Citations

e17511 Background: Cervical cancer is a significant public health concern in Sub-Saharan Africa (SSA), where it remains the leading cause of cancer-related mortality among women. SSA has the highest global incidence and mortality rates, with an estimated 110,300 new cases and 76,700 deaths in 2020. Despite this burden, data on patient characteristics and treatment outcomes remain limited. This study aims to address these gaps by analyzing current treatment patterns and outcomes for cervical cancer in SSA. Methods: A cancer dataset was established at 4 major teaching hospitals in Ghana, Kenya, Ethiopia, and Rwanda to capture data on patient demographics, disease characteristics, and treatment modalities. The dataset encompasses all cancer patients seen between 2016-2023, with over 9,000 cases collected to date. The primary objective of the dataset was to assess impact of COVID-19 pandemic on cancer care in SSA. This study conducted a retrospective analysis of cervical cancer cases within the dataset utilizing descriptive metrics. Results: A total of 2,326 patients were analyzed, with a median age at diagnosis of 56 y (48–65) and 53% having health insurance. The majority had squamous cell carcinoma (87%) and presented with locally advanced disease (FIGO stages IIB–IVA, 88%). Treatment primarily consisted of concurrent chemoradiotherapy (CRT, 34%) or radiotherapy (RT) alone (30%), while smaller proportions received chemotherapy (CT) alone (1.2%) or surgery (1.3%). A total of 33% of patients received no cancer therapy. Among 1,524 patients treated with RT, 1,180 received external beam RT with a median dose of 46 Gy in 23 fractions, using 2D planning in 60% and 3D planning in 40% of cases. Additionally, 25 patients underwent brachytherapy, with 58% receiving low-dose-rate and 42% high-dose-rate treatments. Of 1,011 patients treated with CT, 85% (n=844) completed the intended course, with a median of 4 cycles, primarily delivered concurrently with RT (95%). Only a few received CT as adjuvant (4.8%), neoadjuvant (1.6%), or palliative (3.4%) therapy. Platinum-based regimens were most common, with 43% receiving platinum monotherapy and 5% receiving platinum-taxane combinations. By the end of treatment, 27% (n=633) achieved disease-free status. After a median follow-up of 47 months (range,37–55), 42% were alive, 7% had died, and 53% were lost to follow-up with unknown vital status. Conclusions: This study reveals significant challenges in management and follow-up of cervical cancer in SSA. Most patients were diagnosed at advanced stages, with 32% receiving no treatment and 53% of treated patients lost to follow-up. These findings highlight barriers to early diagnosis, treatment access, and continuity of care. Addressing these issues requires expanding early diagnostic services, increasing vaccination coverage, strengthening healthcare infrastructure, and improving patient retention.

3046 Background: Prior work has shown that detection of circulating tumor DNA (ctDNA) at time of diagnosis of leiomyosarcoma (LMS) is associated with lower likelihood of objective response and patients with detectable ctDNA after two cycles of chemotherapy have worse survival. However, because ctDNA exists at much lower concentrations in plasma compared to cell-free DNA of non-tumor origin, the sensitivity of these prognostic measures to tumor signals remains unclear. With increasing evidence of ctDNA fragments being shorter than the background non-tumor cell-free DNA, we sought to test whether restricting our analysis to smaller fragment sizes would improve detection of ctDNA in LMS. Methods: Plasma was serially collected from patients with LMS undergoing chemotherapy. Cell-free DNA extracted from these samples was profiled by ultra-low-passage whole-genome sequencing (ULPWGS). Copy number alterations were identified and used to detect ctDNA using the ichorCNA algorithm before and after restricting the dataset to fragments of 90-150bp (short). We compared detectability of ctDNA via ichorCNA between analyses using all sequencing data and those using data restricted to short fragments. Results: From 28 patients, 126 plasma samples were profiled. The median fragment length of cell-free DNA was 240bp (IQR 142-349) for patients with LMS, compared to 307bp (IQR 171-465, p < 0.001) in samples collected from healthy controls. Short fragments made up 19.48% of LMS libraries at diagnosis when ctDNA levels were highest, 15.27% of all LMS samples, and 12.96% of libraries from healthy controls. While ctDNA was detectable by ULPWGS in 17% of all samples, detection increased to 40% when analyzed using only short cell-free DNA fragments (p < 0.0001). The proportion of diagnostic samples with detectable ctDNA was nominally higher when analyzed by short fragments (39% vs. 64% with 90-150bp size restriction, p = 0.1078, n = 28) and was significantly higher in samples collected after two cycles of chemotherapy (5% vs. 40% with 90-150bp size restriction, p = 0.0197, n = 20). Increases in ctDNA detectability with fragment size restriction were also observed in each of localized and metastatic subgroups (metastatic: 16% without restriction, 38% with restriction, n = 97, p = 0.0012; localized: 17% vs. 45%, n = 39, p = 0.04). Conclusions: Our results demonstrate that detection of ctDNA is improved by analyzing short fragments of cell-free DNA in samples collected from patients with LMS. These findings represent a potential to increase the sensitivity of an affordable, low-coverage liquid biopsy assay and may enhance the prognostic value of ctDNA detection in these patients. Further study of the association between ctDNA detection and outcome is needed to fully validate the impact of fragment size restricted analysis of cell-free DNA samples in patients with LMS and is currently ongoing in a prospective study.

e16237 Background: Alcohol use (AU) and Liver cell carcinoma (LCC) are significant contributors to adult mortality worldwide. Examining trends and disparities in AU and LCC-related deaths is essential for understanding public health challenges and formulating targeted interventions. This study investigates national mortality patterns related to AU and LCC in the United States from 1999 to 2023, emphasizing demographic, geographic, and temporal disparities. Methods: This descriptive analysis used the CDC WONDER database (1999–2023) to identify AU-related deaths (ICD-10 codes E24.4, F10, G32.2, G62.1, G72.1, I42.6, K70, K85.2, K86.0, R78.0, T51, X65, Y15) and LCC (ICD-10 code C22.0) in adults aged 25 and older. Age-adjusted mortality rates (AAMRs) per 1,000,000 individuals were calculated, stratified by gender, race/ethnicity, census region, urban-rural classification, and state. Trends were analyzed using Joinpoint regression to compute annual percent changes (APCs) and 95% confidence intervals (CIs). Statistical significance was set at p < 0.05, and analyses adhered to STROBE guidelines. Results: From 1999 to 2023, a total of 21,007 deaths were attributed to LCC and AU (Men: 18,836 Women: 2,171). AAMRs showed a stable trend from 1999 to 2003 (APC: 0.0; 95% CI: -8.7 to 4.9) but increased significantly from 2003 to 2019 (APC: 6.1; 95% CI: 5.7 to 7.4), stabilizing from 2019 to 2023 (APC: -0.6; 95% CI: -3.2 to 1.3). Men's AAMRs decreased from 1999 to 2003 (APC: -1.1; 95% CI: -10.4 to 3.4), then rose sharply from 2003 to 2019 (APC: 6.1; 95% CI: 5.6 to 7.1). For women, AAMRs increased significantly, particularly between 2013 and 2017 (APC: 12.4; 95% CI: -9.5 to 25.1). Non-Hispanic Black and White populations experienced notable increases in AAMRs, while Hispanic people showed an initial decline followed by an increase post-2004 (APC: 4.7; 95% CI: 3.7 to 7.9). The West had the highest regional AAMR (5.3; 95% CI: 5.2 to 5.5), while the Northeast recorded the lowest (2.1; 95% CI: 2.0 to 2.2). New Mexico had the highest state AAMR (8.4; 95% CI: 7.4 to 9.4), and Mississippi the lowest (1.2; 95% CI: 0.9 to 1.5). AAMRs rose more sharply in non-metropolitan areas from 1999-2020 (APC: 6.6; 95% CI: 5.9 to 7.8) compared to metropolitan regions from 2004 to 2020 (APC: 5.4; 95% CI: 4.9 to 6.5). Conclusions: AU and LCC-related mortality rates have increased significantly since 2003, with distinct gender, racial, and geographic disparities. Men and rural populations faced higher mortality increases, with notable variations across states and regions. These findings underscore the need for focused public health efforts to mitigate these disparities and address the growing burden of LCC and AU-related mortality.

e16167 Background: Guidelines recommend systemic therapy for uHCC ineligible for locoregional therapy. Until the approval of tremelimumab + durvalumab for uHCC, in Oct 2022, 1L systemic therapies in the US included multikinase inhibitors and atezolizumab (A) + bevacizumab (B). It is crucial to understand factors driving real-world treatment decisions and outcomes in uHCC. Methods: Data were collected from electronic medical records from US Mayo Clinic sites. Pts with uHCC who initiated a 1L systemic therapy between Jun 2020–Oct 2022 (A + B was the only approved 1L immunotherapy (IO)-based regimen) with ≥2 follow-up visits, were included. Index was the date of first 1L systemic therapy. Pts were assessed by risk of post-index gastrointestinal (GI) bleeding (Child-Pugh class B or C, pre-index GI bleeding, uncontrolled hypertension [HTN] [≥2 anti-HTN drugs or ≥2 vital entries of SBP > 140 mmHg or DBP > 90 mmHg]), or significant varices and band ligation). Treatment patterns, overall survival (OS), and post-index GI bleeding were assessed. Results: A total of 186 pts met the inclusion criteria. Most common etiologies of liver disease were MASH (42.7%) and hepatitis C virus (40.2%). Pre-index GI bleeding was reported in 29.0% of pts, of which 46.3% occurred within 6 months (mo) pre-index; 62.4% of pts had EGD, of which 72.4% had varices. There were 128 (68.8%) pts with GI bleeding risk and 58 (31.2%) pts without GI bleeding risk. The most common 1L systemic therapies for pts with GI bleeding risk were A + B (72.7%) and A only (9.4%), while for pts without GI bleeding risk, A + B (29.3%), nivolumab + ipilimumab (13.8%), and B + chemotherapy (12.1%) were the most common. Median OS and OS rates at 12, 18, and 24 mo were lower, and post-index GI bleeding rate was higher in pts with vs without GI bleeding risk (Table). For pts treated with A + B, median OS and OS rates at 12, 18, and 24 mo were lower in pts with vs without GI bleeding risk (Table). Conclusions: In this network, prior to the approval of other 1L IO-based regimens for uHCC, many pts received A + B, despite risk of post-index GI bleeding. Median OS with A + B was shorter in pts with vs without GI bleeding risk. Data highlight the complexity of uHCC and the unmet need for guidance on characteristics-driven treatment decisions. © 2025 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2025 ASCO Gastrointestinal Cancers Symposium. All rights reserved. Table. Full cohort A + B cohort All ptsN=186 GI bleeding risk N=128 No GI bleeding risk N=58 All pts N=110 GI bleeding risk N=93 No GI bleeding risk N=17 Median follow-up, mo 20.6 20.9 20.4 21.3 21.6 20.3 Median OS, mo 14.4 11.4 40.3 13.9 12.8 Not reached OS rates, % 12 mo 55.2 48.9 68.9 55.2 52.3 70.6 18 mo 45.3 38.1 61.1 44.1 41.6 57.8 24 mo 39.4 31.8 56.8 37.1 34.6 51.3 Post-index GI bleed, % 17.2 23.4 3.4 17.3 19.4 5.9

e16157 Background: The optimal treatment for resectable gastric/GEJ AC is unclear due to limited direct comparisons among chemotherapy and chemoradiation regimens. Addressing this gap is critical to improve patient outcomes. We performed this network meta-analysis (NMA) to determine the relative efficacy of multimodality regimens for resectable gastric/GEJ AC. Methods: MEDLINE, EMBASE, Scopus, and CENTRAL were searched from inception till September 20, 2024, to identify phase III trials evaluating perioperative/neoadjuvant systemic therapy ± radiation in resectable gastric/GEJ AC. Primary outcomes were disease-free survival (DFS) and overall survival (OS). A frequentist NMA was conducted to compare hazard ratios (HR) and 95% CI for each outcome. Relative treatment rankings were assessed using P-scores. Results: Fifteen trials (8,072 patients) were analyzed. pFLOT (perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel) ranked highest for DFS in the overall population (P score 91%) (Table), significantly outperforming surgery alone (HR 0.48, 95% CI 0.38-0.60) and nCROSS (neoadjuvant paclitaxel, carboplatin and radiotherapy) (0.67, 0.56-0.81). For OS, nPLF+nCRT(EP) (neoadjuvant cisplatin, leucovorin and fluorouracil for induction, followed by etoposide, cisplatin, and radiotherapy) (P score 90%) and pFLOT (P score 87%) were the top regimens, with pFLOT significantly outperforming surgery alone (0.57, 0.45-0.72), and nCROSS (0.73, 0.60-0.89). Adding neoadjuvant chemoradiation to pFLOT provided no additional OS (1.14, 0.76-1.72) or DFS (1.22, 0.83-1.82) benefit. Similarly, adding pembrolizumab to perioperative chemotherapy (CF/CX) (cisplatin and fluorouracil/capecitabine) was not superior to pFLOT in terms of DFS (1.10, 0.71-1.69) or OS (1.09, 0.69-1.72). Conclusions: pFLOT demonstrated superior efficacy in resectable gastric/GEJ AC, surpassing surgery alone, nCROSS, and other perioperative regimens. The additive role of immunotherapy to pFLOT requires further investigation to refine patient selection and optimize outcomes. Regimen Overall Population GEJ cohort OS DFS OS DFS nPLF+nCRT(EP) 1 (90) 2 (84) 1 (85) NA pFLOT 2 (87) 1 (91) 2 (79) 2 (88) pPembrolizumab+CF/CX 3 (75) 3 (81) 5 (41) - nECX 4 (61) 5 (55) - - pCF 5 (59) 8 (51) 3 (72) - pECF/ECX 6 (47) 6 (55) 7 (40) 3 (57) nECX+aCRT(CX) 7 (45) 7 (52) 9 (31) - nCF 8 (42) 10 (28) 6 (40) - nCROSS 9 (41) 9 (35) 8 (34) 4 (43) pECF/ECX/FLOT+nCRT(F/X) 10 (38) 4 (57) 4 (72) 1 (90) nCRT(CF) 11 (9) 11 (6) - 5 (14) Surgery 12 (7) 12 (5) 10 (5) 6 (9) Data reported as rank (P-score). Abbreviations: n: neoadjuvant; p: perioperative; ECX: epirubicin + cisplatin + capecitabine; CF: cisplatin + fluorouracil; ECF: epirubicin + cisplatin + fluorouracil; aCRT(CX): adjuvant radiotherapy + cisplatin + capecitabine; CRT(F/X): fluorouracil/capecitabine + radiotherapy; CRT(CF): cisplatin + fluorouracil + radiotherapy.

e12615 Background: Breast MRI after completion of neoadjuvant chemotherapy (NAC) has demonstrated high sensitivity and positive predictive value in evaluating response to NAC. It is widely recognized as the most accurate imaging technique for assessing tumor response, outperforming mammography and ultrasound. However, there remains a knowledge gap in its potential as an early predictor of pathological response, when performed at the midpoint of NAC. Here, we investigated the correlation between MRI findings at the midpoint of NAC and subsequent pathological response at definitive surgery. Methods: A retrospective study was performed of patients with breast cancer who received NAC at Mayo Clinic, Florida and had at least 2 breast MRIs, one at midpoint and one either pre- or post-treatment. Patients with prior ipsilateral breast cancer were excluded. Participants were stratified into three molecular subtypes: hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative breast cancer (TNBC). All MRIs were re-reviewed by dedicated breast radiologists, with tumor response classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) based on RECIST criteria. Pathological outcomes, including pathologic complete response (pCR) and residual cancer burden (RCB), were extracted from pathology reports and confirmed by a single breast pathologist, as indicated. pCR was defined as the absence of residual invasive tumor in both the breast and axillary lymph nodes. Results: A total of 154 patients met inclusion criteria from 2012 to 2022. Similar to previous studies, the positive predictive value for the post-treatment MRI was high at 82.4%, with 14 of 17 patients with imaging complete responses (iCR) achieving pCR. For the midpoint MRI, the positive predictive value for patients with iCR was 100%, with 8 out of 8 patients achieving pCR. Patients with certain subtypes of breast cancer with at least PR in both breast and axillary lymph nodes at midpoint MRI had numerically higher pCR rate, specifically HER2+ (22/37, 59.5%) and TNBC (8/13, 61.5%) but not HR+ tumors (12/45, 26.7%). In contrast, patients with less than PR in either breast or axillary lymph nodes showed numerically lower rate pCR in TNBC (7/18, 38.9%) and HR+ tumors (3/18, 16.7%). However, 15/23 (65.2%) patients with HER2+ tumors achieved pCR despite having less than PR at midpoint MRI. Conclusions: Midpoint breast MRI may serve as an early predictor of pathological response, particularly in patients with iCR. Patients with less than PR, especially those with HR+ and TNBC, have lower chances of achieving pCR. These findings highlight the importance of considering additional therapies for these subgroups of patients to improve the treatment outcomes, as they are less likely to achieve pCR with the current standard neoadjuvant chemotherapy regimen.

e23317 Background: mCRC poses significant challenges, particularly in patients (pts) who progress after multiple lines of therapy. Limited effective treatment options are available in the advanced chemotherapy-refractory setting. The FRESCO-2 trial demonstrated that Fruq, a selective VEGFR inhibitor, provides meaningful overall survival (OS) benefit in pts with refractory mCRC. However, there is limited real-world evidence regarding Fruq's efficacy in patients treated after approved third-line therapies. Methods: This retrospective, multi-site cohort study evaluated outcomes in 33 mCRC pts who received Fruq following treatment with Rego and/or TAS-102 with or without bevacizumab. Patients were stratified into two groups: Fruq as a second late-line therapy, after either Rego or TAS-102, (27 patients) and as a third late-line therapy, after both Rego and TAS-102, (6 patients). Overall survival (OS) was calculated from Fruq initiation to death, while time to treatment discontinuation (TTD) was defined as the duration from Fruq initiation to cessation for any reason, including death. Survival analysis was performed using the Kaplan-Meier method to estimate median survival, and the comparison between groups were done using the log-rank test. Results: Among the 33 pts, the median age was 58 years (range: 35–84), with 57.6% being male. Hepatic metastases were present in 78.8%, and 60.6% had left-sided primary tumors. RAS mutations were observed in 63.6%, and 97% were BRAF wild-type. Median OS was significantly longer in pts who received Fruq as a second late-line therapy (7.2 months) compared to those receiving it as a third late-line therapy (4.0 months) (p = 0.039). Median TTD was similar between groups (2.4 vs. 2.8 months, p = 0.916). Conclusions: This real-world analysis highlights the clinical benefit of Fruquintinib in mCRC patients following treatment with Regorafenib and/or TAS-102. The data suggest flexibility in treatment choices, with Fruquintinib showing improved OS when used earlier in the treatment sequence. These findings underscore the importance of exploring optimal sequencing strategies and evaluating Fruquintinib as a potential option before other approved agents in the refractory setting. Clinical outcomes with fruquintinib as second vs. third late-line therapy. Fruq as Second Late-Line Fruq as Third Late-Line p-value Median OS 7.2 months 4 months 0.039 Median TTD 2.4 months 2.8 months 0.916 OS: Overall Survival; TTD: Time to Treatment discontinuation.

e23316 Background: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor, prevents the degradation of HIF and promotes erythropoiesis. It was recently approved by the United States Food and Drug Administration (FDA) for the treatment of chronic kidney disease (CKD) associated anemia. This systematic review and meta-analysis aims to compare the efficacy of daprodustat and the standard recombinant human erythropoietin therapy (rhEPO) in the management of CKD-associated anemia among patients on dialysis. Methods: This study followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. A comprehensive literature search was performed, using relevant key terms. over PubMed/Medline, Cochrane Library, Google Scholar, and clinicaltrials.gov from inception to 15th January 2025. Only randomized clinical trials comparing the impact daprodustat relative to the standard rhEPO therapy among CKD patients on dialysis were included. The analysis was conducted using Comprehensive Meta-analysis Software via a random effect model. Results: Our preliminary search revealed 1375 articles. Following comprehensive screening, five articles, with 3940 participants, were considered eligible for inclusion. Among participants, 2132 were randomized to the intervention arm and 1808 to the control group. Mean change in hemoglobin from baseline was reported by all five studies and pooled comparison revealed non-inferiority among the two treatments (Std diff: -0.072; SE: 0.123; p-value:0.557) with a high heterogeneity (I 2 = 80.196%). The second outcome, adjusted treatment difference, was reported by three studies and again no treatment was found to be inferior to each other (Std diff: 0.112; SE: 0.091; p-value:0.217), with moderate heterogeneity (I 2 = 69.790). Conclusions: Daprodustat demonstrates non-inferiority to standard rhEPO therapy for the management of CKD-associated anemia in patients undergoing hemodialysis. Pooled effect size for change in hemoglobin from baseline. Study name Statistics for each study Author, Year Std diff in means Standard error Variance Lower limit Upper limit Z-Value p-Value Holdstock et al. 2016 (0.5 mg) -0.988 0.348 0.121 -1,671 -0.305 -2.836 0.005 Holdstock et al. 2016 (2 mg) -0.834 0.343 0.118 -1.507 -0.162 -2,433 0.015 Holdstock et al. 2016 (5 mg) 0.236 0.335 0.112 -0.420 0.893 0.706 0.480 Meadowcrot et al. 2018 0.124 0.178 0.032 -0.224 0.472 0.698 0.485 Akizawa et al. 2020 0.000 0.122 0.015 -0.240 0.240 0.000 1.000 Singh et al. 2021 0.234 0.037 0.001 0.162 0.306 6.342 0.000 Coyne et al. 2022 -0.080 0.105 0.011 -0.286 0.126 -0.763 0.446 Combined -0.072 0.123 0.015 -0.312 0.168 -0.587 0.557

3040 Background: EVEREST-2 is a first-in-human, phase 1/2 trial to assess the safety and efficacy of A2B694, an autologous, logic-gated Tmod CAR T therapy targeted to MSLN, which is normally expressed in the mesothelium and can be upregulated in many solid tumors. A2B694 is designed to overcome challenges of on-target, off-tumor toxicity that have limited other MSLN-targeted approaches by combining a CAR-activating receptor targeting MSLN with a blocker CAR that recognizes HLA-A*02, to distinguish between normal and tumor cells (Tokatlian, et al. J Immunother Cancer. 2022). Methods: Adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression who have progressed after standard-of-care therapy are eligible for EVEREST-2. Enrollment to EVEREST-2 and collection of T-cells occurs through the ongoing prescreening study BASECAMP-1 (NCT04981119). When clinically appropriate, A2B694 is manufactured from cryopreserved T cells, and patients undergo lymphodepletion before A2B694 infusion. The dose-escalation phase is evaluating the safety and tolerability of A2B694 to identify the recommended phase 2 dose (RP2D). Dose escalation was started at 1x10 8 Tmod positive cells (dose level [DL] 1) and will increase up to 14x10 8 in combination with low-dose IL-2 (DL 5). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Results: As of January 15, 2025, 5 participants (median age: 60 years; range, 50-84) have enrolled on EVEREST-2 and received A2B694 at DLs 1-2; participants had ovarian cancer (n = 3), pancreatic cancer (n = 1), and non-small cell lung cancer (n = 1) and had received a median of 4 prior lines of therapy (range, 1-7). Lymphodepleting chemotherapy was well tolerated with no significant cytopenias observed. The most common adverse events were lymphopenia (7 [14.6%]) and decreased appetite (6 [12.5%]). There were no dose-limiting toxicities, cytokine release syndrome, nor related neurotoxicity. One participant was admitted to the hospital for decreased appetite. No long-term toxicities have been noted up to 7.5 months post-infusion. Of the participants who have received A2B694, 5 were efficacy evaluable at DLs 1-2. A2B694 was detected post-infusion in the peripheral blood in all patients. Additionally, A2B694 was detected in an abdominal tumor biopsy from a patient with pancreatic cancer 42 days post-infusion. Conclusions: The logic-gated approach was successful at reducing toxicity seen with prior MSLN-targeted CAR T therapies, and A2B694 showed successful CAR T expansion and tumor infiltration. The maximum tolerated dose has not been reached, and results from the dose-escalation phase continue to determine the RP2D. Clinical trial information: NCT06051695 .

3008 Background: Numerous studies have demonstrated the prognostic value of ctDNA analysis after neoadjuvant chemotherapy for early-stage high-risk breast cancer. Few studies have characterized ctDNA in pts receiving NET for early-stage hormone receptor positive (HR+)/HER2- BC that is predicted to benefit less from chemotherapy. Methods: Cell-free DNA (cfDNA) was isolated from 432 plasma samples from 108 pts enrolled in the I-SPY2 EOP trial. Pts had Stage 2/3 HR+/HER2-, MammaPrint low or high risk 1 BC. Pts were randomized to one of 7 neoadjuvant-based treatment arms including arms containing AI, Z-endoxifen, Lasofoxifene, vepdegestrant (ARV-471), and Abemaciclib. Pts were treated for 6 months prior to surgery. Blood was collected at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). A personalized ctDNA test (Signatera) was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The chi-square test was used to assess associations between categorical variables, and the Wilcoxon rank-sum test was used to evaluate differences in medians. Results: ctDNA information was available for 101 patients at baseline (T0) (Table 1). At T0, 36 (35.6%) patients were ctDNA-positive. 23/36 (63.9%) became ctDNA-negative and 13/36 (36.1%) remained ctDNA-positive. At T0, 65/101 patients (64.4%) were ctDNA-negative. Of these, 57 (87.7%) remained negative, while 8 (12.3%) became ctDNA-positive at T1 before reverting to ctDNA-negative. A higher percentage of ctDNA-positive patients at T0 were cN+ compared to ctDNA-negative pts (p = 0.036, 64% vs. 40%). Additionally, ctDNA-positivity at T0 was strongly associated with higher Ki67 (p = 0.03) and larger functional tumor volume by MRI at baseline (p = 0.03). T3/T4 and high-grade tumors at baseline were also associated with having ctDNA positivity at baseline, though this was not statistically significant (p = 0.34 and 0.058, respectively). Conclusions: In this study of pts with Stage 2/3 HR+ HER2- BC with largely MammaPrint low risk signatures, over one-third of pts had detectable ctDNA at baseline. Detectable ctDNA at baseline was associated with cN+ disease, larger FTV, and high baseline Ki67. The majority of pts with positive ctDNA at baseline cleared the ctDNA on NET. Clinical trial information: NCT01042379 . Clinicopathologic characteristics of EOP patients. All Patients(N=101) Age at screening 55 (27-80) years* Clinical N Stage Node+ (cN+) 49 (48.5%) Node- (cN-) 52 (51.5%) SET status High 84 (83.2%) Low 14 (13.9%) Missing 3 (2.97%) MammaPrint (MP) risk** High risk 1 (H1) 15 (14.9%) Low risk 86 (85.1%) *Mean(min-max). **H1: MP score between 0 and -0.57; low: MP score between 0 and 0.355.