While peripheral blood hematopoietic stem cell transplantation (PB-HSCT) supports rapid engraftment and reduces graft failure risk in aplastic anemia (AA) patients, it compromised higher risk of acute graft-versus-host disease (aGVHD), highlighting the need for more effective prophylactic strategies. This phase II clinical trial was designed to assess the efficacy and safety of ruxolitinib, a JAK1/2 inhibitor, as part of GVHD prophylaxis regimen following PB-HSCT. This open-label, single-arm, Phase II clinical trial (ClinicalTrials.gov: NCT05914714) enrolled patients with AA between June 2023 and December 2024. Ruxolitinib was initiated at the start of conditioning and continued for 3months post-transplant at a dose of 5mg twice daily. A historical control cohort receiving standard GVHD prophylaxis between January 2019 and May 2023 was included for comparison. To address baseline imbalances, propensity score-based inverse probability of treatment weighting (IPTW) was applied. The primary objective was the incidence of aGVHD six months after HSCT. Secondary endpoints included one-year overall survival (OS) and GVHD-free, failure-free survival (GFFS). Immune reconstitution-including T cells, B cells, NK cells-and levels of pro-inflammatory cytokines were also evaluated to explore potential mechanisms. A total of 82 patients were enrolled (ruxolitinib group n = 46, historical control cohort n = 36). Comparative analysis showed that ruxolitinib significantly reduced the cumulative incidence of grade II-IV aGVHD (HR 0.24; p = 0.004) and severe aGVHD (0% vs 15.8%; p = 0.008) compared with the control group. At a median follow-up of 417days (range: 112-725), the ruxolitinib group demonstrated significantly superior 1-year GFFS (91.6% vs. 72.1%; HR 0.23, weighted log-rank p = 0.012). Notably, the ruxolitinib group not only exhibited more rapid recovery of CD4 + Tregs at 3months post-HSCT. Notably, but also suppressed proinflammatory cytokine levels during engraftment. The peri-transplantation addition of ruxolitinib to the standard GVHD prophylaxis regimen in PB-HSCT for AA patients has shown to be a safe and effective approach to reducing both the incidence of aGVHD, while improving patient outcomes. Our study suggests that ruxolitinib may offer a promising strategy for improving survival and immune recovery. Trial registration clinicaltrials.gov identifier: NCT05914714.

Adequate lymph node sampling is essential for accurate staging and treatment planning in Wilms tumour. Both SIOP and COG protocols recommend sampling more than six lymph nodes. However, median retrieval rates remain low in both open and minimally invasive approaches. This study aimed to assess the feasibility, safety, and efficacy of intraoperative indocyanine green (ICG) fluorescence imaging for sentinel lymph node (SLN) identification in paediatric renal tumours and to contribute to the standardization of dosage and timing protocols. A two-centre prospective study (2023-2025) was conducted in Wrocław and Gdańsk involving 20 paediatric patients undergoing nephron-sparing surgery (n = 14) or nephrectomy (n = 6) for renal tumours with ambiguous lymphatic drainage. ICG (0.2ml of a 5mg/ml solution) was injected into four sites of healthy renal parenchyma, 1-2cm from the tumour margin, after kidney exposure and before vascular pedicle preparation. Near-infrared (NIR) imaging (Stryker) was used to visualise lymphatic drainage and sentinel nodes. Twenty children were included (median age 3 years, IQR 1.75-5.00). The median number of lymph nodes retrieved was 4 (IQR 3-6), with a median of 3 fluorescent nodes (IQR 1.5-4.5). Sentinel lymph node visualisation was successful in six cases (one benign renal cyst and five nephroblastomas) and failed in chromophobe carcinoma and renal cell carcinoma. No ICG-related adverse events were observed. The number of lymph nodes retrieved did not differ significantly between nephron-sparing surgery and nephrectomy; however, a higher number of fluorescent nodes was observed in the nephron-sparing group (median 3.5 vs. 1.0; p = 0.0757). Compared with historical controls, the ICG-guided cohort demonstrated a significantly higher lymph node yield (median 4.0 vs. 3.0; p = 0.00468). Operative time was significantly longer in the ICG group (median 130.5min [IQR 114.5-145.0] vs. 109.5min [IQR 91.0-112.5]; p = 0.00513), likely reflecting the initial learning curve associated with adoption of the technique. ICG fluorescence imaging is a promising adjunct for SLN mapping in paediatric renal tumours. Standardisation of injection protocols is required to improve reproducibility. The technique is safe, feasible, and may improve staging accuracy while reducing the need for repeat surgeries.

Background: Flanders (Belgium) offers a fecal immunochemical test (FIT) biennially to citizens aged 50–74 years, but uptake is suboptimal (~50%). This study evaluated the impact of a second e-reminder on FIT uptake. Methods: We conducted a quasi-experimental study comparing FIT uptake in individuals who received a first e-reminder during June 2023–May 2024 and a second e-reminder five weeks later (intervention cohort) with those who received a first e-reminder in June 2021–May 2022 without a second reminder (historical control). The study outcome was FIT uptake within one year after the first e-reminder. Analyses were stratified by screening history (regular vs. irregular participants). Results: The study population consisted of 54,734 regular (27,522 control and 27,212 intervention); and 18,492 irregular participants (8565 control and 9927 intervention). Median age was slightly lower in the intervention group (regular: 57 vs. 59 years; irregular: 62 vs. 64 years). Gender distribution was balanced (≈50% men). Regular participants receiving a second e-reminder had 80% higher probability of participation than controls (OR 1.80; 95% CI 1.73–1.86; p < 0.0001); with uptake increasing from 29.5% to 43.7%. Irregular participants with a second e-reminder had a 91% higher probability of participation compared with no second e-reminder (OR 1.91; 95% CI 1.74–2.09; p < 0.0001), with uptake increasing from 9.4% to 18.4%. Conclusions: A second e-reminder significantly increased FIT uptake among both regular and irregular participants in the Flemish colorectal cancer screening program. These findings support its use as a low-cost strategy to improve population-level screening participation.

Introduction: Cephalomedullary nailing is a standard treatment for intertrochanteric fractures, typically performed on a fracture table with traction released before fracture site compression. However, releasing traction requires additional assistance, may prolong the procedure, and could adversely affect fracture alignment. This study evaluates the effectiveness of maintaining continuous traction during intraoperative compression of inter- and pertrochanteric femur fractures, comparing outcomes to the traditional approach involving traction release. Materials and Methods: In this retrospective study, patients with AO/OTA 31A1 and 31A2 fractures treated with cephalomedullary nailing were divided into two groups: one with traction maintained during compression (experimental), and a historical control with traction released before compression. All procedures were performed on a fracture table under longitudinal traction. Intraoperative fluoroscopy was used to measure fracture site compression. Postoperative radiographs were analyzed to assess femoral neck shaft angles as a marker of reduction quality. Results: Average fracture site compression was significantly greater in the traction-maintained group (7.4 mm, 95% CI 6.4–8.4) compared with controls (2.1 mm, 95% CI 1.5–2.7; P <0.001). Neck shaft angles were also increased in the experimental group (131.8°, 95% CI 130.9–132.6) versus the control group (127.7 degrees, 95% CI 126.3–129.2; P <0.001). Discussion: Maintaining traction throughout cephalomedullary nailing, including during fracture compression, is a simplified and effective technique that results in improved fracture compression and alignment compared with standard practice.

Outcomes in extremely preterm neonates after the introduction of early low-dose hydrocortisone treatment: A retrospective case-control study.

Plantar warts are challenging to treat and often recur despite standard therapies. While cryotherapy is effective for their treatment, data on cryotherapy spray techniques are limited, especially in Saudi Arabia. We assessed the efficacy of cryotherapy spray techniques for treating plantar warts, emphasizing cure rates, treatment duration, and side effects. In this single-center comparative before-after study, patients with plantar warts treated using a standardized cryotherapy spray protocol in a dedicated cryotherapy clinic (case group) were compared with a historical control group treated with nonstandardized cryotherapy methods before implementation of the protocol. Control patients were retrospectively identified from medical records and met the same inclusion and exclusion criteria as the case group. We compared cure and recurrence rates, treatment duration, number of treatment sessions, and adverse effects between groups. The standardized cryotherapy spray technique achieved a cure rate of 96.8% and a recurrence rate of 6.5%, compared with 87.9% and 18.2%, respectively, in the control group. Although cure and recurrence rates were numerically more favorable in the case group, these differences were not statistically significant in this small sample. In contrast, the standardized technique was associated with a significantly shorter treatment duration (P = .001), fewer treatment sessions (P < .001), and a lower incidence of pain and erosion (P = .035) than the nonstandardized methods used in the control group. Cryotherapy treatment sessions should be based on the recommended technique in this study, which is a safer, evidence-based method for treating plantar warts, with shorter treatment durations and lower recurrence rates compared to using uncertain cryotherapy methods. Larger, controlled studies are needed to confirm these findings and further define the optimal cryotherapy technique for plantar warts.

Objective: This pilot study explored the feasibility of implementing 3D-printed assistive devices in a hospital-based stroke rehabilitation setting. Methods: Feasibility was evaluated across four domains: acceptability, demand, implementation, and limited efficacy testing. Data were collected from both users and providers. Stroke survivors in the intervention group (n = 15) received a 3D-printed assistive technology intervention emphasising user-centered design and user-provider collaboration. Historical controls (n = 31) receiving usual care were identified from medical records. Propensity score matching generated nine matched pairs for comparison. User outcomes included the Functional Independence Measure (FIM) and the Vitality Index (VI), while occupational therapists’ perspectives (n = 10) as providers were assessed using the Japanese version of the modified Technology Acceptance Model questionnaire for 3D-printing technology (TAM-J). Results: Good acceptability was demonstrated, as all stroke survivors in the intervention group consistently used 3D-printed assistive devices in daily activities, and occupational therapists reported positive technology acceptance on the TAM-J. Strong demand was observed among stroke survivors with moderate to severe upper-extremity impairment. Regarding implementation, there were no dropouts, and user-centered devices were adopted through user-provider collaboration. In limited efficacy testing, no additional improvements in the FIM and VI scores were observed compared with controls. However, the intervention helped stroke survivors address their daily challenges. Conclusion: These findings suggested that integrating 3D-printed assistive devices into clinical workflows could be feasible. Future research needs to employ sensitive, user-centered outcome measures and collaborate with designers or rehabilitation engineers to improve the efficiency and quality of device development.

ABSTRACT Background School choice is framed in global education policy as a mechanism for enabling equitable access to schools. However, research shows that choice is often shaped by racialised, class-based and spatial inequalities. In South Africa, historical state control and its enduring apartheid legacies continue to inform how school choice is practised. Although studies have focused on parental decision-making, there is limited empirical research examining school choice as an agential process involving both parents and teachers navigating a stratified public schooling system. Purpose This article examines how racial, economic, and geographical factors continue to structure school choice in an urban town in South Africa (Stellenbosch), despite post-apartheid reforms aimed at educational equality. It positions that there are few studies in the country that prioritise parents’ and teachers’ agency in the school choice debate. It is essential to consider their perspectives in tangent to each other to understand the embedded racial, economic and spatial reasoning that guides their decision-making around school selection. Method The study made use of qualitative evidence from 11 semi-structured interviews conducted across three High Schools in the town of Stellenbosch, South Africa with parents and teachers. The schools were categorised as either fee paying or no-fee paying. The data were analysed thematically. Findings Parents’ decisions to select schools were influenced by the school’s reputation, wherein they considered safety, resources, discipline, and the symbolic power of historically privileged schools in white and coloured neighbourhoods. Teachers viewed public schooling as an enabling space to support learners to facilitate community upliftment. These divergent but connected forms of agency reflected and responded to the practice of school choice while navigating historical and contemporary inequalities. Conclusion By focusing on parents’ and teachers’ agency in understanding the process of school choice, this research offers an understanding of how educational inequalities persist and are resisted by these two stakeholder groups. School choice practice in Stellenbosch challenges traditional perceptions of schools in township and suburban areas and reframes a social justice analysis where parents and teachers are regarded as informed and engaged in shifting what school choice means in the town and broadly in the country.

Prenatal wildfire smoke exposure and adverse neonatal outcomes in a high-risk cohort of pregnant women with asthma.

At present, no clinical guidelines have been established regarding the use of radiofrequency ablation (RFA) for early stage breast cancer. The Radiofrequency Ablation Therapy for Early Breast Cancer as Local Therapy (RAFAELO) study aimed to assess the efficacy and safety of RFA as an alternative to partial mastectomy in patients with early stage breast cancer. This study was a multicenter, single-arm, phase 3 study. Female patients with a single breast cancer classified as Tis-T1 (tumor size ≤1.5 cm), N0M0 Stage 0-I underwent treatment RFA. All patients then received radiation therapy totaling 45-60 Gy. The primary endpoint was the 5-year ipsilateral breast tumor recurrence-free survival (IBTRFS) rate. The threshold for a clinically unacceptable 5-year IBTRFS rate was set at 90% with a one-sided alpha of 5%. A total of 370 patients underwent RFA and 353 patients (median [IQR] age, 55 [47-65] years) completed the 5-year follow-up. For the primary endpoint, the IBTRFS rate at 5 years was 98.6% (90% CI 97.1-99.3%, 95% CI 96.6-99.4%). The lower limit of the 90% CI was greater than the threshold of 90%, suggesting the noninferiority of RFA to historical control partial mastectomy. During the study, two recurrences were observed in the ipsilateral breast. Skin ulceration grade ≥3 was observed in just one of the 370 patients. RFA was shown to be a safe and minimally invasive treatment for early stage breast cancer, comparable in efficacy to partial mastectomy.

Abstract Background. Luminal B HER2-negative breast cancer (BC) is an aggressive subtype with lower chemosensitivity than HER2-positive or triple-negative disease. Standard neoadjuvant chemotherapy (NCT), consisting of doxorubicin-cyclophosphamide (ACq21 or ddACq14) followed by weekly paclitaxel, yields a pathological complete response (pCR) in approximately 20% of patients, which is significantly lower than in other subtypes. Dose-dense (dd) chemotherapy has been shown to improve outcomes in high-risk BC and even in hormone receptor-positive/HER2-negative patients. Paclitaxel can be delivered weekly, biweekly (dose-dense) or every 3 weeks. Evidence suggests that more frequent (weekly or biweekly) paclitaxel dosing improves long term outcomes compared to 3-week schedule. However, no prospective studies have directly compared weekly and biweekly paclitaxel schedules in luminal B early BC. This exploratory trial aims to detect clinically meaningful differences in efficacy of a biweekly paclitaxel schedule supported by empegfilgrastim in comparison to historical weekly paclitaxel and provide early data to inform the planning of a future phase III trial. Aim. To determine whether a biweekly paclitaxel regimen is not inferior in efficacy (as measured by pCR rate) to the standard weekly paclitaxel regimen in patients with luminal B HER2-negative early or locally advanced BC receiving NCT. Study Design. Prospective, single-center, open-label, non-inferiority phase II trial using historical control. Patients in the intervention group will be treated prospectively and compared to a historical cohort treated with weekly paclitaxel. Matching will be performed in a 1:3 ratio using key clinical and pathological variables (age, clinical stage, Ki-67, tumor grade, ER and PR expression). Population. Eligible patients are adult women (≥18 years) with histologically confirmed luminal B breast cancer, defined as estrogen receptor (ER≥1%) positive, HER2-negative tumors with Ki-67 ≥30%. Patients must have early or locally advanced disease (T2-T4 and/or N1-N3, M0) for which NCT is appropriate. Key exclusions include HER2-positive tumors, metastatic disease and any prior chemotherapy for the current cancer. Treatment. All patients in the prospective arm will receive 4 cycles of ddAC (doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 every 14 days) with empegfilgrastim 7.5 mg as G-CSF support. This is followed by 4 cycles of biweekly paclitaxel (175 mg/m2 every 14 days) with empegfilgrastim 7.5 mg support. The historical control arm will include patients previously treated with AC (q21 or q14) followed by weekly paclitaxel (80 mg/m2 weekly ×12).Primary endpoint is pCR rate, defined as no residual invasive cancer in breast and lymph nodes (ypT0/is, ypN0) at surgery. Secondary endpoints include RCB 0-I rate, event-free survival, relative dose intensity, breast conservation rate, treatment completion rates, and safety outcomes such as neuropathy, neutropenia, and febrile neutropenia. Statistical Analysis. Analyses will be conducted on an intention-to-treat basis. The primary endpoint will be compared between groups using a one-sided 95% confidence interval to evaluate non-inferiority, with a non-inferiority margin of 10%. Propensity score matching (1:3) will balance baseline characteristics. Logistic regression adjusted for matching strata will estimate odds ratios. Secondary endpoints will be analyzed using Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards models for time-to-event outcomes. Sample Size Justification. Assuming a pCR rate of 20% in the historical weekly paclitaxel group and a non-inferiority margin of 10%, a sample size of 102 patients in the prospective biweekly arm and 307 matched historical controls (1:3 ratio) achieves 80% power with one-sided α=0.05. Citation Format: P. Krivorotko, N. Amirov, V. Mortada, A. Emelyanov, R. Pesotskiy, E. Zhiltsova, T. Tabagua. Dose-dense Paclitaxel with Empegfilgrastim vs weekly Paclitaxel in luminal B HER2-negative early breast cancer (PULSE trial) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-11.

Abstract Background: Pts with residual disease (non-pCR) after the KEYNOTE-522 regimen face a 30-40% risk of recurrence within 3 years, underscoring the urgent need for more effective therapies. In preliminary analyses, we identified that ≤80% tumor reduction after 4 cycles of paclitaxel+carboplatin (PC) + pembrolizumab (Pb) predicted a pCR rate of only ∼20%, defining a biologically aggressive subgroup at risk of early recurrence and reduced survival. SG has demonstrated superior clinical efficacy over conventional chemotherapy in metastatic TNBC and emerging data suggest that SG enhances the efficacy of anti-PD-(L)1 therapy. Given the paucity of available evidence regarding the effectiveness of SG with Pb in the neoadjuvant setting, particularly in pts with suboptimal response to PC+Pb, we conducted the first trial of SG+Pb as sequential neoadjuvant therapy (NAT) in pts with high-risk, early-stage TNBC (NCT05675579). Methods: Pts with stage II-III TNBC and suboptimal response to PC+Pb, defined as disease progression or a ≤80% reduction in tumor volume by breast imaging, were eligible. Pts received SG (10mg/kg IV, D1 &amp; 8) + Pb (200mg IV, D1) every 21 days x 4 cycles as the second phase of NAT before undergoing surgery. Blood and tumor biospecimens were collected prior to initiating SG+Pb and at surgery for correlative studies. We employed the Bayesian Optimal Phase II design to detect an improvement in pCR rate from 20% to 45% in order to deem the regimen worthy of further study in a randomized, phase III trial. Success was defined as pCR in 9 out of 25 response-evaluable pts (alpha=4.6%, power=85.8%). Pts not evaluable for response were replaced to ensure N=25 response-evaluable pts. Results: 27 pts were enrolled from 6/22/2023-5/23/2025. All 27 pts were evaluable for safety, and 25 pts were evaluable for response (1 pt completed &amp;lt;2 cycles of study treatment due to an unrelated adverse event; 1 pt was found to have an ineligible histology at surgery). Among the 25 response-evaluable pts, the pCR rate was 48% (95% CI: 28-69%). Clinicopathological characteristics are described in Table 1. Treatment-related adverse events (TRAE, all grades) occurring in ≥20% of safety-evaluable pts included neutropenia (78%), fatigue (37%), leukopenia (30%), and anemia (26%). 16 pts (59%) experienced grade ≥3 neutropenia. Of the 27 safety-evaluable pts, 24 (89%) completed all 4 planned cycles of SG+Pb. The remaining 3 pts discontinued study treatment early due to TRAEs (n=1), AEs unrelated to study treatment (n=1), and disease progression (n=1). Conclusion: These data provide the first evidence of SG+Pb as an effective treatment option in pts with high-risk, early-stage TNBC experiencing poor response to PC+Pb (pCR=48% vs 20% in historical controls), with no new safety signals. Correlative proteomic (including TROP2 IHC), genomic, and immunological studies are ongoing. Citation Format: C. Yam, T. Iwase, B. Nelson, R. L. Bassett Jr, A. Singareeka, G. Whitman, M. Karuturi, B. Adrada, D. Kizub, M. Guirguis, A. Buzdar, T. Moseley, A. Nwosu-Iheme, M. Kapoor, J. Sukumar, P. Thomas, C. H. Barcenas, N. Ibrahim, G. Moscol, A. Nasrazadani, D. Ramirez, M. Wright, J. Lee, W. A. Woodward, J. K. Litton, K. K. Hunt, S. Giordano, D. Tripathy, V. Valero, L. Huo, G. M. Rauch, N. T. Ueno. Neosaci-io: neoadjuvant sacituzumab govitecan (sg) + pembrolizumab (pb) in patients (pts) with early-stage tnbc experiencing suboptimal response to keynote-522 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-12-26.

Abstract Purpose: There are limited prospective data on the efficacy, tolerability, and functional impact of treatments for older and frail adults with HER2+ early breast cancer. We report the first-ever, US-based adjuvant trial dedicated to this population. Methods: We conducted a single arm, phase II, multicenter, investigator-initiated study of adjuvant ado-trastuzumab emtansine (T-DM1) in patients aged 60 and older with stage I-III HER2+ breast cancer who either declined standard adjuvant therapy or were deemed by their physician not to be candidates for standard treatment for any reason. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). The primary endpoint was 5-year invasive disease-free survival (iDFS) with a 2-sided 90% confidence interval. Secondary endpoints presented here are toxicity and 3-year iDFS, invasive breast cancer-free survival (iBCFS), and overall survival (OS). All survival analyses were evaluated using Kaplan Meier methods and began at the time of C1D1 of T-DM1. Results: ATOP enrolled 111 evaluable patients during 2015-2020; median follow-up is 4.9 years (IQR 4.2-5.5). The median age was 71 (range 60-88); 50.4% were aged &amp;gt;70 and 11.7% were aged &amp;gt;80. Overall, 69.4% had stage I, 26.1% had stage II, and 4.5% had stage III disease; 70.3% had hormone receptor-positive tumors. The 5-year iDFS = 84.2% (90% CI 77.1-92.0%). The 3-year iDFS = 91.2% (90% CI 85.9%, 96.9%) and iBCFS = 94.1% (90% CI 89.7-98.8%) (see Table for event details); 3-year OS = 96.1% (90% CI 92.4-99.9%). In total, there were 3 distant recurrences and 2 breast cancer-related deaths. Overall, 82% reported grade 2+ toxicity during treatment; the most common grade 2+ events were fatigue (30.6%) and peripheral sensory neuropathy (19.8%). The most frequent grade 3 events were liver function abnormality, anemia, decreased neutrophil count, and neuropathy (&amp;lt;5% for each); one patient (0.9%) had grade 4 thrombocytopenia. Sixty-five (58.6%) completed all 17 cycles of protocol therapy; 27 (24.3%) completed 10-16 cycles, and 19 (17.1%) completed 1-9 cycles. Reasons for early treatment discontinuation in the remaining 41.4% included toxicity (28.8%), patient withdrawal (6.3%), other (3.6%), disease progression (0.9%), death on study (0.9%, deemed unrelated to treatment), and other complicating disease (0.9%). Conclusions: The ATOP trial demonstrated a favorable 5-year iDFS and manageable toxicity among older adults with early stage HER2+ breast cancer. Although iDFS was numerically worse than historical controls (i.e., 5-year iDFS in the ‘ATEMPT’ trial by Tolaney et al. J Clin Oncol, 2024 was 97% [95% 95.2-98.7]), ATOP’s participants had higher-risk cancers, advanced age, and more competing non-breast cancer events. Future endpoints will include in-depth analyses of patient-reported outcomes, biomarkers of aging, and longitudinal functional status. Citation Format: R. A. Freedman, H. Heiling, K. J. Ruddy, L. Rogak, M. Sedrak, A. Dueck, H. Liu, A. Fraettarelli, S. Atanasov, M. DeMeo, P. Lange, A. Perilla Glen, S. Sinclair, D. Dillon, J. Mortimer, M. Fenton, J. Walsh, L. Spring, H. Muss, N. Sinclair, E. Hamilton, C. Dang, S. Giordano, M. Faggen, S. Lo, C. Kuzma, S. Lemke, P. Stella, R. Mowat, M. Wilkinson, J. Rauch, N. Tayob, E. Winer. Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with HER2+ Breast Cancer - Results from the ATOP Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-04.

Abstract Background: Trastuzumab-deruxtecan (T-DXd) showed impressive efficacy in patients whose breast cancers are either human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) positive or HER2-low/ultralow. In a phase 2 trial, patients with HER2-IHC 0 who received T-DXd had an objective response rate of approximately 30%, revealing activity regardless of HER2-IHC status. In this study, we will treat patients with advanced HER2 IHC 0 breast cancers with T-DXd and assess biomarkers of response and resistance to therapy. We will investigate patients’ tumor biopsies for more precise quantitative HER2 tests, including the High-Sensitivity (HS)-HER2 Troplex testing, that could help determine if T-DXd is active in patients with HER2-IHC 0 tumors regardless of HER2 quantitative expression or if there is a potentially optimal cutoff value of HER2 expression with respect to clinical outcomes for response, improving patient selection and prevention of unnecessary toxicity. Methods: This is a non-randomized, single-arm, open-label, phase 2 study to assess the efficacy and safety of T-DXd in patients whose breast cancer is HER2-IHC 0 (including 0-null and 0-ultralow) in all prior biopsies, with unresectable and/or metastatic disease regardless of hormone receptor (HR) status (NCT06750484). Key eligibility criteria include ECOG-PS 0-2; up to 2 prior lines of systemic cytotoxic therapy for treatment in the metastatic setting; no upper limit of prior endocrine, immunologic or targeted therapy lines. Fifty subjects will be included to achieve 82% power to detect a difference in ORR of 0.15 from historical control (ORR in experimental arm of 0.3 vs. ORR in historical control of 0.15) using a two-sided exact test with a target significance level of 0.1. The study treatment with T-DXd administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight will be continued in the absence of withdrawal of subject consent, progressive disease (PD), death, or unacceptable toxicity. Patients will be followed and evaluated by RECIST v1.1 criteria. Objective response to T-DXd will be evaluated in the entire study population and separately in the High-Sensitivity (HS)-HER2 Troplex detectable and non-detectable cohorts (defined by the limit of detection [LOD] of the analytic HS-HER2 Troplex assay). In addition, HER2 tissue concentrations (measured by the HS-HER2 Troplex assay in attomole/mm2) will be plotted and analyzed as a function of response to determine levels of tumor expression and potential cut-points associated with benefit from T-DXd. Since the Troplex assay simultaneously provides TROP2 levels in attomole/mm2, the influence of TROP2 levels on response to T-DXd will also be exploratorily investigated. Additional objectives are to assess efficacy in terms of progression-free survival and overall survival, safety, and explore potential biomarkers of response and resistance to therapy with T-DXd. The trial is currently open and enrolling patients. Citation Format: A. Kahn, J. Du, N. Casasanta, S. Schellhorn, M. Digiovanna, T. Sanft, M. Rozenblit, A. Silber, L. Pusztai, Z. Rahman, D. O'Neil, R. Legare, W. Kidwai, J. Kanowitz, A. Bulgaru, N. Fischbach, S. Hall, K. Fenn, K. Blenman, O. Blaha, E. Winer, I. Krop, D. Rimm, M. Lustberg. Open-label Single-arm Phase 2 Trial of Trastuzumab Deruxtecan in Previously Treated HER2-Immunohistochemistry (IHC) 0 Advanced Breast Cancer - HER2 PARADIGM trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-07.

Abstract Background Neoadjuvant chemotherapy combined with immune checkpoint blockade (ICB) improves outcomes in high-risk TNBC, but this regimen is not approved and may be overtreatment for cT1N0 TNBC. Preclinical studies show that low dose radiotherapy (RT) can enhance antitumor immunity. In this study, we evaluated whether a neoadjuvant chemotherapy-free regimen of a single pembrolizumab (pembro) dose + a single subablative RT fraction (7Gy) may elicit antitumor immune response and increase stromal tumor infiltrating lymphocytes (sTILs) in TNBC to high levels, defined here as &amp;gt; 50%, which is a biomarker known to correlate with excellent outcomes without chemotherapy. Methods In this open-label phase 1b/2 trial (NCT04454528), participants with histologically confirmed early stage invasive breast cancer planned for standard of care (SOC) upfront surgery were enrolled. Each participant received a single preop dose of pembro either alone or in combination with RT given before or after pembro. The co-primary endpoints were demonstration of 1) feasibility of completing RT + pembro regimen within 21 days without delaying planned surgery &amp;gt; 14 days and 2) immune activation, defined as a) increase in % sTILs, and, b) increase in % proliferating (Ki67+) circulating T cells. Secondary objectives included assessment of tumor response by change in size from baseline. Responders are defined as those with tumor size reduction &amp;gt; 30% (TΔ30). Study sample size was powered for TΔ30. Assuming 40% of treated subjects achieve TΔ30 versus 0% in historical controls, 15 subjects yield 80% power at α=0.05. Exploratory analyses included immune profiling of peripheral blood mononuclear cells (PBMC) by flow cytometry for markers of T-cell activation, proliferation, differentiation and exhaustion, T-cell receptor repertoire (TCR) dynamics, and digital spatial profiling of the tumor immune microenvironment pre and post treatment. All participants received SOC adjuvant therapy after surgery. Findings Between January 6, 2021, and February 18, 2025, 30 participants (12 with HR+HER2-, 17 TNBC and one HER2+) enrolled and completed the preop regimen. All participants proceeded to surgery without delay. Median follow-up was 29 months (IQR 14 - 45). There were no adverse events (AEs) ≥ grade 2 which included one grade 2 immune-related AE (hypothyroidism). TΔ30 rate was significantly higher in RT + pembro arms (14 of 25, 56%, including 3 with pCR) compared to pembro only arm (0 of 5, 0%), p = 0.024. Post-treatment, sTILs shifted rightward from 20% (IQR 5 - 50 ) to 50% (IQR 10 - 60) overall and from 40% (IQR 20 - 55) to 60% (IQR 50 - 70) in TNBC. The proportion of TNBC with high sTILs (&amp;gt;50%) increased from 3 of 11 (27%) to 7 of 13 (54%) post treatment. Immune profiling of PBMC from responders demonstrated increased proportions of early-memory CD4+ and CD8+ T cells at baseline, marked expansion of activated, Ki67+ CD4+ and CD8+ T cells post treatment, and a higher and more diverse TCR repertoire both pre- and post-treatment. Spatial transcriptomic analyses demonstrated that tumor regions directly interacting with T-cells in responders were enriched for gene signatures of cGAS-STING-pathway activation, antigen processing and presentation, and response to ICB. Interpretation In this small single institution study, we demonstrate that a single pembro dose + a single sub-ablative RT fraction can elicit anti-tumor immune response and increase sTILs from low to high levels in TNBC. As only ∼20% TNBC have high sTILs, this well tolerated neoadjuvant chemotherapy-free regimen may be evaluated in future studies as an immune induction strategy to expand the number of patients eligible to enroll in adjuvant chemotherapy omission trials such as the OPTImaL study. Citation Format: J. Tchou, A. Nayak, H. N. Xu, J. Kollmar, E. H. Smith, M. Z. Mazur, L. Keele, A. Clark, N. Taunk, J. Fraietta, on behalf of the BreastVax Study Team. A single preoperative pembrolizumab dose plus a single subablative radiotherapy fraction (7 Gy) elicits anti-tumor immune response and increases stromal tumor infiltrating lymphocytes in triple negative breast cancer: a phase 1b/2 study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-07-15.

Abstract Background: HER2-positive breast cancer, characterized by the overexpression of the HER2 protein, has been associated with an aggressive disease course, higher rates of recurrence, and poorer prognosis compared to HER2-negative breast cancer and accounts for approximately 15-20% of all breast cancer cases. The introduction of HER2-targeted therapies has transformed the treatment of HER2+ breast cancer and significantly improved survival rates. A major challenge for patients is the development of brain metastases, which can occur in up to 30–50% of patients with breast cancer. Patients with HER2+ breast cancer have a higher risk of developing brain metastases. Immune system cells, specifically T-cells, are one of the few modalities that are capable of crossing the blood brain barrier and may offer an immunologic approach to the prevention of brain metastases in high risk patients. We have been immunizing HER2+ breast cancer patients with HER2 directed vaccines for over 2 decades and sought to determine the impact of HER2-targeted cancer vaccines on the development of brain metastases compared to historical controls. In addition, we will explore the link between the clinical outcomes of patients and the level of immunity they achieved after HER2 specific immunization. Methods: We conducted a retrospective review of 146 patient medical records of advanced stage (III or IV) breast cancer patients, with a HER2+ breast cancer diagnosis confirmed by either IHC 3+ or FISH amplification, who had received a HER2 directed vaccine from one of four clinical trials conducted at the University of Washington, Cancer Vaccine Institute. Patients were followed for the development of brain metastases from the time of initiation of vaccination for at least 5 years. The diagnosis of brain metastases was based on surgical and pathological reports or radiology records and clinical notes from the medical record. IRB approval was obtained prior to initiation of the study. Results: Of the 146 patients with retrospective data, 12 patients had documented brain metastases prior to trial enrollment and were excluded from further evaluation. Of the remaining 134 patients who had no brain metastases at enrollment and subsequently received HER2-targeted vaccines, 21 developed brain metastases, yielding a cumulative incidence (CI) of 15.7%. Stratified by hormone receptor (HR) status, the incidence was 16.9% in HR+/HER2+ patients (n = 13) and 14.5% in HR-/HER2+ patients (n = 8). When compared to a recent historical control cohort of 18,075 real-world patients from the U.S. Flatiron Health database, which reported a 60-month CI of brain metastases of 22.7% in HR+/HER2+ and 33.6% in HR-/HER2+ subgroups, our findings suggest a 26% relative reduction of brain metastases in HR+/HER2+ patients and a 57% reduction in HR-/HER2+ patients. Conclusion: HER2 directed vaccination could have a protective effect on the development of brain metastases in patients with advanced stage HER2+ breast cancer. Phase II trials are planned to prospectively evaluate the vaccine in this setting. Citation Format: Y. Liu, J. Bahia, C. Haghighi, S. Vinayak, J. S. Childs, M. L. Disis. Incidence of the development of brain metastases in patients with advanced stage HER2+ breast cancer who have previously received a HER2 directed cancer vaccine [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-04.

Abstract Introduction: Abemaciclib, a CDK4/6 inhibitor, reduces the risk of recurrence in patients (pts) with high-risk HR+/HER2- early breast cancer; use is associated with toxicities, particularly diarrhea, which can impact pts’ ability to maintain dose and/or remain on therapy. TRADE (NCT06001762) is a phase 2, investigator-initiated single-arm trial designed to evaluate whether an initial dose-escalation strategy improves adjuvant abemaciclib tolerability. The study met its primary endpoint, showing the dose escalation strategy reduced treatment discontinuation and improved ability to reach/maintain the target dose of 150 mg BID at 12 weeks (wks), compared to historical controls. Here, we present 6-month follow-up results from TRADE. Methods: Pts with HR+/HER2- early breast cancer eligible for abemaciclib with adjuvant endocrine therapy were enrolled. All pts initiated abemaciclib at 50 mg BID for 2 wks, escalated to 100 mg BID for 2 wks, and then to 150 mg BID onward for a planned 2-year course. Dose escalation required the absence of ongoing grade 3/4 or persistent grade 2 adverse events (AEs). Management of AEs and dose reductions beyond 12 wks was per standard of care. Data on adherence to oral therapy and ctDNA dynamics were collected. Results: Ninety pts were enrolled; median age was 58 years (range 24-78), and the majority were White (80.0%). 51.1% had stage II disease and 48.9% stage III disease. 73.3% had received chemotherapy in the neo/adjuvant setting. All pts received an adjuvant aromatase inhibitor (AI), 17.8% with ovarian function suppression. One pt had progression within 24 wks of treatment, hence was excluded from dose-related analyses. Out of 89 evaluable pts, 72 (80.9%) remained on treatment at 24 wks; 46 (63.9%) were receiving abemaciclib at 150 mg BID, 18 (25.0%) at 100 mg BID and 8 (11.1%) at 50 mg BID. Abemaciclib discontinuation occurred in 6 pts (6.7%) during the first 12 wks and in an additional 11 pts (12.4%) between wks 12 and 24, resulting in a cumulative discontinuation rate of 19.1% (n=17) over the initial 24 wks of exposure. The most common reasons for discontinuation were AEs (7, 7.9%) and withdrawal of consent/patient preference (6, 6.7%). Specific AEs contributing to discontinuation included diarrhea (2, 2.2%), pneumonitis (2, 2.2%), transaminitis (1, 1.1%), allergic reaction (1, 1.1%), and other (1, 1.1%). Of those who discontinued for patient preference, 5 of the 6 had reached target dose, of whom 3 did not have a dose reduction. A total of 12 pts (13.5%) did not reach target dose, and 29 (32.6%) required dose reductions within 24 wks, primarily due to gastrointestinal or hematologic toxicities, 22 (24.7%) with reductions from 150 mg dosing. The most frequently reported AEs overall were diarrhea (grade ≥2 32.2%, grade 3 5.6%), neutropenia (31.1%, grade ≥3 4.4%), and fatigue (25.6%, no grade ≥3). When analyzed by 4-wk intervals, rates of grade &amp;gt;2 diarrhea were 8.9% (wks 1-4), 19.1% (wks 5-8), 16.5% (wks 9-12), 12.0% (wks 13-16), 8.9% (wks 17-20), and 9.5% (wks 21-24), showing an early peak and gradual decline over time. Patient-reported outcomes, measured by FACT-B assessments, indicated that quality of life remained stable throughout the study period. Additional analyses, including evaluation of adherence and ctDNA, are ongoing. Conclusions: In the TRADE study, after initial dose escalation, abemaciclib was generally well tolerated, with a cumulative discontinuation rate of 19.1% at 24 wks, 7.9% for AE. The incidence of grade &amp;gt;2 diarrhea peaked at month 2 and declined over time. The majority of pts maintained quality of life and were able to remain on therapy with manageable and expected toxicities. These updated findings continue to support the feasibility of an initial abemaciclib dose-escalation approach to optimize drug exposure and reduce early discontinuation, while preserving therapeutic intensity. Citation Format: I. Schlam, D. Trapani, S. Kim, M. Faggen, N. Sinclair, P. Sanz-Altamira, C. Battelli, S. Berwick, S. Lo, J. Acevedo, S. Sinclair, A. Malcom, L. Varella, S. L. Sammons, S. T. Schumer, P. D. Poorvu, E. P. Wallace, E. Pasternak, N. Tayob, S. M. Tolaney, E. L. Mayer. Trade: 6-month abemaciclib tolerability after initial dose escalation in early HR+/HER2- breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD1-08.

Can a single-step warming protocol for vitrified blastocysts provide comparable or superior outcomes to a conventional multi-step warming approach in a clinical IVF setting? Single-step warming resulted in higher blastocyst survival, intactness, and transfer rates compared to the conventional multi-step protocol, with comparable ongoing pregnancy rates and a consistent trend toward lower miscarriage rates across all subgroups. While vitrification has become the gold standard for embryo cryopreservation, the warming process remains critical to embryo survival and implantation potential. Traditional warming relies on multi-step dilution protocols to minimize osmotic stress. Preliminary studies have suggested that single-step rehydration protocols may be equally effective, but data on clinical validation remain scarce. A three-phase validation study was conducted at a single university-based IVF centre including (i) risk analysis, (ii) preclinical validation (n = 246 blastocysts), and (iii) a clinical comparison of outcomes over one year (March 2024-March 2025) between single-step warming (n = 1925 cycles) and the conventional multi-step protocol (n = 1744 cycles, March 2023-March 2024). In the preclinical phase, vitrified surplus and PGT blastocysts were rewarmed using the single-step protocol and compared to historical controls. Survival (≥50% intact cells), intactness (100% intact), and transfer suitability were assessed. Single-step warmed blastocysts were monitored for 24 h post-warming in a time-lapse incubator, and viability was further evaluated using live/dead fluorescent staining to quantify cell damage. In the clinical phase, outcomes (survival, transfer rate, pregnancy, ongoing pregnancy, miscarriage) were retrospectively compared across protocols, stratified by PGT status and day of vitrification. In the preclinical phase, blastocyst survival was ≥50% in 99.1% of cases after single-step warming versus 96.8% after multi-step warming (P = 0.0924). Fully intact blastocysts were significantly more frequent in the single-step group (85.4% vs. 76.3%, P = 0.0058), and transfer suitability at 2 h post-warming was also higher (96.7% vs. 91.2%, P = 0.0076). Time-lapse monitoring confirmed a high re-expansion rate (93.9%) with a mean re-expansion time of 3.3 ± 2.7 h. Fluorescent viability staining showed that 90.5% of blastocysts exhibited no or minimal cell damage. In the clinical cohort, significantly higher survival rates were seen in the single-step group across multiple subgroups, including non-PGT Day 5 (98.5% vs. 96.1%, P = 0.0003) and PGT Day 5 (100% vs. 98.2%, P = 0.0407) blastocysts. Fully intact rates were significantly higher in all subgroups and transfer rates were significantly higher in the single-step group for non-PGT Day 6 (97.2% vs. 92.8%, P = 0.0060) and PGT Day 5 cycles (100% vs. 97.8%, P = 0.0209). While some early pregnancy outcomes (e.g. clinical pregnancy in non-PGT Day 5) favoured the multi-step protocol (40.5% vs. 35.7%, P = 0.0286), ongoing pregnancy rates were not significantly different in any subgroup. Miscarriage rates showed a consistent trend in favour of single-step warming but did not reach statistical significance. This was a single-centre study, and the control group was retrospective. The single-step warming protocol is a clinically validated, safe, and efficient alternative to conventional multi-step warming. Its implementation may improve workflow and streamline blastocyst handling without compromising clinical outcomes. No external funding was received. The authors declare no conflicts of interest apart from KT, who has received travel support related to the manuscript from Fuijifilm Irvine Scientific, in the form of payment to her institution. N/A.

Abstract Introduction: Preoperative localization of non-palpable breast lesions, whether performed the day before or on the day of surgery, can be anxiety-inducing for patients. The scheduling in a busy operating theater for short procedures is highly sensitive to even minor delays. Localization appointments may cause such delays, as well as raise potential timing confusions between surgery time, arrival time at the care center, and localization time. Moreover, wire-guided localization requires specific radiology sessions and coordination with radiologists specialized in breast imaging. For these reasons, we progressively implemented preoperative localization using a magnetic clip. Placement is done a few days before surgery, which also allows a comprehensive re-review of the radiologic images. The objective is to describe the organizational impact and the re-excision rate of the systematic use of magnetic seeds in a single institution. Methods: Retrospective single-center study. We describe the characteristics of cases with magnetic seed localization and compare these features, as well as ambulatory stay durations, to a historical control group that underwent wire-guided localization. For this comparison, only consecutive patients who had unifocal, unilateral breast cancer and were treated on an outpatient basis were included. Results: Between March 2024 and June 2025, 261 patients were referred to the radiology department for magnetic seed placement before surgery. During imaging review, additional lesions were detected in 21 patients (8%), leading to total mastectomy in 5 cases. Excluding 8 patients (3%) who were scheduled for inpatient admission, 232 underwent magnetic seed placement, including 35 (15%) for benign lesions. We compared 197 patients who had magnetic seed localization for cancer between March 2024 and June 2025 to 60 patients in the historical control group who underwent wire localization for cancer between November and December 2023. The median age in both groups was 62 years (p = 0.98). The control group had a higher proportion of in situ ductal carcinoma (n = 18, 30% vs. n = 27, 15%, p = 0.02), while the magnetic seed group underwent more axillary procedures (n = 170, 86% vs. n = 42, 70%, p = 0.009). Tumor size was slightly larger in the magnetic seed group (10 mm vs. 8 mm, p = 0.04). Fewer re-excisions for positive margins occurred in the magnetic seed group (n = 3, 1.5% vs. n = 8, 13%, p &amp;lt; 0.01). This result was confirmed in multivariate analysis : use of magnetic seed reduced independently the rate of re-excision with an OR of 0.37 (IC95%[0.002-0.001], p=0,0018). Operating time was equivalent in both groups (32 min vs. 33 min, p = 0.87), but ambulatory stay was reduced by more than 2 hours in the magnetic seed group (5h 14 vs. 7h 19, p &amp;lt; 0.01). Conclusion: The use of magnetic seeds enables time savings on the day of surgery, streamlining the operating theater schedule and reducing patient anxiety associated with pre-surgical delays. Re-excision rates is dramatically decreased when using magnetic seeds. Citation Format: D. Hequet, A. Hababou, G. Aubry, R. Salmon, S. Harguem, M. Bou Antoun, J. Seror. Magnetic seed for preoperative localization of non-palpable breast cancer: impact on care pathway organization and re-excision rate [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-01-02.

Abstract Background: Patients receiving treatment with aromatase inhibitors (AIs) often suffer from Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness. These often lead to discontinuation and could impact breast cancer outcomes. We conducted the prospective single arm Zoledronic Acid Prophylaxis (ZAP) trial, which demonstrated that zoledronic acid administered prior to initiating letrozole and after 6 months was associated with a reduced incidence of AIMSS compared to historical controls (BCRT 2018). Our correlative analysis aims to elucidate the mechanism by which AIs contribute to the development of AIMSS. We hypothesize that alterations in muscle injury, vitamin D deficiency, inflammation, and estrogen deprivation may be associated with AIMSS. Methods: Participants from ZAP were postmenopausal women with stage 0-III breast cancer receiving adjuvant letrozole, who also received zoledronic acid at study entry and 6-months. Blood samples were obtained at baseline and 6 months. Blood-based correlatives included serial assessments of 25-OH vitamin D, CK-MB, a multiplex cytokine array, and estradiol (ultrasensitive). At baseline we also collected whole blood for pharmacogenomic analysis SNPs in a target genes list. AIMSS was assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI) and Visual Analog Scale (VAS) at 6 months. AIMSS was defined as an increase of 0.22 in a scale of 0-3 in the HAQ-DI and/or an increase of 2.0 cm in a scale of 10 cm in the VAS. We also evaluated other patient reported outcomes (PROs): depression (CESD), anxiety and depression (HADS-A), hot flashes (HFRDI), menopausal symptoms (NSABP-MSQ), sleep quality (PSQI), and quality of life (EuroQol). ROC analysis evaluated the predictive accuracy of biomarker changes for AIMSS. Pearson correlation assessed inter-biomarker correlations. Results: From 2011 to 2013, 59 postmenopausal women enrolled in ZAP. Samples were collected in 59 and 49 participants at baseline and 6 months, respectively. Of the cohort included in this analysis, the median age was 59.0. Among 59 women, 5(8.5%) were Black, 59(100%) were non-Hispanic. The median BMI was 28.5 kg/m2 and baseline arthritis was present in 30 (50.8%). Decreases in TNF-b and MCP4 were significantly associated with cumulative incidences of AIMSS (p=0.023, p=0.03) where those who developed AIMSS had a 16% median decrease in TNF-b, 11% median decrease in MCP4 versus a 13% median increase in TNF-b and 12% median increase in MCP4 in those who did not develop AIMSS. Increase in VAS cumulative incidence was significantly associated with decreases in IL27 (p=0.025), IL21 (p=0.026), and VEGFA (p=0.034). Increase in HAQ was significantly associated with decrease in TNF-b (p=0.01), IL17B (p=0.03), but increase in IL1RA (p=0.043). ROC curve-based analyses show that TNF-b exhibits high negative predictive values (NPVs) in classifying AIMSS (0.824; 95%CI [0.566, 0.962]), HAQ (1; 95%CI [0.824, 1]), and VAS (0.824; 95%CI [0.566, 0.962]). IL1RA (0.97; 95%CI [0.82,1]) and IL17B (0.93; 95%CI [0.79, 0.98]) show high NPV for HAQ classification. IL27 (0.815; 95%CI [0.619, 0.937]), IL21 (0.821; 95%CI [0.631, 0.939]), VEGFA (0.8; 95%CI [0.593, 0.932]), and MCP4 (0.81; 95%CI [0.581, 0.946]) achieve similarly good discriminatory ability for VAS classification. Other cytokines and vitamin D levels were not significantly associated with AIMSS. We will report pharmacogenomic associations of genes and estradiol with AIMSS, and biomarker associations with PROs at the conference. Conclusions: Decreases in TNF-beta and MCP4 were associated with the reporting of AIMSS. Early changes in cytokines profile may identify those at greater risk for AIMSS and who may derive greater benefit from earlier symptom management to prevent discontinuation. Citation Format: J. Sheng, R. Chen, J. Zacharski, D. Tsang, A. Yende, H. Qi, v. stearns, D. sharma, C. Santa-Maria. The Mechanisms and Predictors of Aromatase Inhibitor-associated MusculoSkeletal Symptoms: The ZAP Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-08-24.