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Prognostic value of baseline 18F-FDG PET/CT in first-line pembrolizumab plus chemotherapy for metastatic triple-negative breast cancer.
e13111 Background: The treatment landscape of metastatic triple-negative breast cancer (mTNBC) is rapidly evolving. Pembrolizumab with chemotherapy has been the first-line standard; more recently, improved efficacy has been reported with sacituzumab govitecan. Therefore, biomarkers beyond PD-L1 CPS are urgently needed to better guide treatment selection. We aimed to evaluate the prognostic value of baseline 18F-FDG PET/CT in patients with mTNBC treated with first-line pembrolizumab and chemotherapy. Methods: This multinational, multicenter retrospective study was conducted within the CEBCC-101 real-world evidence project across 18 cancer centers. Female patients with histologically confirmed mTNBC who received first-line pembrolizumab combined with chemotherapy outside of clinical trials in Poland, the Czech Republic and Slovakia between September 2022 and June 2025 were included. Among 178 eligible patients, 53 underwent baseline 18F-FDG PET/CT. The highest tumor SUVmax was analyzed as a prognostic biomarker for progression-free survival (PFS) and overall survival (OS). Results: SUVmax, analyzed as a continuous variable, was significantly associated with PFS, with a 3.8% increase in the hazard of PFS event per 1-unit increase. The optimal SUVmax cut-off for PFS was 7.3 (sensitivity 0.95, specificity 0.44, AUC 0.70). Patients with SUVmax > 7.3 (highSUV) had significantly shorter PFS compared with those with SUVmax ≤7.3 (lowSUV) (median PFS 6.7 vs 16.1 months; HR 2.90; 95% CI 1.19–7.08; p = 0.019). Twelve-month PFS rates were 29.8% and 73.4%, respectively. HighSUV was also associated with inferior OS (HR 8.40; 95% CI 1.08–64.9; p = 0.042), with 2-year OS rates of 35.7% versus 83.3%. In multivariable analysis, SUVmax remained independently associated with inferior PFS and OS, irrespective of age, ECOG performance status, de novo versus recurrent disease, and metastatic site. Each 5-unit increase in SUV was associated with a higher risk of a PFS event (HR 1.35; 95% CI 1.10–1.66; p = 0.004) and with an increased risk of death (HR 1.60; 95% CI 1.13–2.28; p = 0.009). Conclusions: Baseline 18F-FDG PET/CT–derived SUVmax is a strong prognostic biomarker in patients with mTNBC treated with first-line pembrolizumab and chemotherapy. High SUVmax identifies a subgroup of patients with substantially poorer PFS and OS, and may help guide risk-adapted therapeutic strategies.
Trends in malignant melanoma in the African Union from 1980-2023: Insights from the GBD 2023 study.
e21522 Background: Malignant melanoma is the leading cause of skin cancer deaths worldwide. There is a lower incidence but higher mortality among African individuals, especially due to late diagnosis. However, African populations remain underrepresented in current epidemiological literature. This study aims to address this gap by examining trends in malignant melanoma-associated mortality and morbidity in the African Union. Methods: The Global Burden of Disease Study (GBD) 2023 was used to extract mortality data for malignant melanoma from 1980 to 2023. Age-standardized death rates (ASDRs), age-standardized incidence rates (ASIRs), age-standardized prevalence rates (ASPRs), and disability-adjusted life years (DALYs) per 100,000 people were assessed. The African Union was stratified by geographic region. The Joinpoint Regression Program was used to calculate the annual percentage changes (APCs) and average annual percentage changes (AAPCs). Results: In the African Union as a whole, there was a rising trend in the ASDRs and DALYs for malignant melanoma, despite interim declines. In 1980, the ASDR was 0.47, which rose to 0.67 by 2023 (AAPC = 0.85; 95% CI, 0.80–0.90). DALYs increased from 16.42 to 23.62 between 1990 and 2023 (AAPC = 1.11; 95% CI, 1.03–1.19). The ASIR and ASPR also demonstrated a similar overall upward trend, with intermittent periods of decline (AAPC = 1.80; 95% CI, 1.70–1.91; AAPC = 2.71; 95% CI, 2.48–2.95, respectively). Regionally, Southern Africa had the highest ASDRs and DALYs for most of the study period, followed by Central Africa. However, Central Africa exhibited higher ASDRs and DALYs in recent years. Meanwhile, Northern Africa had the lowest ASDRs and DALYs, although it had the steepest rise (AAPC = 1.53; 95% CI, 1.45–1.61; AAPC = 1.42; 95% CI 1.35 to 1.48 respectively). Similarly, Southern Africa demonstrated the highest ASIRs and ASPRs throughout most of the study period. However, Central Africa overtook Southern Africa in recent years. Northern Africa consistently exhibited the lowest incidence and prevalence. Conclusions: Malignant melanoma mortality and incidence increased throughout the study period across the African Union, highlighting the need for early detection and public health campaigns. Furthermore, targeted preventive strategies and improved resource allocation are essential for addressing regional disparities.
Cancer CARE (Connected Access and Remote Expertise) beyond walls: Pilot, phase 2 clinical trial to evaluate administration of cancer-directed therapy in the patient’s homes versus in clinic in the Florida Panhandle and surrounding areas.
TPS1679 Background: Cancer care in the United States remains highly centralized, imposing substantial time, caregiver, and financial burdens on patients, particularly those residing in rural and medically underserved regions. While international experience supports the feasibility of home-based cancer therapy delivery, prospective U.S. clinical trial data are limited. The Cancer CARE Beyond Walls (CCBW) program was developed to address these gaps through a decentralized cancer care model integrating virtual oversight, remote monitoring, mobile clinical services, and community-based nursing partners. The study evaluates the feasibility, safety, and patient-centered impact of delivering cancer-directed therapy in patients’ homes or near-home mobile units in the Florida Panhandle, a region characterized by long travel distances to tertiary centers and limited oncology infrastructure. Methods: This is a phase 2, single-arm clinical trial evaluating the delivery of standard-of-care cancer-directed therapy outside of traditional infusion centers. Eligible adult patients (ECOG 0–3) with histologically confirmed malignancies receiving guideline-supported or FDA-approved systemic cancer therapy must demonstrate tolerability of at least one prior in-clinic treatment cycle. Following registration, patients transition to home-based or near-home mobile unit administration for a minimum of 12 weeks, with an option to continue up to 24 weeks. Care delivery is coordinated through a virtual command center providing real-time virtual oversight, remote monitoring, and escalation pathways. Treatment administration is performed by trained local home health nurses, medication shipping, and digital interaction with the electronic health record. A fully equipped mobile unit extends access to rural areas not covered by home health agencies. The primary endpoint is patient preference for treatment location at week 12. Secondary endpoints include safety, avoidable acute care utilization, patient-reported function and global health/quality of life, patient-reported symptoms, and satisfaction with care. Exploratory endpoints assess travel burden, patient perceptions of caregiver experience, and patient perceptions of home versus mobile unit care. Enrollment of 27 patients will provide 80% power to reject a 50% null rate (2-sided exact test, α=0.10), assuming 75% prefer decentralized care or express no preference. This investigator-initiated trial is open to accrual and is supported by a grant from the Florida Cancer Innovation Fund. Clinical trial information: NCT07285044 .
Phase Ib study of momelotinib during and following hematopoietic stem cell transplantation for patients with primary or secondary myelofibrosis.
TPS6607 Background: Despite progress in the treatment of myelofibrosis (MF) with multiple approved JAK inhibitors (JAKi), the only curative therapy is allogeneic hematopoietic cell transplantation (HCT). Discontinuation of JAKi's before HCT is challenging as patients experience return of symptoms, moreover, hematopoietic recovery post-HCT is challenging as fibrosis takes many months to resolve. Although we have shown that ruxolitinib can be safely used during and after HCT with excellent survival, low rates of GVHD, and no adverse impact on engraftment (Hobbs et al., JCO Advances 2025), important unmet needs persist: better prevention of GVHD and improved management of post-transplant anemia and residual symptoms. Momelotinib is a JAK1/JAK2, ROCK2 and ACVR1 inhibitor that may help prevent GVHD via JAK1 and ROCK2 inhibition, which play key roles in immune cell function and inflammatory signaling. Moreover, in addition to momelotinib’s efficacy in spleen and symptom control, this agent improves anemia through ACVR1 inhibition. Thus, we aim to conduct a phase Ib study to determine the safety and tolerability of momelotinib in the peri/post-HCT period along with its impact on reducing transfusion needs. Methods: This is a phase Ib, single institution study investigating momelotinib given pre-, during- and for 1-year post-HCT for patients with primary or secondary MF (NCT 07104799). The primary endpoint is 1-year GVHD-free, relapse-free survival (GRFS). Secondary endpoints include overall (OS) and progression free survival (PFS), engraftment, and incidence of acute and chronic GVHD. Patients will be treated with reduced intensity conditioning with fludarabine (30mg/m 2 /d x 5 days) and melphalan (100 or 140mg/m 2 x 1). Patients will receive peripheral blood stem cell grafts from either 7/8 or 8/8 HLA-matched donors. GVHD prophylaxis will consist of standard tacrolimus and methotrexate. We will conduct a 3+3 dose escalation of momelotinib starting on day -7 of HCT through engraftment to test the safety of momelotinib at 100 mg, 150 mg and 200 mg during the peri and early post-HCT period. Once patients achieve engraftment, dose escalation to the approved dose of 200 mg daily will be allowed and continued for one-year post-HCT. We will collect samples for correlative analysis at baseline, day +100 and 1 year post-HCT. This study is the first to test momelotinib use pre-, during- and post-HCT in patients with MF. We have demonstrated that ruxolitinib use during and after-HCT leads to excellent GRFS and OS, however, post-HCT cytopenias remain an issue. Moreover, as more JAKi become available, it is important to evaluate the safety and efficacy of different JAKi during the time of HCT. This trial is open to accrual as of January of 2026. Funding and Product for this study is provided by GSK. Clinical trial information: NCT 07104799 . Clinical trial information: NCT 07104799 .
Machine learning (ML)-based prediction of fatal immune checkpoint inhibitor (ICI)–associated myocarditis (MC) with multi-cohort validation.
12019 Background: ICI-associated MC is a rare but highly fatal immune-related adverse event (irAE). Identifying clinical predictors of MC-specific fatality remains an unmet need. Herein, we develop and externally validate an ML model to predict ICI-MC fatality using clinical and laboratory features. Methods: The WHO Vigibase database was queried through December 22, 2024, to identify cases of ICI-MC with complete clinical data, including age, sex, cancer and ICI type, co-occurring irAEs, overlap status with myositis (MS) and/or myasthenia gravis (MG), MC timing from ICI start, and MC-specific fatality. Multivariable logistic regression was used to assess correlates of MC-specific fatality. An XGBoost ML model using all collected clinical data was trained to predict MC-specific fatality using an 80/20 split of data for training and testing. We augmented our clinical ML model with troponin (T or I) values at the time of ICI-MC diagnosis from two institutions (n = 37: OU n = 13, MGH n = 24), normalized to institutional upper limits of normal. Two additional external cohorts (n = 68: VUMC n = 18, MDACC n = 50) were used to validate our final clinical and augmented models. Results: We identified 822 cases from VigiBase with ICI-MC, with a median age of 69 years (IQR: 60-76), 59.1% (n = 486) were males. Pts with lung cancer had the highest proportion of cases (23.7%, n = 195). Most patients received ICI monotherapy (59%, n = 485). Median time to MC onset was 30.4 days (IQR: 21-91.3). MC occurred alone in 588 cases (71.5%) and with MS and/or MG in the remainder. MC-specific fatality occurred in 147 cases (17.9%). After multivariable adjustments, MC onset within the first month of ICI start was associated with higher MC-fatality odds vs. later onset (vs 1-3 months: ROR = 0.38 [0.21-0.67], vs 3-12 months: ROR = 0.5 [0.25-0.95]). Co-occurring non-MC major cardiac adverse events (ROR: 0.27 [0.17 - 0.44]) and pneumobronchitis (ROR: 0.29 [0.11 - 0.78]) were also associated with increased MC-specific fatality. The optimized MC-fatality clinical ML model achieved AUCs of 0.76 (training) and 0.73 (testing), with early MC onset as the most contributing feature. External validation (n = 37) of our clinical model yielded an AUC of 0.74. Augmenting our clinical ML model with baseline troponin (n = 37) significantly improved performance (AUC: 0.79, likelihood-ratio p = 0.046), with a further external validation (n = 68) AUC of our augmented ML model of 0.67. Our ML model is available online for use through: https://ohbiolab.shinyapps.io/ici-mc_fatality_predictor/. Conclusions: ICI-MC timing and co-occurring cardio-pulmonary reactions are key determinants of MC-specific fatality. Our findings highlight the potential promise for early risk stratification to identify high-risk pts with ICI-MC who could benefit from closer monitoring or more tailored immunosuppressive interventions at ICI-MC diagnosis.
ASCERTAIN: Real-world asciminib (ASC) effectiveness in patients (pts) with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL).
6526 Background: ATP-competitive tyrosine kinase inhibitors (TKIs) in combination with chemoimmunotherapy have improved outcomes in Ph+ ALL; still, some pts relapse despite appropriate frontline therapy and have limited options. ASC is approved for Ph+ chronic myeloid leukemia in chronic phase. The ASC managed access program (MAP) allowed adults with Ph+ ALL refractory/resistant or intolerant to available treatment (Tx) to receive ASC as monotherapy or combination under individual request when the potential benefit outweighed the risk. Methods: This was a non-interventional, multi-country, retrospective chart review in eligible pts with Ph+ ALL aged ≥18 who were refractory/resistant or intolerant to available Tx and who received ≥1 dose of ASC within the MAP. Index date (date of first ASC administration) occurred between 1 March 2019 and 30 June 2023. Existing data were extracted from index date up to 13 months (mo), or until discontinuation, death or last visit, whichever occurred first. The primary endpoint was complete hematologic remission (CR) and CR with incomplete count recovery (CRi) anytime in the first 3 mo of Tx based on peripheral blood assessments. Results: A total of 37 pts were enrolled. At Tx start, 25 pts (67.6%) received ASC as monotherapy. Median ASC dose intensity was 400 mg/day (range 71.6–400.0). Overall, 23 pts (62.2%) achieved CR/CRi within 3 months (95% CI: 44.8, 77.5). Median duration of response was 7.4 mo. Median overall survival was 7.7 mo. Nineteen pts were assessed for minimal residual disease (MRD) at time of CR/CRi and 7 (36.8%) were MRD-. Of the 13 pts with T315I mutation, 10 achieved CR or CRi at any time during follow-up. Thirty-three pts (89.2%) permanently discontinued ASC; reasons for permanent discontinuation included disease progression (n=16) and adverse events (AEs, n=5). Any-grade Tx-emergent AEs were reported in 73.0% (Grade ≥3, 56.8%) of pts; the most common any-grade AE was neutropenia (21.6%). No new safety signals were observed. Most deaths (22/28) were Ph+ ALL related. Conclusions: Adults with Ph+ ALL that was relapsed, resistant/refractory or intolerant to previous Tx achieved high rates of CR/CRi with ASC as monotherapy or in combination with chemotherapy/immunotherapy, despite most pts being heavily pretreated and/or harboring poor prognosis markers (Table). The safety profile was consistent with previous studies. Results, while positive, should be cautiously interpreted given the retrospective nature of the study and heterogenous population. Pt baseline characteristics. Pts N=37 Median age (range), years 53 (19─84) Disease status (bone marrow blasts), %≥5%<5%Unknown 67.624.38.1 Prior treatment lines, %123≥4 2.732.421.643.2 Ponatinib pretreatment, % 94.6 T315I mutation, % 35.1 Reason for starting ASC, %RelapseSpecific mutationsResistanceIntoleranceOther 67.627.024.318.913.5
Nutritional and inflammatory factors associated with chemotherapy response and survival in advanced high-grade serous ovarian cancer: A machine learning–based analysis.
e17582 Background: The chemotherapy response score is a well-established prognostic predictor in high-grade serous ovarian carcinoma, with CRS3 (complete or near-complete response) consistently associated with improved progression-free survival and overall survival. We evaluated nutritional and inflammatory factors associated with achieving CRS3 and examined the impact of chemotherapy response score on survival outcomes using conventional survival analyses and machine learning–based modeling. Methods: This retrospective study included 75 patients with stage III–IV ovarian cancer treated with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery. Patients were classified as CRS1–2 or CRS3. Survival outcomes were analyzed using Kaplan–Meier estimates and log-rank tests. Multivariable analysis was performed to identify factors associated with achieving CRS3. A random forest model incorporating nutritional, inflammatory, and clinical variables was developed to predict CRS3. Model performance was evaluated using 5-fold cross-validated area under the curve, and model interpretability was assessed using SHAP-based analyses. Results: Nineteen patients achieved CRS3, and no significant differences were observed between the CRS3 and CRS1–2 groups with respect to age, ECOG performance status, disease stage, or number of NACT cycles. Patients achieving CRS3 demonstrated significantly improved survival outcomes. Median overall survival was 30.7 months in the CRS3 group compared with 8.5 months in the CRS1–2 group (log-rank p = 0.002), and median progression-free survival was 30.7 versus 8.5 months, respectively (log-rank p < 0.001). In multivariable analysis, a higher prognostic nutritional index (PNI) and a lower C-reactive protein–albumin ratio (CAR) were independently associated with achieving CRS3. The random forest model incorporating all variables achieved a mean area under the curve of 0.69. A nutritional biomarker–based model (PNI, albumin, HALP) demonstrated superior performance (mean AUC = 0.72) compared with an inflammatory biomarker–based model (CAR, NLR, PLR; mean AUC = 0.54). SHAP-based model interpretation identified CAR and PNI as the most influential predictors of CRS3. Interaction analysis suggested that the negative impact of elevated systemic inflammation on the probability of achieving CRS3 was more pronounced in patients with poor nutritional status. Conclusions: Both nutritional and inflammatory parameters were associated with CRS3. Machine learning–based analyses suggested a slightly greater discriminatory contribution of nutritional parameters. Further prospective studies are warranted.
Trends and disparities in hepatocellular carcinoma vs intrahepatic cholangiocarcinoma–related mortality in adults aged ≥ 45 years in the United States (1999-2024): A comparative CDC WONDER analysis.
e16489 Background: Hepatocellular Carcinoma (HCC) and Intrahepatic Cholangiocarcinoma (ICC) are the two most common types of primary liver cancers and together account for a substantial proportion of cancer incidence worldwide. These remain a major global health concern, with a high prevalence in the United States. This study aims to compare trends and geodemographic disparities in mortality from HCC and ICC in the U.S. from 1999 to 2024. Methods: We conducted a comparative analysis of mortality between HCC and ICC using CDC WONDER Multiple Cause of Death data and ICD-10 codes for HCC (C22.0) and ICC (C22.1). Age Adjusted Mortality Rates (AAMRs) per 1million of adults aged ≥ 45years were calculated and stratified by gender, ethnicity, age, and demographic variables. Join point regression was employed to assess the Average Annual Percentage Change (AAPC) with 95% Confidence Interval (CI). * Indicates p < 0.05. Results: From 1999 to 2024, a total of 258,738 deaths were recorded due to HCC, and 149,258 deaths were attributed to ICC. Despite more deaths due to HCC, mortality due to ICC increased more rapidly (AAPC: 3.57*) than HCC (AAPC: 2.07*) over the past two decades. The persistent increase was observed in the females for both ICC (AAPC: 3.70*) and HCC (AAPC: 2.01*) as compared to the males with (AAPC: 3.37*) and (AAPC: 1.89*) respectively. Among age groups, adults aged 45-64 years are more affected by ICC (AAPC: 4.01*) as compared to HCC (AAPC: 0.41*). But individuals of age ≥ 65years are aggressively affected by both, ICC (AAPC: 3.41*) and HCC (AAPC: 2.95*). Across racial groups, ICC caused a more pronounced increase in Non-Hispanic (NH) Blacks (AAPC: 4.22*) and NH Whites (AAPC: 3.62*) as compared to other groups. Similarly, HCC also affected the NH Blacks (AAPC: 1.42*) and NH Whites (AAPC: 2.51*) but a significant decrease in NH Asians (AAPC: -2.22*) was observed. Regionally, ICC caused a significant and steady increase in mortality across all census regions with AAPC ranging from 3.28* to 3.83* but HCC greatly affected the south region (AAPC: 2.63*), and the northeast (AAPC: 1.28*) was least affected. Mortality due to ICC was higher in metropolitan areas (AAPC: 3.51*) while HCC affected non-metropolitan areas (AAPC: 4.03*). Conclusions: Our findings revealed distinct differences in mortality due to HCC and ICC in the United States. Overall, ICC demonstrated a steady increase in mortality as compared to HCC. Adults aged 45-64years are more susceptible to ICC while adults aged 65+ are more vulnerable to HCC. Urban areas have a high incidence of ICC, and rural areas are more affected by HCC. These findings highlight the need for effective screening measures aligned with AASLD guidelines, targeted prevention strategies, and public health initiatives to address persistent and widening disparities among the high-risk populations.
Clinical characteristics and survival outcomes of early-onset renal cell carcinoma by metastatic status: A National Cancer Database study.
e16510 Background: Early-onset RCC may reflect distinct biology and hereditary predisposition, yet data on stage-specific clinical features and outcomes remain limited. We comprehensively evaluated age-stratified, stage-specific clinical features and survival outcomes using the National Cancer Database. Methods: Adults with histologically confirmed RCC diagnosed between 2004 and 2022 were analyzed. Patients were categorized into three groups by age at diagnosis: early-onset ( < 40 years), middle-aged (40–50 years), and late-onset ( > = 50 years). The sociodemographic and clinical characteristics, comorbidities, histology, and treatment patterns were compared using descriptive statistics. Overall survival (OS) was evaluated using Cox proportional hazards models, adjusting for the aforementioned variables. Stage-specific analyses were conducted, including a metastatic disease cohort. Results: Among 742,114 patients, 4.3% were classified as early-onset, 10.9% as middle-aged, and 84.8% as late-onset. Overall, 12.6% presented with metastatic disease. Compared with late-onset, early-onset patients were more likely to be from racial minority populations (non-White: 16.9 % vs. 20.2 % in late-onset), uninsured, and had fewer comorbidities (Charlson–Deyo score 0: 85.2% vs. 65.2%). Early-onset RCC was characterized by a lower proportion of papillary RCC (8.9% vs. 12.5%) and higher proportions of clear cell (54.9% vs. 50.8%) and chromophobe RCC (9.3% vs. 4.5%) than late-onset RCC and more likely to undergo partial nephrectomy (50.4% vs. 30.2%). They also presented with earlier-stage disease, with lower rates of stage III (7.4% vs. 10.2% vs. 13.4%) and stage IV disease (5.4% vs. 8.9% vs. 13.5%) compared with middle-aged and late-onset groups. Among patients with metastatic disease, early-onset RCC demonstrated higher minority representation (30.8% vs. 14.1%) and a higher prevalence of non-clear cell histology (70.6% vs. 58.1%). In multivariable analysis, compared with early-onset RCC, middle-aged (HR 1.44, 95% CI 1.39–1.50; P < 0.001) and late-onset patients (HR 2.83, 95% CI 2.74–2.93; P < 0.001) experienced significantly worse OS. However, among metastatic disease, this survival advantage was attenuated. Early-onset patients had similar OS to middle-aged patients (HR 0.99, 95% CI 0.93–1.05, p = 0.69) and late-onset patients only had a modestly worse OS than the early-onset group (HR 1.09, 95% CI 1.03–1.15 p = 0.003). Conclusions: Early-onset RCC was associated with more favorable baseline characteristics, earlier stage at diagnosis, and higher utilization of nephron-sparing nephrectomy, corresponding to improved OS. However, this survival advantage diminishes in metastatic disease despite better baseline health, highlighting stage-dependent differences in outcomes and suggesting distinct histologic patterns in advanced early-onset RCC.
Early discontinuation of <sup>177</sup> Lu-PSMA-617 after ≤ 3 doses in prostate cancer: A single-center retrospective cohort study.
e17074 Background: 177 Lu-PSMA-617 is an FDA-approved radioligand therapy for prostate cancer. In clinical practice, some patients discontinue therapy early. We characterized treatment delivery and reasons for early discontinuation among patients receiving ≤3 doses of 177 Lu-PSMA-617 at a tertiary academic center. Methods: We performed a single-center retrospective cohort study at Indiana University of prostate cancer patients treated with 177 Lu-PSMA-617 from March 23, 2022 to December 17, 2025 who received ≤3 doses. Reasons for early treatment discontinuation were abstracted from the medical record. Descriptive statistics were used. Results: A total of 103 of 276 patients (37.3%) discontinued 177 Lu-PSMA-617 after ≤3 doses (1: 23.3%, 2: 34.0%, 3: 42.7%). Median age at 177 Lu-PSMA-617 initiation was 74 years (range, 50-92). Median follow-up from 177 Lu-PSMA-617 start to last contact was 3 months (range, 0-22). The median interval between doses was 42 days (range, 39-133). Dose delays were uncommon (n = 8, 7.8%) and were primarily related to intercurrent medical events, including acute kidney injury, infections (osteomyelitis, COVID-19, urinary tract infection), procedural needs (ureteral stent exchange, gangrenous cholecystectomy), symptomatic back pain, or anemia. Dose reductions were rare (n = 2, 1.9%) and occurred in the setting of pancytopenia and extensive bone metastases. The most common reason for early discontinuation were progression in 80 patients (77.7%). Grade ≥3 cytopenia contributed to discontinuation in 18 patients (17.5%), including cytopenia alone in 14 (13.6%) and cytopenia + progression in 4 (3.9%). Among those with grade ≥3 cytopenia (n = 18), thrombocytopenia was most frequent (83.3%), followed by anemia (61.1%) and leukopenia (16.7%). Among these 18 patients, 14 (77.8%) had extensive bone metastases prior to treatment (≥10 bone lesions). Baseline hematologic abnormalities were common, including anemia in 13 (72.2%) patients, thrombocytopenia in 3 (16.7%), and leukopenia in 1 (5.6%). One patient had significant comorbidities contributing to treatment intolerance, including renal failure, heart failure, neuroendocrine carcinoma, and stage 3 chronic kidney disease. At most recent follow-up 90.3% of patients were dead of prostate cancer, 1.0% were dead of other causes (sepsis), and 8.7% were alive with disease. Conclusions: In a real-world single-center cohort, most early discontinuations of 177Lu-PSMA-617 after ≤3 doses were due to disease progression, while grade ≥3 cytopenias accounted for nearly one-fifth of discontinuations and were predominantly thrombocytopenia, frequently occurring in patients with extensive bone metastases and baseline cytopenias. Earlier identification of patients at high risk for progression or marrow toxicity may help optimize patient selection, supportive care, and treatment completion.
Molecular characterization of ABL kinase domain mutations associated with imatinib resistance in chronic myeloid leukemia patients, including a novel pathogenic D276V variant.
e18598 Background: Imatinib resistance in chronic myeloid leukemia (CML) is frequently driven by BCR-ABL–dependent mechanisms, particularly mutations in the ABL tyrosine kinase domain that can disrupt imatinib binding, creating a need for early mutation screening to guide treatment adaptation. Methods: We conducted molecular monitoring by qRT-PCR in 90 CML patients and performed Sanger sequencing of the ABL kinase domain in patients who did not achieve molecular remission. Results: Out of 90 patients, 22 lacked molecular remission; among these, 7 patients harbored resistance-associated mutations in the BCR-ABL transcript. The detected mutations included T315I (57%), E255V (29%), and a case with G250E plus an additional D276V variant. Bioinformatics analyses supported D276V as a novel pathogenic mutation. (The patient with G250E+D276V subsequently died). Conclusions: In this cohort, ABL kinase domain mutations were identified in a subset of patients with absent molecular remission on imatinib, supporting the clinical value of early mutational profiling to inform therapeutic adjustment.
Individualized recurrence risk prediction as a challenge to conventional eligibility criteria in phase III adjuvant immunotherapy trials for renal cell carcinoma.
e16501 Background: Adjuvant immunotherapy is recommended for high-risk patients with renal cell carcinoma (RCC) following surgery. However, inconsistent efficacy across phase III trials suggests that current clinicopathologic eligibility criteria may inadequately reflect the true risk of recurrence. We explored whether machine learning-based individualized risk prediction better discriminates outcomes than trial-defined eligibility in real-world patients with clear-cell RCC. Methods: Using the French national kidney cancer registry (UroCCR), we identified 2’403 patients with clear-cell RCC who underwent curative-intent surgery for non-metastatic disease or resected metastatic disease (M1 NED) prior to the approval of adjuvant pembrolizumab. Eligibility criteria from three phase III trials (KEYNOTE-564, IMmotion010, and CheckMate 914) were replicated to generate real-world trial cohorts. Individual recurrence risk was estimated with UroPredict 2, a machine-learning model derived from UroCCR data. Patients were stratified by predicted risk regardless of trial eligibility. Actual disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier analyses and compared across risk strata with trial eligiblity criteria. Results: Marked variability in predicted recurrence risk was observed within both eligible and ineligible populations across all trial emulations. A substantial subset of patients meeting trial criteria were categorized as low risk (approximately 10% of eligible patients according to each trial eligibility criteria) and showed favorable DFS after surgery alone (actual DFS probabilities at 5 years above 81% for all criteria), consistent with limited expected benefit from adjuvant therapy. In contrast, more than 30% of patients excluded by each trial criteria were reclassified as intermediate or high risk by the predictor, and experienced poor oncologic outcomes (actual 5-year DFS probabilities of 57%–62%, depending on the trial eligibility criteria). Predicted risk groups consistently demonstrated clear separation of DFS and OS curves in each emulated trial cohort. Conclusions: Conventional eligibility criteria in phase III adjuvant immunotherapy trials incompletely identify patients at highest risk of recurrence after nephrectomy for RCC. Machine-learning-based individualized risk prediction may offer a more refined framework for selecting patients for adjuvant immunotherapy and for aligning treatment intensity with personalized recurrence risk.
Can transcriptome-based risk modeling improve survival stratification across cytogenetic groups in acute myeloid leukemia?
6533 Background: Cytogenetic risk stratification is central to prognostication in acute myeloid leukemia (AML), yet survival outcomes vary considerably within each group. We hypothesized that transcriptomic features could further stratify survival within these cytogenetic categories, independent of clinical factors. Methods: We analyzed gene expression microarray data for 172 AML patients from the TCGA-LAML cohort (dbGaP phs000178). Multivariable Cox proportional hazards modeling incorporating age, gender, and CALGB cytogenetic risk was used to identify genes independently associated with overall survival. LASSO regression was applied to derive a transcriptomic gene signature and compute a patient-level transcriptomic risk score. Kaplan–Meier survival analysis, log-rank testing, and Cox modelling were performed in the overall cohort and within each cytogenetic subgroup. Model performance was assessed using concordance index (C-index) and likelihood ratio testing. Differential expression and Gene Ontology Biological Process (GOBP) enrichment were performed between high and low transcriptomic risk groups. Results: The transcriptomic risk score significantly stratified overall survival and, importantly, retained prognostic significance within favorable, intermediate, and poor cytogenetic risk groups (Table). The concordance index improved from 0.69 with clinical variables (age, gender, cytogenetics) alone to 0.82 after adding the transcriptomic risk score. Likelihood ratio testing confirmed a highly significant improvement in model fit with the inclusion of the transcriptomic score (χ² = 98.7, p < 2.2×10⁻¹⁶). GOBP enrichment of DEGs between high and low transcriptomic risk groups revealed upregulation of CD4-positive T-cell activation (STAT6, IL12RB1, ZBTB7B), negative regulation of immune response (LGALS9, PTPN6, FGL2), regulation of leukocyte and lymphocyte differentiation (ZC3H12A, VNN1, HCLS1), and response to bacterial molecules and lipopolysaccharide (NLRP3, MYD88, CASP1) confirming dysregulated immune signaling as a hallmark of adverse prognosis. Conclusions: A transcriptomic risk score provides powerful, independent prognostic information beyond cytogenetics and clinical factors in AML. These findings support the integration of transcriptomic biomarkers into existing risk models to refine AML prognostication. Survival association of transcriptomic risk score across CALGB groups in AML patients. CALGB Group HR* (95% CI) p value** All AML patients (N =172) 3.74 (2.48–5.63) 2.81×10⁻¹⁰ Favourable (N= 34) 14.53 (1.87–112.83) 1.05×10⁻² Intermediate (N = 97) 6.49 (3.43–12.26) 8.43×10⁻⁹ Poor (N = 38) 2.68 (1.26–5.69) 1.01×10⁻² *HR: High vs Low genomic risk. **Cox p from multivariable Cox model.
Efficacy of immune therapy–based regimens in sarcomatoid lung cancer: A systematic review and meta-analysis.
e20769 Background: Sarcomatoid lung cancer/Pulmonary Sarcomatoid Carcinoma (PSC) is a rare, poorly differentiated, chemoresistant, highly aggressive variant of non-small-cell lung cancer (NSCLC) with poor outcomes with conventional cytotoxic therapy. Immune checkpoint inhibitors (ICIs) that restore antitumor T-cell activity are effective in PSC due to high PD-L1 expression, mutational burden, immune infiltration, and distinct genomic landscape involving TP53, KRAS, MET exon 14 skipping, and chromatin remodeling, differentiating them from classic oncogene (EGFR/ALK)-driven Non Small-Cell Lung Cancer, which often exhibits immune exclusion and ICI Resistance. Retrospective cohorts have shown that immunotherapy-based approaches yield higher OS and PFS than chemotherapy, with emerging evidence in the neoadjuvant and adjuvant settings. Methods: This Systematic Review and meta-analysis evaluated immunotherapy-based systemic treatments and non-immunotherapy regimens in adults with PSC across all (I-IV) disease stages, including recurrent/metastatic cases, and was conducted per PRISMA guidelines, using PubMed, Embase, and the Cochrane Library till October 2025. Studies that were single-arm studies, non-human, non-English, non-dedicated or lacked full-text availability were excluded. Immunotherapy interventions, ICI monotherapy/dual-therapy, or ICI-chemotherapy combinations, were compared with other non-ICI regimens. Primary outcomes included overall survival (OS) and objective response rate (ORR). Secondary outcomes included progression-free survival (PFS). Disease control rate (DCR) and treatment-related adverse events couldn’t be analyzed due to incomplete reporting across studies. A random effects model was used, with outcomes reported as odds ratios (ORs) or hazard ratios (HRs), with 95% CIs, statistical significance set at p < 0.05, and heterogeneity assessed using the I 2 statistic, with I 2 < 75% considered highly heterogeneous. Results: Five Retrospective two arm studies met the inclusion criteria. ICI-based regimens had higher OS/Overall Survival reported in 5 studies (HR 0.46, 95% CI 0.32-0.64; p = 0.003, I² = 11.5%), PFS/Progression Free Survival reported in 3 studies (HR 0.44, 95% CI 0.20-1.00; p = 0.049, I² = 26.3%). Objective response rate (ORR), evaluated in two small studies, numerically favored immunotherapy but did not reach statistical significance (OR 4.87, 95% CI 0.001-37,218; p = 0.27) and was limited by wide confidence intervals and small sample size. Conclusions: This Meta-analysis showed significant survival benefits with Immunotherapy-based regimens compared with conventional chemotherapy in PSC. RCT’s are precluded due to the rarity of sarcomatoid lung cancer, and the benefit consistency across various disease stages and treatment lines remains uncertain, warranting more systematic evidence/research in this area.
Real-world use of regorafenib for refractory metastatic colorectal cancer: Survival outcomes and associated clinical features.
e15627 Background: Treatment options for refractory metastatic colorectal cancer (mCRC) remain limited. Regorafenib is commonly used in the late-line setting; however, outcomes vary substantially among patients in real-world practice. Rather than focusing on the causal efficacy of regorafenib, understanding the clinical contexts in which regorafenib-based strategies are associated with more favorable outcomes may provide practical guidance for patient selection and treatment planning. Methods: This retrospective observational study included patients with refractory mCRC treated with regorafenib at a single tertiary center between November 2015 and October 2024. All patients had received standard prior therapies, including fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF agents, and anti-EGFR agents when indicated. Progression-free survival (PFS) and overall survival (OS) were analyzed according to clinical and treatment-related factors, including prior treatment duration, metastatic pattern, feasibility of local treatment, and treatment strategies administered during regorafenib therapy. Results: A total of 123 patients were analyzed. The median OS was 8.4 months (IQR: 4.1–14.6), and the median PFS was 2.6 months (IQR: 1.7–5.8). Considerable heterogeneity in outcomes was observed. Patients with a prior stage IV treatment duration exceeding 18 months demonstrated significantly longer PFS and OS compared with those with shorter treatment histories. Similarly, patients who underwent local treatment, such as metastasectomy, radiotherapy, or ablation, during the course of regorafenib therapy exhibited more favorable survival outcomes. The presence of lung metastasis was also associated with prolonged PFS and OS compared with other metastatic patterns. These factors were consistently associated with improved outcomes within the regorafenib-treated cohort, whereas molecular characteristics such as KRAS status showed no clear association with survival. Conclusions: In this real-world cohort of refractory mCRC patients treated with regorafenib, survival outcomes varied widely and were strongly associated with clinical characteristics reflecting disease biology and treatment feasibility. Prolonged prior treatment duration, the presence of lung metastasis, and the ability to integrate local treatment were associated with more favorable PFS and OS. These findings suggest that regorafenib-based strategies are most commonly associated with better outcomes in patients with indolent disease phenotypes and preserved opportunities for multidisciplinary management, rather than indicating a uniform treatment effect across all patients.
Anti–PD-1 (PD-1) monotherapy versus combination with anti–CTLA-4 for metastatic uveal melanoma (MUM) patients (pts).
9535 Background: MUM carries a poor prognosis with few effective treatments, especially for HLA-A*02:01-negative pts. While a subset of MUM pts responds to immune checkpoint inhibitors, the comparative efficacy of IPI+PD1 versus PD1 monotherapy is unclear. This study compares objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety between these regimens in MUM. Methods: MUM pts treated with PD1 or IPI+PD1 at 15 major melanoma centres (from Australia, Europe, United States and Israel) were included. Demographics, patient and disease characteristics, and clinical outcomes were examined. Univariate and multivariate (MVA) analyses were performed to identify clinical predictors of response and survival. Results: Of 412 MUM pts treated, 150 (36%) had PD1 and 262 (64%) received PD1+IPI. Compared to the PD1 group, PD1+IPI-treated pts were younger (64 vs. 70 years; p<0.001), had higher rate of elevated LDH (44% vs. 31%; p=0.037), and more frequently had prior treatment with tebentafusp (6.5% vs. 1.3%; p=0.031). Median follow-up from commencement of PD1+/-IPI was 4.9 years (95% CI 4.7 – 6.1). ORR was higher in IPI+PD1 group (18%) vs. PD1 (9%) (p=0.008), particularly in males (p=0.009), patients with liver metastases (p=0.018) and with lung metastases (p=0.011), with elevated LDH (p=0.047) and with no prior treatment with tebentafusp (p=0.007). PFS and OS at 1 and 2 years were numerically higher with IPI+PD1 (1- and 2-year PFS: 23% and 15%; 1- and 2-year OS: 63% and 39%) vs. PD1 (1- and 2-year PFS: 17% and 11%; 1- and 2-year OS: 54% and 36%), but these differences were not statistically significant (p>0.05). On MVA, adjusting for predefined variables (age, gender, ECOG PS, LDH, presence/absence of liver/lung metastases, prior treatment with tebentafusp), IPI+PD1 was associated with higher ORR (OR 2.71, 1.30 – 6.05; p=0.01) but not with PFS or OS compared to PD1. Presence of liver metastases (ORR [OR 0.28; 95% CI 0.13 - 0.64], PFS [HR 1.61; 95% CI 1.11 - 2.34], OS [HR 2.02; 95% CI 1.32 - 3.10]), ECOG PS≥2 (PFS [HR 1.82; 95% CI 1.07 - 3.10], OS [HR 2.24; 95% CI 1.25-4.01]), elevated LDH (PFS [HR 1.66; 95% CI 1.30 - 2.11], OS [HR 2.39; 95% CI 1.84-3.10]) and prior tebentafusp treatment (OS [HR 2.36; 95% CI 1.21-4.59]) were also independent predictors of response and/or survival. A higher percentage of pts experienced grade ≥3 immune-related adverse events (irAEs) in the IPI+PD1 group compared to the PD1 group (34% vs 13%, p<0.0001). Most pts ceased treatment due to progression (234, 57%), and more pts stopped due to toxicity in the IPI+PD1 vs. PD1 group (25% vs. 9%, p<0.0001). Conclusions: In pts with MUM, IPI+PD1 demonstrated a higher ORR but did not improve survival compared with PD1 alone. IPI+PD1 was more toxic, leading to early treatment discontinuation in one-quarter of pts. These findings may help guide treatment selection in MUM.
Baseline spatial tumor microenvironment states to define response and primary resistance to immune checkpoint inhibition in recurrent/metastatic head and neck squamous cell carcinoma.
6068 Background: Despite the clinical impact of immune checkpoint inhibitors (ICIs) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), durable benefit is limited to a minority of patients and robust predictive biomarkers are lacking. PD-L1 combined positive score incompletely captures response heterogeneity, likely due to the spatial complexity of the tumor microenvironment (TME). We used spatial transcriptomics to identify baseline TME architectures associated with ICI response. Methods: Pre-treatment primary tumor samples from 12 patients with R/M HNSCC treated with ICIs were profiled using high-resolution spatial transcriptomics (Xenium In Situ, 10x Genomics; 380-gene immuno-oncology panel). Exceptional responders (ER) were defined by progression-free survival (PFS) ≥20 months, while poor responders (PR) had PFS ≤3 months. Differential gene expression and Gene Ontology (GO) enrichment were integrated with cell-type–resolved analyses to map transcriptional programs to cellular compartments. Results: Distinct baseline TME architectures separated ER and PR. ER tumors showed coordinated upregulation of interferon-related and immune activation genes (STAT1, MX1, CD274) together with cell-cycle-associated genes (MKI67, CDK1). Functional enrichment highlighted immune signaling, chemokine-mediated recruitment, and vascular remodeling, consistent with an immune-inflamed and spatially permissive microenvironment. In contrast, PR tumors exhibited dominant fibroblast-driven extracellular matrix and inflammatory programs, with enrichment of FN1, SPARC, LUM, VCAN and IGFBP7. GO enrichment in PR highlighted integrin-mediated processes, PDGFR-centered signaling, TGF-β–related pathways, and platelet-related signaling programs. Cell-type–resolved spatial mapping showed that fibroblast/ECM programs in PR were predominantly localized to fibroblast-enriched stromal compartments, whereas interferon-response programs in ER were distributed across both tumor and immune compartments. Conclusions: Baseline spatially organized TME states are associated with ICI outcomes in R/M HNSCC. ER exhibit an interferon-enriched, immune-permissive architecture, whereas primary resistance is linked to a fibroblast-dominated, ECM-rich and immune-restrictive niche. Proteomic validation of key spatial signals is ongoing to prioritize candidate predictive biomarkers for evaluation in a larger cohort. Enrichment of integrin-mediated processes and PDGFR-centered signaling in PR highlights actionable stromal vulnerabilities warranting translational investigation.
Evaluation of the antitumor effect of 2-(1,1-Dimethyl-1h-benzo[E]indol-2-Yl)-5,6,7-trichloro-1,3-tropolone in in vivo models in monotherapy mode.
e14058 Background: This study evaluated the in vivo efficacy and safety of JO-122(2) (2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-5,6,7-trichloro-1,3-tropolone), a newly synthesized compound, in a subcutaneous U87MG glioblastoma xenograft model. Methods: The novel compound JO-122(2) was administered intragastrically as a starch gel/DMSO suspension (0.2 mL, 3x/week for 25 days) to BALB/c nude mice bearing U87MG glioblastoma xenografts. The study was conducted in two stages. In the first stage, 24 animals (four males and four females per group) were divided into four groups: JO-122(2) at doses of 10, 20, or 30 mg/kg (administered intragastrically three times per week) and a control group (1% starch gel with DMSO). Since there was no significant effect, the second stage investigated doses of 40, 50, and 60 mg/kg (groups 5–7), as well as a control group (group 8), for a total of 32 animals. Tumor growth dynamics were assessed every three days, starting from the first administration of the compounds. The analysis included tumor growth inhibition (TGI), body weight, and organ-to-body weight ratios (liver, kidneys, spleen, heart, and lungs). Hematological and biochemical blood parameters were also analyzed. Statistical analysis accounted for sex; when no differences were observed, the data were pooled. Results: At doses of 10–30 mg/kg, no differences in tumor growth were detected compared to the control group. On day 25, the tumor volumes were 1,437.86 ± 121.03 mm³ (10 mg/kg), 1,256.02 ± 201.64 mm³ (20 mg/kg), and 1,291.35 ± 252.15 mm³ (30 mg/kg), versus 1,430.87 ± 284.21 mm³ in the control group. In the second stage, at doses of 40–60 mg/kg, pronounced dose-dependent antitumor activity was observed. On day 25, the tumor volume in the 60 mg/kg group was 784.47 ± 142.62 mm³ (1.65 times smaller than the control group's volume of 1,297.41 ± 153.53 mm³; p < 0.0083), with TGI reaching 39.54%. The relative tumor weight decreased to 6.02% ± 1.23% (control: 12.94% ± 2.71%; p < 0.0083). At a dose of 50 mg/kg, the tumor volume was 853.68 ± 107.46 mm³ (TGI: 34.20%), and at 40 mg/kg, the tumor volume was 1,098.5 ± 229.43 mm³. Toxicity was assessed based on body weight stability (initial/final: 20.50–27.50 g/21.50–31.50 g), organ-to-body weight ratios, and laboratory parameters. Hematological analysis revealed no differences in 12 parameters. Biochemical indicators also did not exceed control values. Conclusions: JO-122(2) demonstrates significant in vivo antitumor activity only at doses ≥50 mg/kg, inhibiting glioblastoma growth by 34.2–39.5% (TGI). The low efficacy at doses of 10–30 mg/kg is likely due to the limited bioavailability of the compound. The obtained data justify the potential of JO-122(2) for further studies, including investigation of its mechanisms of action (presumably, inhibition of proliferative signaling pathways) and optimization of the dosing regimen.
Unmet rehabilitation needs in cancer survivors: A population-level analysis.
1584 Background: Decades of evidence demonstrate that patients across the cancer continuum may benefit from validated rehabilitation services, yet delivery remains inconsistent. Prior reports of underuse have largely relied on small, single-site cohorts and have lacked population-level estimates of service need, referral, and visit completion, contributing to the assumption that provider reluctance to refer is a primary driver. Using post hoc exploratory analyses of population-level trial data, we evaluated patient- and system-level factors associated with non-use of rehabilitation services. Methods: This secondary analysis used data from the Enhanced Electronic Health Record–Facilitated Cancer Symptom Control (E2C2) pragmatic trial, an unblinded, stepped-wedge, cluster-randomized cohort study comparing an EHR-embedded symptom surveillance and management system with usual care. All patients receiving care in Mayo Clinic Midwest medical oncology practices were enrolled regardless of cancer stage or phase. Symptoms and physical function were assessed using 11-point numerical rating scales linked to oncology encounters. Sociodemographic and clinical characteristics and all outpatient rehabilitation encounters across the Mayo Clinic Enterprise were extracted from the EHR. Rates and types of completed, canceled, and no-show rehabilitation encounters were examined. Results: Between March 28, 2019, and January 31, 2023, 50,207 patients were enrolled; 34% reported moderate or severe physical function impairment during follow-up. Despite this, only 8,818 patients (17.6%) completed at least one rehabilitation encounter. Of 91,220 encounters scheduled, 57,669 (63.3%) were completed (mean 6.5; median 3 per participant), leaving a substantial proportion canceled or no-showed (n=33,523, 36.7%). Completed encounters were predominantly physical therapy (68.3%), with fewer occupational therapy (16.4%), physician (9.4%), and speech therapy (4.2%) visits. Encounters were concentrated among patients with breast, hematologic, gastrointestinal, and genitourinary cancers. Completion was more likely among patients who were older, female, partnered, retired, and federally insured, whereas cancellations and no-shows were more common among younger, racial or ethnic minority, urban, unpartnered, employed, college-educated, and commercially insured patients (all P <0.001). Virtual visits and encounters in community (vs academic) settings were more likely to be completed (all P <0.001). Conclusions: A substantial gap persists between cancer survivors’ rehabilitation needs and service receipt, varying by cancer type and sociodemographic factors. High cancellation and no-show rates suggest that underuse extends beyond referral and underscore the need for redesigned, more accessible rehabilitation delivery models.
Bisphenol BPAF and BPC are agonists for estrogen receptor ERα but antagonists for N-terminal domain-lacking ERα
In the DNA complex of coactivator-bound estrogen receptor alpha (ERα), the N-terminal domain (NTD) and C-terminal ligand-binding domain (LBD) interact specifically. ERα-NTD and LBD constitute activation function 1 (AF-1) and activation function 2 (AF-2), respectively. We recently revealed that, despite the complete inactivity of ERα-NTD(AF-1), desNTD(AF-1)-ERα exhibited approximately 65% of the activity of the natural estrogen 17β-estradiol (E2) for wild-type full-length ERα. It remains unclear how a deficiency of NTD(AF-1) influences the activity of desNTD(AF-1)-ERα especially with respect to other estrogens and xenoestrogens. The major objective of this study is to evaluate the ligand specificity of desNTD(AF-1)-ERα for a series of xenoestrogens, including bisphenol A (BPA), BPAF, and BPC, together with E2, and the antagonists 4-hydroxytamoxifen (4-OHT) and ICI 182,780 (ICI). The receptors were transiently expressed in HeLa cells, and receptor activation activity was evaluated by luciferase reporter gene assay. Antagonist activity was examined for ERα and desNTD(AF-1)-ERα using E2 as a reference agonist. E2 exhibited full agonist activity for both ERα and desNTD(AF-1)-ERα, whereas 4-OHT and ICI were completely inactive and exhibited antagonist activity for E2 in both ERα and desNTD(AF-1)-ERα. All bisphenols were active for full-length ERα. Surprisingly, however, BPAF and BPC were almost completely inactive for desNTD(AF-1)-ERα, whereas BPA was fully active. BPAF and BPC exhibited distinct antagonist activity for E2 in desNTD(AF-1)-ERα, with pA 2 values of 7.62 and 7.86, respectively. The present results revealed that the presence of the N-terminal NTD(AF-1) domain substantiates the agonist activity of halogen-containing BPAF and BPC in wild-type full-length ERα. ERα-NTD(AF-1) plays an essential role in determining the agonist/antagonist activity of BPAF and BPC for estrogen receptor ERα.