase is a trimeric enzyme consisting of enzymatic, myosin targeting (MYPT1) and a 20kDa subunit of unknown function. Two isoforms of MYPT1 are produced by alternative mRNA splicing, which differ by the presence or absence of a COOH-terminal leucine zipper (LZ+/-), and the relative expression of LZ+/LZ- MYPT1 determines the sensitivity to NO mediated vasodilatation. We defined NM myosin expression using two-dimensional SDS PAGE and LZ+/LZ- MYPT1 expression using immunoblotting in aortic and tertiary mesenteric smooth muscle from 6mo and 24mo old Fischer344 rats. The data demonstrate that aging is associated with a significant decrease in the expression of both LZ+ MYPT1 and NM myosin. The reduction in LZ+ MYPT1 expression would both decrease the sensitivity to NO mediated smooth muscle dilatation and increase vascular tone, which is a hallmark of the vasculature in aging. On the other hand, the reduction in NM myosin would result in a decrease in vascular tone and could represent a compensatory mechanism to normalize blood pressure during aging. These data demonstrate that there are changes in the expression of smooth muscle regulatory and contractile proteins during aging and these changes in protein expression contribute to molecular mechanism for the decrease in sensitivity to NO mediated vasodilatation as well as the increase in vascular tone or the vascular dysfunction that occurs with aging. Supported by a Mayo CV Prospective Grant (FVB). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.